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43 results on '"Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID"'

1. Can Omics Biology Go Subjective because of Artificial Intelligence? A Comment on 'Challenges and Opportunities for Bayesian Statistics in Proteomics' by Crook et al

Author: Thomas Burger, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID
Subjects: Proteomics, Proteome, Artificial Intelligence, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Computational Biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Bayes Theorem, General Chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biochemistry, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: In their recent review (
Published: 2022
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2. The histone methyltransferase DOT1L regulates chromatin reorganization and gene expression during the postmeiotic differentiation of male germ cells

Author: Blanco, Mélina, Khattabi, Laila El, Gobé, Clara, Crespo, Marion, Coulée, Manon, de la Iglesia, Alberto, Ialy-Radio, Côme, Lapoujade, Clementine, Givelet, Maëlle, Delessard, Marion, Seller-Corona, Ivan, Yamaguchi, Kosuke, Vernet, Nadège, van Leeuwen, Fred, Lermine, Alban, Okada, Yuki, Daveau, Romain, Oliva, Rafael, Fouchet, Pierre, Ziyyat, Ahmed, Pflieger, Delphine, Cocquet, Julie, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, The University of Tokyo (UTokyo), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], ANR-17-CE12-0004,CHROMATOZOA,(Dé)régulation génique et chromatinienne pendant la spermiogénèse: acteurs & conséquences sur la descendance(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), PFLIEGER, Delphine, (Dé)régulation génique et chromatinienne pendant la spermiogénèse: acteurs & conséquences sur la descendance - - CHROMATOZOA2017 - ANR-17-CE12-0004 - AAPG2017 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID
Subjects: histone-to-protamine replacement, chromatin compaction, flagellum development, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DOT1L, H3K79 methylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], gene regulation, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], spermatogenesis, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis
Abstract: International audience; Spermatozoa have a unique genome organization: their chromatin is almost completely devoid of histones and is formed instead of protamines which confer a higher level of compaction than nucleosomes and preserve paternal genome integrity until fertilization. Histone-to-protamine transition takes place in postmeiotic male germ cells called spermatids, and is indispensable for the production of functional spermatozoa and thus for male fertility. Here we show that the H3K79 (histone 3 lysine 79) methyltransferase DOT1L controls spermatid chromatin remodelling and subsequent reorganization and compaction of spermatozoon genome. Using a mouse model in which Dot1l is knocked-out in adult male germ cells, we found that the chromatin of Dot1l -knockout (KO) spermatozoa is less compact and characterized by a higher level of retained histones and of immature forms of protamine 2. Proteomic analyses performed on differentiating male germ cells reveal that Dot1l KO extensively modifies the spermatid chromatin prior to histone removal. By transcriptomics, we also show that Dot1l KO deregulates the expression of ~1500 genes, many of which are involved in other essential aspects of spermatid differentiation such as flagellum formation. As a consequence of all these chromatin and gene expression defects, Dot1l -KO spermatozoa have misshapen and less compact heads, and are less motile, which results in impaired fertility.
Published: 2023
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3. Challenging Targets or Describing Mismatches? A Comment on Common Decoy Distribution by Madej et al

Author: Thomas Burger, Lucas Etourneau, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: Genomics (q-bio.GN), Proteomics, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], General Chemistry, Quantitative Biology - Quantitative Methods, Biochemistry, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Tandem Mass Spectrometry, FOS: Biological sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quantitative Biology - Genomics, Databases, Protein, Peptides, Quantitative Methods (q-bio.QM), Algorithms
Abstract: International audience; In their recent article, Madej et al. 1 proposed an original way to solve the recurrent issue of controlling for the false discovery rate (FDR) in peptide-spectrum-match (PSM) validation. Briefly, they proposed to derive a single precise distribution of decoy matches termed the Common Decoy Distribution (CDD) and to use it to control for FDR during a target-only search. Conceptually, this approach is appealing as it takes the best of two worlds, i.e., decoy-based approaches (which leverage a large-scale collection of empirical mismatches) and decoy-free approaches (which are not subject to the randomness of decoy generation while sparing an additional database search). Interestingly, CDD also corresponds to a middle-of-the-road approach in statistics with respect to the two main families of FDR control procedures: Although historically based on estimating the falsepositive distribution, FDR control has recently been demonstrated to be possible thanks to competition between the original variables (in proteomics, target sequences) and their fictional counterparts (in proteomics, decoys). Discriminating between these two theoretical trends is of prime importance for computational proteomics. In addition to highlighting why proteomics was a source of inspiration for theoretical biostatistics, it provides practical insights into the improvements that can be made to FDR control methods used in proteomics, including CDD.
Published: 2022

4. Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase

Author: Christopher Swale, Valeria Bellini, Matthew W. Bowler, Nardella Flore, Marie-Pierre Brenier-Pinchart, Dominique Cannella, Lucid Belmudes, Caroline Mas, Yohann Couté, Fabrice Laurent, Artur Scherf, Alexandre Bougdour, Mohamed-Ali Hakimi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), European Molecular Biology Laboratory [Grenoble] (EMBL), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Integrated Structural Biology Grenoble (ISBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation pour la Recherche Medicale (EQU202103012571), Roux-Cantarini Fellowship, ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-18-CE15-0023,HostQuest,Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée(2018), ANR-21-CE35-0010,ApiNewDrug,Identification de nouvelles cibles thérapeutiques parmi des médicaments repositionnables pour traiter des maladies dues à des parasitaire apicomplexes(2021), ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), European Project: 614880,Hosting Toxo, Laurent, Fabrice, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée - - HostQuest2018 - ANR-18-CE15-0023 - AAPG2018 - VALID, Identification de nouvelles cibles thérapeutiques parmi des médicaments repositionnables pour traiter des maladies dues à des parasitaire apicomplexes - - ApiNewDrug2021 - ANR-21-CE35-0010 - AAPG2021 - VALID, Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme - - EpiKillMal2020 - ANR-20-CE18-0006 - AAPG2020 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, and ERC Consolidator grant - Hosting Toxo - 614880 - INCOMING
Subjects: [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine
Abstract: The Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include Toxoplasma gondii , Plasmodium , and Cryptosporidium spp., which infect humans and animals and cause severe parasitic diseases. Available therapeutics against these diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. We use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index when used against T. gondii . We have identified Tg PRP4K of T. gondii as the primary target of altiratinib using genetic target deconvolution, which highlighted key residues within the kinase catalytic site that conferred drug resistance when mutated. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K and for its Plasmodium falciparum counterpart, Pf CLK3. Our data identified structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
Published: 2022
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5. Proteomics Evidence of a Systemic Response to Desiccation in the Resurrection Plant Haberlea rhodopensis

Author: Petko Mladenov, Diana Zasheva, Sébastien Planchon, Céline C. Leclercq, Denis Falconet, Lucas Moyet, Sabine Brugière, Daniela Moyankova, Magdalena Tchorbadjieva, Myriam Ferro, Norbert Rolland, Jenny Renaut, Dimitar Djilianov, Xin Deng, Institute of Botany [Beijing] (IB-CAS), Chinese Academy of Sciences [Beijing] (CAS), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Agrobioinstitute, Agricultural Academy Bulgaria, Bulgarian Academy of Sciences (BAS), Luxembourg Institute of Science and Technology (LIST), LIPID, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Dynamique du protéome et biogenèse du chloroplaste (ChloroGenesis), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Medical University of Sofia [Bulgarie], The Fonds National de la Recherche, Luxembourg (Project SMARTWALL C15/SR/10240550), CAS PRESIDENT’S INTERNATIONAL FELLOWSHIP INITIATIVE GRANT (2021PB0101), National Key R&D program of China (2021YFE0102600), Bulgarian Science Fund (KP06-H-41-IP-Kitai), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), Martin-Laffon, Jacqueline, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID
Subjects: dehydrin, Organic Chemistry, drought stress, systems biology, General Medicine, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Catalysis, Computer Science Applications, subcellular fractionation, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, Inorganic Chemistry, resurrection plant, proteomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; Global warming and drought stress are expected to have a negative impact on agricultural productivity. Desiccation-tolerant species, which are able to tolerate the almost complete desiccation of their vegetative tissues, are appropriate models to study extreme drought tolerance and identify novel approaches to improve the resistance of crops to drought stress. In the present study, to better understand what makes resurrection plants extremely tolerant to drought, we performed transmission electron microscopy and integrative large-scale proteomics, including organellar and phosphorylation proteomics, and combined these investigations with previously published transcriptomic and metabolomics data from the resurrection plant Haberlea rhodopensis. The results revealed new evidence about organelle and cell preservation, posttranscriptional and posttranslational regulation, photosynthesis, primary metabolism, autophagy, and cell death in response to desiccation in H. rhodopensis. Different protective intrinsically disordered proteins, such as late embryogenesis abundant (LEA) proteins, thaumatin-like proteins (TLPs), and heat shock proteins (HSPs), were detected. We also found a constitutively abundant dehydrin in H. rhodopensis whose phosphorylation levels increased under stress in the chloroplast fraction. This integrative multi-omics analysis revealed a systemic response to desiccation in H. rhodopensis and certain targets for further genomic and evolutionary studies on DT mechanisms and genetic engineering towards the improvement of drought tolerance in crops.
Published: 2022
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6. Mixotrophic growth of the extremophile Galdieria sulphuraria reveals the flexibility of its carbon assimilation metabolism

Author: Andreas P.M. Weber, Phillip Westhoff, Marianne Tardif, Denis Falconet, Erika Guglielmino, Dagmar Lyska, Benoit Gallet, Giovanni Finazzi, Gilles Curien, Clément Hallopeau, Michele Carone, Davide Dal Bo, Claire Remacle, Johan Decelle, Sabine Brugière, Myriam Ferro, Janina Janetzko, Light Photosynthesis & Metabolism (Photosynthesis), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Cluster of Excellence on Plant Sciences (CEPLAS), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]-Max Planck Institute for Plant Breeding Research (MPIPZ)-Universität zu Köln = University of Cologne, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Photosymbiose, Institut de biologie structurale (IBS - UMR 5075), LIPID, Université de Liège, ARC grant (DARKMET proposal) for Concerted Research Actions (17/21-08), financed by the French Community of Belgium (Wallonia-Brussels Federation)., Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany´s Excellence Strategy – EXC-2048/1 – project ID 390686111, ANR-17-CE05-0029,MoMix,Modélisation de la Mixotrophie chez l'algue extrêmophile Galdieria sulphuraria(2017), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 833184, ChloroMito, Martin-Laffon, Jacqueline, Modélisation de la Mixotrophie chez l'algue extrêmophile Galdieria sulphuraria - - MoMix2017 - ANR-17-CE05-0029 - AAPG2017 - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Chloroplast and Mitochondria interactions for microalgal acclimation - ChloroMito - 833184 - INCOMING, Universität zu Köln-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]-Max Planck Institute for Plant Breeding Research (MPIPZ), and InBios/Phytosystems Research Unit, University of Liege
Subjects: Proteomics, 0106 biological sciences, 0301 basic medicine, photorespiration, Physiology, Heterotroph, Plant Science, Photosynthesis, 7. Clean energy, 01 natural sciences, Galdieria sulphuraria, Extremophiles, 03 medical and health sciences, mixotrophy, Total inorganic carbon, Botany, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, red algae, photosynthesis, biology, Chemistry, Research, RuBisCO, Heterotrophic Processes, Carbon Dioxide, Full Papers, 15. Life on land, Carbon, 030104 developmental biology, Rhodophyta, biology.protein, Photorespiration, Energy source, Mixotroph, 010606 plant biology & botany
Abstract: Summary Galdieria sulphuraria is a cosmopolitan microalga found in volcanic hot springs and calderas. It grows at low pH in photoautotrophic (use of light as a source of energy) or heterotrophic (respiration as a source of energy) conditions, using an unusually broad range of organic carbon sources. Previous data suggested that G. sulphuraria cannot grow mixotrophically (simultaneously exploiting light and organic carbon as energy sources), its photosynthetic machinery being repressed by organic carbon.Here, we show that G. sulphuraria SAG21.92 thrives in photoautotrophy, heterotrophy and mixotrophy. By comparing growth, biomass production, photosynthetic and respiratory performances in these three trophic modes, we show that addition of organic carbon to cultures (mixotrophy) relieves inorganic carbon limitation of photosynthesis thanks to increased CO2 supply through respiration. This synergistic effect is lost when inorganic carbon limitation is artificially overcome by saturating photosynthesis with added external CO2.Proteomic and metabolic profiling corroborates this conclusion suggesting that mixotrophy is an opportunistic mechanism to increase intracellular CO2 concentration under physiological conditions, boosting photosynthesis by enhancing the carboxylation activity of Ribulose‐1,5‐bisphosphate carboxylase‐oxygenase (Rubisco) and decreasing photorespiration.We discuss possible implications of these findings for the ecological success of Galdieria in extreme environments and for biotechnological applications.
Published: 2021
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7. Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Author: Céline Brochier-Armanet, Yohann Couté, Pierre Simon Garcia, Angélique Fraudeau, Jan Felix, Patricia Renesto, Caroline Mas, Jérôme Nigou, Irina Gutsche, Karine Huard, Claire Siebert, Julia Novion Ducassou, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), The platforms of the Grenoble Instruct center (ISBG, UMS 3518 CNRS-CEA-UJF-EMBL), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Brochier-Armanet, Céline, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, 0301 basic medicine, DNA Repair, Carboxy-Lyases, Mutant, DETERMINANTS, SUSCEPTIBILITY, Virulence factor, Mice, Francisella tularensis, Tularemia, Cells, Cultured, Aromatic L-amino acid decarboxylase, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Virulence, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Lysine decarboxylase, Biological techniques, TULAREMIA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, Phylogenetics, ACID, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Francisella, Medicine, Microbiology techniques, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, 030106 microbiology, Proteomic analysis, Article, INTRACELLULAR SURVIVAL, 03 medical and health sciences, Bacterial Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Escherichia coli, Animals, VIBRIO-VULNIFICUS, BIOSYNTHESIS, Amino Acid Sequence, Structure determination, Gene, Mass spectrometry, Macrophages, TULARENSIS PATHOGENICITY ISLAND, Biology and Life Sciences, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, POLYAMINES, Oxidative Stress, 030104 developmental biology, VIRULENCE, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Sequence Alignment
Abstract: Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.
Published: 2021
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8. In Depth Exploration of the Alternative Proteome of Drosophila melanogaster

Author: Fabre, Bertrand, Choteau, Sebastien A, Duboé, Carine, Pichereaux, Carole, Montigny, Audrey, Korona, Dagmara, Deery, Michael, Camus, Mylène, Brun, Christine, Burlet-Schiltz, Odile, Russell, Steve, Combier, Jean-Philippe, Lilley, Kathryn S, Plaza, Serge, Peptides et petits ARN, Laboratoire de Recherche en Sciences Végétales (LRSV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-16-CE12-0018,biomiPEPs,Vers une compréhension globale des miPEPs(2016), Brun, C., Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Vers une compréhension globale des miPEPs - - biomiPEPs2016 - ANR-16-CE12-0018 - AAPG2016 - VALID, Pichereaux, Carole [0000-0002-7559-5358], Apollo - University of Cambridge Repository, Deery, Michael [0000-0001-6895-9814], Russell, Steve [0000-0003-0546-3031], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell and Developmental Biology, short open reading frame–encoded polypeptide, microprotein, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], alternative proteins, peptidomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], mass spectrometry
Abstract: Recent studies have shown that hundreds of small proteins were occulted when protein coding genes were annotated. These proteins, called alternative proteins, have failed to be annotated notably due to the short length of their open reading frame (less than 100 codons) or the enforced rule establishing that messenger RNAs (mRNAs) are monocystronic. Several alternative proteins were shown to be biologically active molecules and seem to be involved in a wide range of biological functions. However, genome wide exploration of the alternative proteome is still limited to a few species. In the present article we describe a deep peptidomics workflow which enabled the identification of 401 alternative proteins in Drosophila melanogaster. Subcellular localization, protein domains and short linear motifs were predicted for 235 of the alternative proteins identified and point towards specific functions of these small proteins. Several alternative proteins had approximated abundances higher than their canonical counterparts, suggesting that these alternative proteins are actually the main products of their corresponding genes. Finally, we observed fourteen alternative proteins with developmentally regulated expression patterns and ten induced upon heat shock treatment of embryos, demonstrating stage or stress specific production of alternative proteins.
Published: 2022
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9. Probing the mechanism of the peroxiredoxin decamer interaction with its reductase sulfiredoxin from the single molecule to the solution scale

Author: Audrey Beaussart, Florent Canonico, Hortense Mazon, Jorge Hidalgo, Sarah Cianférani, Hélène Le Cordier, Alexandre Kriznik, Sophie Rahuel-Clermont, Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Infrastructure Nationale de Protéomique, FR2048 ProFI, Ingénierie, Biologie et Santé en Lorraine (IBSLor), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE11-0034,PrxAGE,Mécanismes d'action des peroxirédoxines dans la réponse au stress oxydant et le vieillissement(2017), ANR-20-CE34-0005,ANATOMIC,Evaluation des mécanismes moléculaires conduisant à la toxicité des nanoparticules sur les algues(2020), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), GONNET, JULIE, Mécanismes d'action des peroxirédoxines dans la réponse au stress oxydant et le vieillissement - - PrxAGE2017 - ANR-17-CE11-0034 - AAPG2017 - VALID, Evaluation des mécanismes moléculaires conduisant à la toxicité des nanoparticules sur les algues - - ANATOMIC2020 - ANR-20-CE34-0005 - AAPG2020 - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biophysics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Materials Science, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Peroxiredoxins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Microscopy, Atomic Force, Oxidoreductases, Catalysis
Abstract: Peroxiredoxins from the Prx1 subfamily (Prx) are highly regulated multifunctional proteins involved in oxidative stress response, redox signaling and cell protection. Prx is a homodimer that associates into a decamer. The monomer C-terminus plays intricate roles in Prx catalytic functions, decamer stability and interaction with its redox partner, the small reductase sulfiredoxin (Srx), that regulates the switching between Prx cellular functions. As only static structures of covalent Prx-Srx complexes have been reported, whether Srx binding dissociates the decameric assembly and how Prx subunit flexibility impacts complex formation are unknown. Here, we assessed the non-covalent interaction mechanism and dynamics in the solution of
Published: 2022
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10. Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter

Author: Vincent Chaptal, Veronica Zampieri, Benjamin Wiseman, Cédric Orelle, Juliette Martin, Kim-Anh Nguyen, Alexia Gobet, Margot Di Cesare, Sandrine Magnard, Waqas Javed, Jad Eid, Arnaud Kilburg, Marine Peuchmaur, Julien Marcoux, Luca Monticelli, Martin Hogbom, Guy Schoehn, Jean-Michel Jault, Ahcène Boumendjel, Pierre Falson, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-13-BSV5-0001,CLAMP,Détergents stabilisants des protéines membranaires par réseau de ponts salins multiples pour leur étude et cristallisation en solution. Application aux pompes ABC d'efflux de multiples médicaments.(2013), ANR-14-CE09-0024,BmrA-NMX,Révéler les détails conformationnels d'une pompe d'efflux membranaire(2014), ANR-17-CE11-0015,CAVEOTANK,Production de protéines membranaires recombinantes insérées dans les membranes de cavéoles hétérologues(2017), ANR-18-CE11-0002,CLAMP2,Stabilisateurs moléculaires des protéines membranaires pour leur étude structurale en solution(2018), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-19-CE11-0023,BIOTIFLUX,Dissection du mécanisme moléculaire d'un transporteur d'antibiotiques(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Institut de biologie et chimie des protéines [Lyon] (IBCP), Unité Mathématique Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Arrhenius Laboratories for Natural Sciences, Stockholm University, Martin, Juliette, Blanc 2013 - Détergents stabilisants des protéines membranaires par réseau de ponts salins multiples pour leur étude et cristallisation en solution. Application aux pompes ABC d'efflux de multiples médicaments. - - CLAMP2013 - ANR-13-BSV5-0001 - Blanc 2013 - VALID, Appel à projets générique - Révéler les détails conformationnels d'une pompe d'efflux membranaire - - BmrA-NMX2014 - ANR-14-CE09-0024 - Appel à projets générique - VALID, Production de protéines membranaires recombinantes insérées dans les membranes de cavéoles hétérologues - - CAVEOTANK2017 - ANR-17-CE11-0015 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Stabilisateurs moléculaires des protéines membranaires pour leur étude structurale en solution - - CLAMP22018 - ANR-18-CE11-0002 - AAPG2018 - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Dissection du mécanisme moléculaire d'un transporteur d'antibiotiques - - BIOTIFLUX2019 - ANR-19-CE11-0023 - AAPG2019 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV] Life Sciences [q-bio], Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV]Life Sciences [q-bio], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg 2+ –bound outward-facing conformations of the Bacillus subtilis (homodimeric) BmrA by x-ray crystallography and single-particle cryo–electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in B. subtilis . Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1–2 of one monomer and TM5′–6′ of the other. They induce a rearrangement of TM1–2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open.
Published: 2022
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11. Kinetic proofreading through the multi-step activation of the ZAP70 kinase underlies early T cell ligand discrimination

Author: Guillaume Voisinne, Marie Locard-Paulet, Carine Froment, Emilie Maturin, Marisa Goncalves Menoita, Laura Girard, Valentin Mellado, Odile Burlet-Schiltz, Bernard Malissen, Anne Gonzalez de Peredo, Romain Roncagalli, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2011), European Project: 322465,EC:FP7:ERC,ERC-2012-ADG_20120314,INTEGRATE(2013), European Project: 787300,BASILIC, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Gonzalez de Peredo, Anne, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Biologie des cellules dendritiques - - DCBIOL2011 - ANR-11-LABX-0043 - LABX - VALID, Integrative biology of T cells and dendritic cells in vivo. - INTEGRATE - - EC:FP7:ERC2013-07-01 - 2018-06-30 - 322465 - VALID, and Decoding at systems-level the crosstalk between the T cell antigen receptor, the CD28 costimulator and the PD-1 coinhibitor under physiological and pathological conditions - BASILIC - 787300 - INCOMING
Subjects: Proteomics, ZAP-70 Protein-Tyrosine Kinase, [SDV]Life Sciences [q-bio], T-Lymphocytes, Immunology, Receptors, Antigen, T-Cell, Kinases, Ligands, [SDV] Life Sciences [q-bio], Kinetics, Immunology and Allergy, T-cell receptor, Antigens, Phosphorylation
Abstract: T cells recognize a few high-affinity antigens among a vast array of lower affinity antigens. According to the kinetic proofreading model, antigen discrimination properties could be explained by the gradual amplification of small differences in binding affinities as the signal is transduced downstream of the T cell receptor. Which early molecular events are affected by ligand affinity, and how, has not been fully resolved. Here, we used time-resolved high-throughput proteomic analyses to identify and quantify the phosphorylation events and protein–protein interactions encoding T cell ligand discrimination in antigen-experienced T cells. Although low-affinity ligands induced phosphorylation of the Cd3 chains of the T cell receptor and the interaction of Cd3 with the Zap70 kinase as strongly as high-affinity ligands, they failed to activate Zap70 to the same extent. As a result, formation of the signalosome of the Lat adaptor was severely impaired with low- compared with high-affinity ligands, whereas formation of the signalosome of the Cd6 receptor was affected only partially. Overall, this study provides a comprehensive map of molecular events associated with T cell ligand discrimination.
Published: 2022
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12. Slightly different metabolomic profiles are associated with high or low weight duck foie gras

Author: Bara Lo, Nathalie Marty-Gasset, Helene Manse, Cecile Canlet, Renaud Domitile, Herve Remignon, LESUR, Hélène, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Metatoul AXIOM (E20 ), MetaboHUB-MetaToul, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ToxAlim (ToxAlim), IDENA, For this specific study we received a grant from the ANR-T (grant number = ANR-2017/1414) to partly cover Bara LO’s PhD. salary.An other financial support (number = ANR-10-INBS-08) was previously given to the technical platform in charge of our metabolomics analysis, and ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010)
Subjects: Fatty Liver, [SDV] Life Sciences [q-bio], Multidisciplinary, Ducks, Thinness, [SDV]Life Sciences [q-bio], Hyperaldosteronism, Animals, Metabolomics
Abstract: Understanding the evolution of fatty liver metabolism of ducks is a recurrent issue for researchers and industry. Indeed, the increase in weight during the overfeeding period leads to an important change in the liver metabolism. However, liver weight is highly variable at the end of overfeeding within a batch of animals reared, force-fed and slaughtered in the same way. For this study, we performed a proton nuclear magnetic resonance (1H-NMR) analysis on two classes of fatty liver samples, called low-weight liver (weights between 550 and 599 g) and high-weight liver (weights above 700 g). The aim of this study was to identify the differences in metabolism between two classes of liver weight (low and high). Firstly, the results suggested that increased liver weight is associated with higher glucose uptake leading to greater lipid synthesis. Secondly, this increase is probably also due to a decline in the level of export of triglycerides from the liver by maintaining them at high hepatic concentration levels, but also of hepatic cholesterol. Finally, the increase in liver weight could lead to a significant decrease in the efficiency of aerobic energy metabolism associated with a significant increase in the level of oxidative stress. However, all these hypotheses will have to be confirmed in the future, by studies on plasma levels and specific assays to validate these results.
Published: 2022
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13. Quantitative proteomic analyses reveal the impact of nitrogen starvation on the proteome of the model diatom Phaeodactylum tricornutum

Author: Josselin Lupette, Marianne Tardif, Sabine Brugière, Yohann Couté, Juliette Salvaing, Eric Maréchal, LIPID, Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), Salvaing, Juliette, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID
Subjects: Diatoms, Proteomics, Proteome, Nitrogen, Nitrogen starvation, Phaeodactylum, Fatty Acids, Diatom, Biochemistry, Carbon, Proteome remodelling, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quantitative proteomics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Triglycerides
Abstract: Data Paper; International audience; Diatoms are one of the largest groups in phytoplankton biodiversity. Understanding their response to nitrogen variations, present from micromolar to near-zero levels in oceans and fresh waters, is essential to comprehend their ecological success. Nitrogen starvation is used in biotechnological processes, to trigger the remodeling of carbon metabolism in the direction of fatty acids and triacylglycerol synthesis. We evaluated whole proteome changes in Phaeodactylum tricornutum after 7 days of cultivation with 5.5-mM nitrate (+N) or without any nitrogen source (-N). On a total of 3768 proteins detected in biological replicates, our analysis pointed to 384 differentially abundant proteins (DAP). Analysis of proteins of lower abundance in -N revealed an arrest of amino acid and protein syntheses, a remodeling of nitrogen metabolism, and a decrease of the proteasome abundance suggesting a decline in unselective whole-proteome decay. Analysis of proteins of higher abundance revealed the setting up of a general nitrogen scavenging system dependent on deaminases. The increase of a plastid palmitoyl-ACP desaturase appeared as a hallmark of carbon metabolism rewiring in the direction of fatty acid and triacylglycerol synthesis. This dataset is also valuable to select gene candidates for improved biotechnological properties.
Published: 2022
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14. Proteomics unveil a central role for peroxisomes in butyrate assimilation of the heterotrophic Chlorophyte alga Polytomella sp

Author: J. Lacroux, A. Atteia, S. Brugière, Y. Couté, O. Vallon, J.-P. Steyer, R. van Lis, Laboratoire de Biotechnologie de l'Environnement [Narbonne] (LBE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biologie du chloroplaste et perception de la lumière chez les micro-algues, Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), European Union from the Occitanie region, France, with complementary funding from FEDER, National Institute of Agriculture, Alimentation and Environment (INRAE), the CNRS, and was supported by the FermALip project, funded by the Carnot institute 3BCAR as well as by the 'Initiative d'Excellence' program from the French State (Grant DYNAMO', ANR-11-LABX-0011-01), ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), PhD fellowship from European Union from the Occitanie region, France, with complementary funding from FEDER., National Institute of Agriculture, Alimentation and Environment (INRAE), the CNRS, and was supported by the FermALip project, funded by the Carnot institute 3BCAR, Fournier, Dominique, Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire. - - DYNAMO2011 - ANR-11-LABX-0011 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID
Subjects: Microbiology (medical), quantitative proteomics, heterotrophy, [SDE.IE]Environmental Sciences/Environmental Engineering, microalgae, volatile fatty acids, [SDV]Life Sciences [q-bio], metabolic pathways, [SDE.IE] Environmental Sciences/Environmental Engineering, Microbiology
Abstract: Volatile fatty acids found in effluents of the dark fermentation of biowastes can be used for mixotrophic growth of microalgae, improving productivity and reducing the cost of the feedstock. Microalgae can use the acetate in the effluents very well, but butyrate is poorly assimilated and can inhibit growth above 1 gC.L-1. The non-photosynthetic chlorophyte alga Polytomella sp. SAG 198.80 was found to be able to assimilate butyrate fast. To decipher the metabolic pathways implicated in butyrate assimilation, quantitative proteomics study was developed comparing Polytomella sp. cells grown on acetate and butyrate at 1 gC.L-1. After statistical analysis, a total of 1772 proteins were retained, of which 119 proteins were found to be overaccumulated on butyrate vs. only 46 on acetate, indicating that butyrate assimilation necessitates additional metabolic steps. The data show that butyrate assimilation occurs in the peroxisome via the β-oxidation pathway to produce acetyl-CoA and further tri/dicarboxylic acids in the glyoxylate cycle. Concomitantly, reactive oxygen species defense enzymes as well as the branched amino acid degradation pathway were strongly induced.Although no clear dedicated butyrate transport mechanism could be inferred, several membrane transporters induced on butyrate are identified as potential condidates. Metabolic responses correspond globally to the increased needs for central cofactors NAD, ATP and CoA, especially in the peroxisome and the cytosol.
Published: 2022
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15. A drug repurposing screen identifies altiratinib as a selective inhibitor of a key regulatory splicing kinase and a potential therapeutic for toxoplasmosis and malaria

Author: Caroline Mas, Dominique Cannella, Artur Scherf, Christopher Swale, Lucid Belmudes, Fabrice Laurent, Mohamed-Ali Hakimi, Matthew W. Bowler, Marie-Pierre Brenier-Pinchart, Yohann Couté, Nardella Flore, Alexandre Bougdour, Valeria Bellini, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), European Molecular Biology Laboratory [Grenoble] (EMBL), Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Integrated Structural Biology Grenoble (ISBG - UMS 3518 ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), (FRM Equipe # EQU202103012571), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), ANR-18-CE15-0023,HostQuest,Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée(2018), ANR-21-CE35-0010,ApiNewDrug,Identification de nouvelles cibles thérapeutiques parmi des médicaments repositionnables pour traiter des maladies dues à des parasitaire apicomplexes(2021), ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), European Project: 614880,Hosting Toxo, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Integrated Structural Biology Grenoble (ISBG), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chanteloup, Nathalie Katy, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Stratégies de Persistence de Toxoplasma gondii : Conquérir la Cellule Hôte et Echapper à la Réponse Immune Innée - - HostQuest2018 - ANR-18-CE15-0023 - AAPG2018 - VALID, Identification de nouvelles cibles thérapeutiques parmi des médicaments repositionnables pour traiter des maladies dues à des parasitaire apicomplexes - - ApiNewDrug2021 - ANR-21-CE35-0010 - AAPG2021 - VALID, Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme - - EpiKillMal2020 - ANR-20-CE18-0006 - AAPG2020 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, and ERC Consolidator grant - Hosting Toxo - 614880 - INCOMING
Subjects: 0303 health sciences, biology, drug repurposing, Kinase, kinase, Plasmodium falciparum, Intron, Toxoplasma gondii, Computational biology, biology.organism_classification, 3. Good health, Apicomplexa, 03 medical and health sciences, Drug repositioning, splicing, 0302 clinical medicine, CLK3, RNA splicing, parasitic diseases, Protozoa, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Altiratinib, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Introductory paragraphThe apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution, highlighting key residues within the kinase catalytic site that, when mutated, confer resistance to the drug. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for TgPRP4K as well as for its P. falciparum counterpart PfCLK3. Our data also point to structural features critical for binding of the other PfCLK3 inhibitor, TCMDC-135051. Consistent with the role of this kinase family in splicing in a broad spectrum of eukaryotes, we have shown that altiratinib causes global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum. Thus, our data establish parasitic PRP4K/CLK3 as a promising pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
Published: 2021

16. Francisella tularensis: FupA mutation contributes to fluoroquinolone resistance by increasing vesicle secretion and biofilm formation

Author: Corinne Villers, Patricia Renesto, Sandrine Boisset, Claire Siebert, Julien Pérard, Max Maurin, Helena Lindgren, Sabrina Ferré, Céline Brochier-Armanet, Anders Sjöstedt, Yohann Couté, RENESTO, PATRICIA, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre National de Référence des Francisella [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Umeå University, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de Recherche Risques Microbiens (U2RM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Laboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Etude de la dynamique des protéomes (EDyP ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biocatalyse (BIOCAT ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Biologie des Métaux (BioMet), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)
Subjects: 0301 basic medicine, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Epidemiology, 030106 microbiology, Immunology, Virulence, Microbiology, DNA gyrase, Article, antibiotics, Microbiology in the medical area, Tularemia, 03 medical and health sciences, Antibiotic resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Drug Discovery, Mikrobiologi inom det medicinska området, medicine, Secretion, fluoroquinolones, Francisella, Francisella tularensis, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, General Medicine, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Infectious Diseases, OMVs, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Parasitology, biofilms, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Bacterial outer membrane
Abstract: International audience; Francisella tularensis is the causative agent in tularemia for which the high prevalence of treatment failure and relapse is a major concern. Directed-evolution experiments revealed that acquisition of fluoroquinolone (FQ) resistance was linked to factors in addition to mutations in DNA gyrase. Here, using F. tularensis live vaccine strain (LVS) as a model, we demonstrated that FupA/B (Fer-Utilization Protein) expression is linked to FQ susceptibility, and that the virulent strain F. tularensis subsp. tularensis SCHU S4 deleted for the homologous FupA protein exhibited even higher FQ resistance. In addition to an increased FQ minimal inhibitory concentration, LVS Delta fupA/B displayed tolerance toward bactericidal compounds including ciprofloxacin and gentamicin. Interestingly, the FupA/B deletion was found to promote increased secretion of outer membrane vesicles (OMVs). Mass spectrometry-based quantitative proteomic characterization of vesicles from LVS and LVS Delta fupA/B identified 801 proteins, including a subset of 23 proteins exhibiting differential abundance between both strains which may therefore contribute to the reduced antibiotic susceptibility of the FupA/B-deleted strain. We also demonstrated that OMVs are key structural elements of LVS Delta fupA/B biofilms providing protection against FQ. These results provide a new basis for understanding and tackling antibiotic resistance and/or persistence of Francisella and other pathogenic members of the Thiotrichales class.
Published: 2019
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17. Three-Dimensional Envelope and Subunit Interactions of the Plastid-Encoded RNA Polymerase from Sinapis alba

Author: Rémi Ruedas, Soumiya Sankari Muthukumar, Sylvie Kieffer-Jaquinod, François-Xavier Gillet, Daphna Fenel, Grégory Effantin, Thomas Pfannschmidt, Yohann Couté, Robert Blanvillain, David Cobessi, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Dynamiques Chromatiniennes et Transitions Développementales (ChromDev), Physiologie cellulaire et végétale (LPCV), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), ANR-17-CE11-0031,PEPRegulChloro3D,Biogenèse du chloroplaste: fonction, régulation et structure de l'ARN-polymérase plastidiale et de ses protéines associées PAP(2017), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Thomas, Frank, Biogenèse du chloroplaste: fonction, régulation et structure de l'ARN-polymérase plastidiale et de ses protéines associées PAP - - PEPRegulChloro3D2017 - ANR-17-CE11-0031 - AAPG2017 - VALID, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: photosynthesis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], plastid-encoded RNA polymerase, Organic Chemistry, General Medicine, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, PEP associated proteins, Catalysis, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, photomorphogenesis, Computer Science Applications, Inorganic Chemistry, chloroplast biogenesis, Sinapis alba, transcription, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; RNA polymerases (RNAPs) are found in all living organisms. In the chloroplasts, the plastid-encoded RNA polymerase (PEP) is a prokaryotic-type multimeric RNAP involved in the selective transcription of the plastid genome. One of its active states requires the assembly of nuclear-encoded PEP-Associated Proteins (PAPs) on the catalytic core, producing a complex of more than 900 kDa, regarded as essential for chloroplast biogenesis. In this study, sequence alignments of the catalytic core subunits across various chloroplasts of the green lineage and prokaryotes combined with structural data show that variations are observed at the surface of the core, whereas internal amino acids associated with the catalytic activity are conserved. A purification procedure compatible with a structural analysis was used to enrich the native PEP from Sinapis alba chloroplasts. A mass spectrometry (MS)-based proteomic analysis revealed the core components, the PAPs and additional proteins, such as FLN2 and pTAC18. MS coupled with crosslinking (XL-MS) provided the initial structural information in the form of protein clusters, highlighting the relative position of some subunits with the surfaces of their interactions. Using negative stain electron microscopy, the PEP three-dimensional envelope was calculated. Particles classification shows that the protrusions are very well-conserved, offering a framework for the future positioning of all the PAPs. Overall, the results show that PEP-associated proteins are firmly and specifically associated with the catalytic core, giving to the plastid transcriptional complex a singular structure compared to other RNAPs.
Published: 2022
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18. LEAFY protein crystals with a honeycomb structure as a platform for selective preparation of outstanding stable bio-hybrid materials

Author: Sylvie Kieffer-Jaquinod, Philippe Carpentier, Stéphane Ravanel, Renaud Dumas, Julien Pérard, Olivier Hamelin, Stéphane Ménage, Alice Gogny, David Cobessi, Lucile Chiari, Catalyse Bioinorganique et Environnement (BioCE ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biocatalyse (BIOCAT), European Synchrotron Radiation Facility (ESRF), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), BioEnergie et Environnement (BEE), Plantes, Stress & Métaux (MetalStress), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Régulateurs du développement de la fleur (Flo_RE ), 80|PRIME Program (CNRS), DRF Impulsion program (CEA), ANR-11-LABX-0003,ARCANE,Grenoble, une chimie bio-motivée(2011), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), GON, Nathalie, Grenoble, une chimie bio-motivée - - ARCANE2011 - ANR-11-LABX-0003 - LABX - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: Materials science, chemistry.chemical_element, Nanotechnology, 010402 general chemistry, 01 natural sciences, Mass Spectrometry, symbols.namesake, Honeycomb, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Materials Science, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Leafy, Enzymatic digestion, 010405 organic chemistry, Ginkgo biloba, Proteins, [PHYS.COND.CM-MS] Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], 0104 chemical sciences, Ruthenium, Plant Leaves, Honeycomb structure, chemistry, symbols, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], Raman spectroscopy, Hybrid material, Protein crystallization, Chromatography, Liquid
Abstract: International audience; Well-organized protein assemblies offer many properties that justify their use for the design of innovative bionanomaterials. Herein, crystals of the oligomerization domain of the LEAFY protein from Ginkgo biloba, organized in a honeycomb architecture, were used as a modular platform for the selective grafting of a ruthenium-based complex. The resulting bio-hybrid crystalline material was fully characterized by UV-visible and Raman spectroscopy and by mass spectrometry and LC-MS analysis after selective enzymatic digestion. Interestingly, insertion of complexes within the tubular structure affords an impressive increase in stability of the crystals, eluding the use of stabilizing cross-linking strategies.
Published: 2021
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19. The box C/D snoRNP assembly factor Bcd1 interacts with the histone chaperone Rtt106 and controls its transcription dependent activity

Author: Laurence Decourty, Séverine Massenet, Stéphane Labialle, Marie-Eve Chagot, Guillaume Terral, Benoît Bragantini, Marc Quinternet, Maxime Bourguet, Cosmin Saveanu, Edouard Bertrand, Decebal Tiotiu, Christophe Charron, Sarah Cianférani, Bruno Charpentier, Xavier Manival, Jean-Marc Strub, Arnaud Paul, Steve Hessmann, Hélène Marty, Benjamin Rothé, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Mayo Clinic [Rochester], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Génétique des Interactions macromoléculaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie, Biologie et Santé en Lorraine (IBSLor), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Centre National de la Recherche Scientifique (CNRS), Université de Lorraine (UL), and Université de Strasbourg, the Agence Nationale de la Recherche [ANR-06-BLAN-0208, ANR-11-BSV8-01503, ANR-16-CE11-0032-04, ANR-08-JCJC-0019], the French Proteomic Infrastructure (ProFI, ANR-10-INBS-08-03). The authors thank GIS IBiSA, Région Alsace, Communauté Urbaine de Strasbourg, FEDER, and the IdeX program of the University of Strasbourg for financial support in purchasing HDX-MS and native MS instruments. B.B., B.R., and A.P. are fellows of the French Ministère de l’Enseignement Supérieur et de la Recherche. M.B. was supported by a fellowship from the Région Alsace. G.T. was supported by the Région Alsace and Novalix., ANR-06-BLAN-0208,RNPASSEMBLY,Nufip/Rsa1: a common assembly machine for snoRNPs, telomerase, and selenoprotein mRNPs.(2006), ANR-08-JCJC-0019,GENO-GIM,Obtention d'une carte d'interactions génétiques à l'échelle génomique chez la levure(2008), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Génétique des Interactions macromoléculaires / Genetics of Macromolecular Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Charpentier, Bruno, Programme 'blanc' - Nufip/Rsa1: a common assembly machine for snoRNPs, telomerase, and selenoprotein mRNPs. - - RNPASSEMBLY2006 - ANR-06-BLAN-0208 - BLANC - VALID, Jeunes chercheuses et jeunes chercheurs - Obtention d'une carte d'interactions génétiques à l'échelle génomique chez la levure - - GENO-GIM2008 - ANR-08-JCJC-0019 - JCJC - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Transcription, Genetic, hal-03181046, General Physics and Astronomy, RNA polymerase II, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Crystallography, X-Ray, Histones, Transcription (biology), Ribonucleoproteins, Small Nucleolar, Multidisciplinary, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, RNA-Binding Proteins, Chromatin, Cell biology, Histone, Box C/D snoRNP assembly, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Polymerase II, Structural biology, Transcription, Ribosomal Proteins, Transcriptional Activation, Saccharomyces cerevisiae Proteins, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, Chromatin remodelling, Saccharomyces cerevisiae, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Histone H3, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nuclear Magnetic Resonance, Biomolecular, R2TP complex, Cell Proliferation, 030102 biochemistry & molecular biology, Small RNAs, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Chromatin Assembly and Disassembly, 030104 developmental biology, Chaperone (protein), biology.protein, Ribosomes, Molecular Chaperones
Abstract: Biogenesis of eukaryotic box C/D small nucleolar ribonucleoproteins initiates co-transcriptionally and requires the action of the assembly machinery including the Hsp90/R2TP complex, the Rsa1p:Hit1p heterodimer and the Bcd1 protein. We present genetic interactions between the Rsa1p-encoding gene and genes involved in chromatin organization including RTT106 that codes for the H3-H4 histone chaperone Rtt106p controlling H3K56ac deposition. We show that Bcd1p binds Rtt106p and controls its transcription-dependent recruitment by reducing its association with RNA polymerase II, modulating H3K56ac levels at gene body. We reveal the 3D structures of the free and Rtt106p-bound forms of Bcd1p using nuclear magnetic resonance and X-ray crystallography. The interaction is also studied by a combination of biophysical and proteomic techniques. Bcd1p interacts with a region that is distinct from the interaction interface between the histone chaperone and histone H3. Our results are evidence for a protein interaction interface for Rtt106p that controls its transcription-associated activity., Biogenesis of small nucleolar RNAs ribonucleoproteins (snoRNPs) requires dedicated assembly machinery. Here, the authors show that a subset of snoRNP assembly factors interacts, genetically or directly, with factors modulating chromatin architecture, suggesting a link between ribosome formation and chromatin functions.
Published: 2021
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20. Well Plate Maker: A user-friendly randomized block design application to limit batch effects in largescale biomedical studies

Author: Virginie Brun, Hélène Borges, Anne-Marie Hesse, Alexandra Kraut, Yohann Couté, Thomas Burger, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID
Subjects: Statistics and Probability, Computer science, Sample (statistics), computer.software_genre, Proteomics, Mass spectrometry, Biochemistry, Bioconductor, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Limit (mathematics), Molecular Biology, Throughput (business), ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 030304 developmental biology, 0303 health sciences, User Friendly, Scale (chemistry), Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Data mining, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, 030217 neurology & neurosurgery
Abstract: Summary Many factors can influence results in clinical research, in particular bias in the distribution of samples prior to biochemical preparation. Well Plate Maker is a user-friendly application to design single- or multiple-well plate assays. It allows multiple group experiments to be randomized and therefore helps to reduce possible batch effects. Although primarily fathered to optimize the design of clinical sample analysis by high throughput mass spectrometry (e.g. proteomics or metabolomics), it includes multiple options to limit edge-of-plate effects, to incorporate control samples or to limit cross-contamination. It thus fits the constraints of many experimental fields. Availability and implementation Well Plate Maker is implemented in R and available at Bioconductor repository (https://bioconductor.org/packages/wpm) under the open source Artistic 2.0 license. In addition to classical scripting, it can be used through a graphical user interface, developed with Shiny technology.
Published: 2021
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21. CHICKN: extraction of peptide chromatographic elution profiles from large scale mass spectrometry data by means of Wasserstein compressive hierarchical cluster analysis

Author: Thomas Burger, Thomas Fortin, Anne-Marie Hesse, Alexandra Kraut, Olga Permiakova, Romain Guibert, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Proteomics, Similarity (geometry), Computer science, Large-scale cluster analysis, Liquid chromatography, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Wasserstein kernel, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, Structural Biology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Optimal transport, Cluster Analysis, Cluster analysis, lcsh:QH301-705.5, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, Chromatography, Mass spectrometry, Applied Mathematics, Scale (chemistry), Methodology Article, 030302 biochemistry & molecular biology, Data Compression, Computer Science Applications, Hierarchical clustering, lcsh:Biology (General), Kernel (statistics), lcsh:R858-859.7, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Peptides, Algorithms, Curse of dimensionality, Chromatography, Liquid
Abstract: Background The clustering of data produced by liquid chromatography coupled to mass spectrometry analyses (LC-MS data) has recently gained interest to extract meaningful chemical or biological patterns. However, recent instrumental pipelines deliver data which size, dimensionality and expected number of clusters are too large to be processed by classical machine learning algorithms, so that most of the state-of-the-art relies on single pass linkage-based algorithms. Results We propose a clustering algorithm that solves the powerful but computationally demanding kernel k-means objective function in a scalable way. As a result, it can process LC-MS data in an acceptable time on a multicore machine. To do so, we combine three essential features: a compressive data representation, Nyström approximation and a hierarchical strategy. In addition, we propose new kernels based on optimal transport, which interprets as intuitive similarity measures between chromatographic elution profiles. Conclusions Our method, referred to as CHICKN, is evaluated on proteomics data produced in our lab, as well as on benchmark data coming from the literature. From a computational viewpoint, it is particularly efficient on raw LC-MS data. From a data analysis viewpoint, it provides clusters which differ from those resulting from state-of-the-art methods, while achieving similar performances. This highlights the complementarity of differently principle algorithms to extract the best from complex LC-MS data.
Published: 2021
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22. Phylogenetic and functional diversity of aldehyde-alcohol dehydrogenases in microalgae

Author: Sabine Brugière, Ariane Atteia, Benoist Laurent, Olivier Vallon, Yohann Couté, Nicolas J Tourasse, Wolfgang Nitschke, Robert van Lis, Bioénergétique et Ingénierie des Protéines (BIP ), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Laboratoire de Biotechnologie de l'Environnement [Narbonne] (LBE), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS), Biologie du chloroplaste et perception de la lumière chez les micro-algues, Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro - Montpellier SupAgro, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), MARine Biodiversity Exploitation and Conservation (UMR MARBEC), Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), ATTEIA, Ariane, Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire. - - DYNAMO2011 - ANR-11-LABX-0011 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut de Recherche pour le Développement (IRD)
Subjects: 0303 health sciences, biology, Phylogenetic tree, [SDE.IE]Environmental Sciences/Environmental Engineering, [SDV]Life Sciences [q-bio], 030302 biochemistry & molecular biology, Polytomella, Aldehyde dehydrogenase, Plant Science, General Medicine, biology.organism_classification, Genome, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Biochemistry, Algae, Phylogenetics, Genetics, biology.protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Agronomy and Crop Science, Gene, hormones, hormone substitutes, and hormone antagonists, 030304 developmental biology, Alcohol dehydrogenase
Abstract: International audience; Aldehyde-alcohol dehydrogenases (ADHEs) are large metalloenzymes that typically perform the two-step reduction of acetyl-CoA into ethanol. These enzymes consist of an N-terminal acetylating aldehyde dehydrogenase domain (ALDH) and a C-terminal alcohol dehydrogenase (ADH) domain. ADHEs are present in various bacterial phyla as well as in some unicellular eukaryotes. Here we focus on ADHEs in microalgae, a diverse and polyphyletic group of plastid-bearing unicellular eukaryotes. Genome survey shows the uneven distribution of the ADHE gene among free-living algae, and the presence of two distinct genes in various species. We show that the non-photosynthetic Chlorophyte alga Polytomella sp. SAG 198.80 harbors two genes for ADHE-like enzymes with divergent C-terminal ADH domains. Immunoblots indicate that both ADHEs accumulate in Polytomella cells growing aerobically on acetate or ethanol. ADHE1 of ~ 105-kDa is found in particulate fractions, whereas ADHE2 of ~ 95-kDa is mostly soluble. The study of the recombinant enzymes revealed that ADHE1 has both the ALDH and ADH activities, while ADHE2 has only the ALDH activity. Phylogeny shows that the divergence occurred close to the root of the Polytomella genus within a clade formed by the majority of the Chlorophyte ADHE sequences, next to the cyanobacterial clade. The potential diversification of function in Polytomella spp. unveiled here likely took place after the loss of photosynthesis. Overall, our study provides a glimpse at the complex evolutionary history of the ADHE in microalgae which includes (i) acquisition via different gene donors, (ii) gene duplication and (iii) independent evolution of one of the two enzymatic domains.
Published: 2021
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23. Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Author: Shima Ghoroghi, Benjamin Mary, Annabel Larnicol, Nandini Asokan, Annick Klein, Naël Osmani, Ignacio Busnelli, François Delalande, Nicodème Paul, Sébastien Halary, Frédéric Gros, Laetitia Fouillen, Anne-Marie Haeberle, Cathy Royer, Coralie Spiegelhalter, Gwennan André-Grégoire, Vincent Mittelheisser, Alexandre Detappe, Kendelle Murphy, Paul Timpson, Raphaël Carapito, Marcel Blot-Chabaud, Julie Gavard, Christine Carapito, Nicolas Vitale, Olivier Lefebvre, Jacky G Goetz, Vincent Hyenne, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biogenèse membranaire (LBM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Neurochimie, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de Strasbourg Europe (ICANS), Garvan Institute of medical research, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INCa (PLBIO19-291), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-19-CE44-0019,PA-Box,Etude des fonctions pléiotropiques de l'acide phosphatidique dans la sécrétion régulée à l'aide d'une nouvelle boite à outils moléculaires(2019), ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), The Garvan Institute of Medical Research [Sydney, Australia], Bernardo, Elizabeth, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Etude des fonctions pléiotropiques de l'acide phosphatidique dans la sécrétion régulée à l'aide d'une nouvelle boite à outils moléculaires - - PA-Box2019 - ANR-19-CE44-0019 - AAPG2019 - VALID, and Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation - - METABOHUB2011 - ANR-11-INBS-0010 - INBS - VALID
Subjects: pre-metastatic niche, QH301-705.5, Science, Aucun, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Exosomes, GTP Phosphohydrolases, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, cell biology, Human Umbilical Vein Endothelial Cells, Animals, Humans, exosome, human, Neoplasm Metastasis, Biology (General), mouse, cancer biology, Multivesicular Bodies, zebrafish, Medicine, inserm-03103515, Research Article, Ral GTPase
Abstract: International audience; Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146 dependent manner.
Published: 2021
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24. The Functionally Unannotated Proteome of Human Male Tissues: A Shared Resource to Uncover New Protein Functions Associated with Reproductive Biology

Author: Yves Vandenbrouck, Lydie Lane, Charles Pineau, BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre médical universitaire de Genève (CMU), the Swiss State Secretariat for Education, Research and Innovation SERI funding to the SIB Swiss Institute of Bioinformatics (LL)., This work was also supported by grants from Biogenouest, IBiSA, the Conseil Régional de Bretagne (CP), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), Chard-Hutchinson, Xavier, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: human proteome project, Male, Proteomics, Proteome, [SDV]Life Sciences [q-bio], Knowledge Bases, Context (language use), Computational biology, Biology, Biochemistry, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, functionally unannotated proteins, Ciliogenesis, Human proteome project, cancer/testis antigens, Humans, protein interaction networks, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], ddc:616, 0303 health sciences, protein complexes, biocuration, Reproduction, 030302 biochemistry & molecular biology, Computational Biology, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, General Chemistry, bioinformatics, data mining, spermatogenesis, [SDV] Life Sciences [q-bio], Cancer/testis antigens, acrosome, male reproduction, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Function (biology), ciliogenesis
Abstract: International audience; In the context of the Human Proteome Project, we built an inventory of 412 functionally unannotated human proteins for which experimental evidence at the protein level exists (uPE1) and which are highly expressed in tissues involved in human male reproduction. We implemented a strategy combining literature mining, bioinformatics tools to collate annotation and experimental information from specific molecular public resources, and efficient visualization tools to put these unknown proteins into their biological context (protein complexes, tissue and subcellular location, expression pattern). The gathered knowledge allowed pinpointing five uPE1 for which a function has recently been proposed and which should be updated in protein knowledge bases. Furthermore, this bioinformatics strategy allowed to build new functional hypotheses for five other uPE1s in link with phenotypic traits that are specific to male reproductive function such as ciliogenesis/flagellum formation in germ cells (CCDC112 and TEX9), chromatin remodeling (C3orf62) and spermatozoon maturation (CCDC183). We also discussed the enigmatic case of MAGEB proteins, a poorly documented cancer/testis antigen subtype. Tools used and computational outputs produced during this study are freely accessible via ProteoRE (http://www.proteore.org), a Galaxy-based instance, for reuse purposes. We propose these five uPE1s should be investigated in priority by expert laboratories and hope that this inventory and shared resources will stimulate the interest of the community of reproductive biology.
Published: 2020
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25. Beyond target-decoy competition: stable validation of peptide and protein identifications in mass spectrometry-based discovery proteomics

Author: Yohann Couté, Christophe Bruley, Thomas Burger, Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID
Subjects: False discovery rate, Proteomics, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, Computer science, Stability (learning theory), Peptide, Computational biology, Mass spectrometry, computer.software_genre, 01 natural sciences, Mass Spectrometry, Analytical Chemistry, Competition (economics), 010104 statistics & probability, 03 medical and health sciences, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, 0101 mathematics, Throughput (business), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, 030302 biochemistry & molecular biology, Proteins, Reproducibility of Results, chemistry, Data mining, Peptides, Decoy, computer
Abstract: In bottom-up discovery proteomics, target-decoy competition (TDC) is the most popular method for false discovery rate (FDR) control. Despite unquestionable statistical foundations, this method has drawbacks, including its hitherto unknown intrinsic lack of stability vis-à-vis practical conditions of application. Although some consequences of this instability have already been empirically described, they may have been misinter-preted. This article provides evidence that TDC has become less reliable as the accuracy of modern mass spectrometers improved. We therefore propose to replace TDC by a totally different method to control the FDR at spectrum, peptide and protein levels, while benefiting from the theoretical guarantees of the Benjamini-Hochberg framework. As this method is simpler to use, faster to compute and more stable than TDC, we argue that it is better adapted to the standardization and throughput constraints of current proteomic platforms.
Published: 2020
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26. Multi-omics analysis delineates the distinct functions of sub-cellular acetyl-CoA pools in Toxoplasma gondii

Author: Joachim Kloehn, Rebecca D. Oppenheim, Ghizal Siddiqui, Pieter-Jan De Bock, Sunil Kumar Dogga, Yohann Coute, Mohamed-Ali Hakimi, Darren J. Creek, Dominique Soldati-Favre, University of Geneva [Switzerland], Monash University [Parkville, VIC, Australie], Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Epigenetic and Parasites [La Tronche], Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), This research was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 695596. Proteomic experiments were partly supported by the Agence Nationale de la Recherche (ANR-10-INBS-08-01 ProFI grant and ANR-12-BSV3-0009 TOXOHDAC grant). MAH was supported by the LabEx ParaFrap [ANR-11-LABX-0024] and the ERC [Consolidator Grant no. 614880 Hosting TOXO]. RDO was supported by the iGE3 program from the University of Geneva. The project was also supported by the SNSF (CRSII3_160702 and 51PHP0_157303)., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-12-BSV3-0009,TOXOHDAC,Le réseau de régulation de HDAC3, une nouvelle voie épigénétique pour explorer la différenciation et la pathogénèse chez Toxoplasma gondii(2012), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: 614880,EC:FP7:ERC,ERC-2013-CoG,HOSTINGTOXO(2014), Bodescot, Myriam, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, BLANC - Le réseau de régulation de HDAC3, une nouvelle voie épigénétique pour explorer la différenciation et la pathogénèse chez Toxoplasma gondii - - TOXOHDAC2012 - ANR-12-BSV3-0009 - BLANC - VALID, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Toxoplasma gondii secretes an armada of effector proteins to co-opt its host cell transcriptome and microRNome to promote sustained parasitism - HOSTINGTOXO - - EC:FP7:ERC2014-05-01 - 2019-04-30 - 614880 - VALID, Université de Genève = University of Geneva (UNIGE), and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)
Subjects: ddc:616, Formate/nitrite transporter (FNT), Multi-omics, Phosphoenolpyruvate carboxykinase (PEPCK), Acetyl-CoA synthetase (ACS), Proteome, Protozoan Proteins, Toxoplasma gondii, ATP citrate lyase (ACL), Acetylome, Metabolism, lcsh:Biology (General), Acetyl Coenzyme A, Acetyl-CoA, Metabolome, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Transcriptome, lcsh:QH301-705.5, Toxoplasma, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, Branched-chain α-keto acid dehydrogenase-complex (BCKDH)
Abstract: International audience; Background: Acetyl-CoA is a key molecule in all organisms, implicated in several metabolic pathways as well as in transcriptional regulation and post-translational modification. The human pathogen Toxoplasma gondii possesses at least four enzymes which generate acetyl-CoA in the nucleo-cytosol (acetyl-CoA synthetase (ACS); ATP citrate lyase (ACL)), mitochondrion (branched-chain α-keto acid dehydrogenase-complex (BCKDH)) and apicoplast (pyruvate dehydrogenase complex (PDH)). Given the diverse functions of acetyl-CoA, we know very little about the role of sub-cellular acetyl-CoA pools in parasite physiology. Results: To assess the importance and functions of sub-cellular acetyl-CoA-pools, we measured the acetylome, transcriptome, proteome and metabolome of parasites lacking ACL/ACS or BCKDH. We demonstrate that ACL/ACS constitute a synthetic lethal pair. Loss of both enzymes causes a halt in fatty acid elongation, hypo-acetylation of nucleo-cytosolic and secretory proteins and broad changes in gene expression. In contrast, loss of BCKDH results in an altered TCA cycle, hypo-acetylation of mitochondrial proteins and few specific changes in gene expression. We provide evidence that changes in the acetylome, transcriptome and proteome of cells lacking BCKDH enable the metabolic adaptations and thus the survival of these parasites. Conclusions: Using multi-omics and molecular tools, we obtain a global and integrative picture of the role of distinct acetyl-CoA pools in T. gondii physiology. Cytosolic acetyl-CoA is essential and is required for the synthesis of parasite-specific fatty acids. In contrast, loss of mitochondrial acetyl-CoA can be compensated for through metabolic adaptations implemented at the transcriptional, translational and post-translational level.
Published: 2020
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27. Bile acids associate with glucose metabolism, but do not predict conversion from impaired fasting glucose to diabetes

Author: Matthieu Pichelin, Marielle Joliveau, Edith Bigot-Corbel, Amandine Descat, Bart Staels, Oscar Chávez-Talavera, Rémy Hanf, Cédric Le May, Jean-François Goossens, Emmanuelle Vallez, Samy Hadjadj, Mostafa Kouach, Matthieu Wargny, Bertrand Cariou, Anne Tailleux, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Derudas, Marie-Hélène, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de recherche de l'institut du thorax (ITX-lab), Université de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Genfit SA [Loos, France], Entreprise biopharmaceutique GENFIT Loos, ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Le May, Cedric, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Male, liquid chromatography tandem mass spectrometry, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, ECLIA, Takeda G protein coupled Receptor 5, UDCA, electrochemiluminescent enzyme immunoassay, hazard ratio, 0302 clinical medicine, Endocrinology, SFSTP, Chenodeoxycholic acid, CYP, HR, 6α-OH, Glucose homeostasis, fasting plasma glucose, HCA, Relationship between Insulin Sensitivity and Cardiovascular disease cohort, T2D, Prospective Studies, cholesterol associated with low density lipoproteins, 6α-hydroxylated, DCA, triglycerides, ComputingMilieux_MISCELLANEOUS, NOD, LCA, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, cholic acid, [SDV] Life Sciences [q-bio], FPG, cholesterol associated with high density lipoproteins, FXR, deoxycholic acid, Disease Progression, CYP27A1, ANR, 7α-hydroxy-4-cholesten-3-one, standard deviation, non-diabetic group, CYP cholesterol 27α-hydroxylase, medicine.medical_specialty, high molecular weight, interquartile range, IFG, Carbohydrate metabolism, HDCA, 03 medical and health sciences, Agence Nationale pour la Recherche, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Glucose Intolerance, tandem mass spectrometry, MS/MS, Humans, LC-MS/MS, 12α-hydroxylated, Aged, C4, methanol, SD, CYP cholesterol 7α-hydroxylase, medicine.disease, MeOH, HMW, hyocholic acid, Bile acids, 030104 developmental biology, Glucose, chemistry, Diabetes Mellitus, Type 2, glucagon-like peptide-1, homeostasis model assessment of insulin resistance, IR, CDCA, LDL-c, GLP-1, Prediabetes, Biomarkers, farnesoid X receptor, 0301 basic medicine, CYP7A1, [SDV]Life Sciences [q-bio], Société Française des Sciences et Techniques Pharmaceutiques, Type 2 diabetes, HOMA-IR, Bile acids Impaired fasting glucose Prediabetes New onset diabetes Hyocholic acid C4 HOMA-IR 12α-OH, BAs, Cohort Studies, chemistry.chemical_compound, impaired fasting glucose, insulin resistance, new onset diabetes, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, CA, IQR, TGR5, total cholesterol, RISC, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, ursodeoxycholic acid, lithocholic acid, Female, chenodeoxycholic acid, HDL-c, TG, type 2 diabetes, TC, Adult, cytochrome P450, 030209 endocrinology & metabolism, body mass index, Bile Acids and Salts, Prediabetic State, BMI, Insulin resistance, Predictive Value of Tests, Internal medicine, Diabetes mellitus, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], HbA 1C, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Impaired fasting glucose, hyodeoxycholic acid, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, ND, business, Follow-Up Studies, glycated hemoglobin
Abstract: International audience; Objective: Bile acids (BAs) are signaling molecules controlling lipid and glucose metabolism. Since BA alterations are associated with obesity and insulin resistance, plasma BAs have been considered candidates to predict type 2 diabetes (T2D) risk. We aimed to determine (1) the association of BAs with glucose homeostasis parameters and (2) their predictive association with the risk of conversion from prediabetes to new-onset diabetes (NOD) in a prospective cohort study. Design: 205 patients with impaired fasting glucose (IFG) were followed each year during 5 years in the IT-DIAB cohort study. Twenty-one BA species and 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA synthesis, were quantified by LC/MS-MS in plasma from fasted patients at baseline. Correlations between plasma BA species and metabolic parameters at baseline were assessed by Spearman's coefficients and the association between BAs and NOD was determined using Cox proportional-hazards models. Results: Among the analyzed BA species, total hyocholic acid (HCA) and the total HCA/total chenodeoxycholic acid (CDCA) ratio, reflecting hepatic BA 6α-hydroxylation activity, negatively correlated with BMI and HOMA-IR. The total HCA/total CDCA ratio also correlated negatively with HbA 1C. Conversion from IFG to NOD occurred in 33.7% of the participants during the follow-up. Plasma BA species were not independently associated with the conversion to NOD after adjustment with classical T2D risk factors. Conclusions: Fasting plasma BAs are not useful clinical biomarkers for predicting NOD in patients with IFG. However, an unexpected association between 6α-hydroxylated BAs and glucose parameters was found, suggesting a role for this specific BA pathway in metabolic homeostasis. IT-DIAB study registry number: NCT01218061.
Published: 2020
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28. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

Author: Caroline Imbert, Stéphane Carpentier, Nathalie Andrieu-Abadie, Marlène Marcellin, Marine Fraisse, Pierre Brousset, Florie Bertrand, Elodie Martin, Céline Colacios, Bruno Ségui, Philippe Rochaix, Odile Burlet-Schiltz, Nicolas Meyer, Virginie Garcia, Thierry Levade, Anne Montfort, Laurence Lamant, Anne Gonzalez de Peredo, Elie Marcheteau, Julia Gilhodes, Thomas Filleron, Florent Puisset, Sophie Tartare-Deckert, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Équipe labellisée Ligue Nationale Contre le Cancer [Toulouse], Ligue Nationale Contre le Cancer [Paris] (LNCC), Université Fédérale Toulouse Midi-Pyrénées, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Institut de pharmacologie et de biologie structurale (IPBS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], This work was supported by INSERM, Paul Sabatier University, Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisée 2013), INSERM Transfert, Cancéropôle Grand Sud-Ouest, ROTARY Toulouse clubs, Fondation Toulouse Cancer Santé and Fondation ARC (IMMUSPHINX project). The research leading to these results has received funding from the Transcan-2 Research Program, which is a transnational R&D program jointly funded by national funding organizations within the framework of the ERA-NET Transcan-2. C.I. is a recipient of a fellowship from LNCC and Fondation pour la Recherche Médicale (FRM). The IBiSA Toulouse Proteomics facility is supported by the following institutions: Région Midi-Pyrénées, Fonds Européens de Développement Régional, Toulouse Métropole, and the French Ministry of Research with the ‘Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program’ (Proteomics French Infrastructure project, ANR-10-INBS-08). P.B. is supported by the LABEX TOUCAN., ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-IDEX-0002-02/11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bodescot, Myriam, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID
Subjects: 0301 basic medicine, Male, Skin Neoplasms, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Melanoma, Experimental, General Physics and Astronomy, Cancer immunotherapy, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Tumour biomarkers, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, polycyclic compounds, Molecular Targeted Therapy, lcsh:Science, Melanoma, Mice, Inbred BALB C, Multidisciplinary, biology, Middle Aged, Cancer metabolism, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, Phosphotransferases (Alcohol Group Acceptor), medicine.anatomical_structure, Nivolumab, Sphingosine kinase 1, 030220 oncology & carcinogenesis, Veterinary medicine and animal Health, Female, hormones, hormone substitutes, and hormone antagonists, Regulatory T cell, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biotechnologies, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, Gene Expression Regulation, Enzymologic, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Gene silencing, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Aged, Tumor microenvironment, Sphingosine, business.industry, General Chemistry, Immunotherapy, medicine.disease, Médecine vétérinaire et santé animal, 030104 developmental biology, chemistry, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Tumor Escape, lcsh:Q, business
Abstract: Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy., There are many patients who do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Here, the authors show a significant negative correlation between sphingosine kinase-1 (SK1) expression and survival for ICI-treated melanoma patients, and further show that targeting SK1 improves response to ICI in mouse cancer models.
Published: 2020
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29. The ex planta signal activity of a Medicago ribosomal uL2 protein suggests a moonlighting role in controlling secondary rhizobial infection

Author: Sorroche, Fernando, Morales, Violette, Mouffok, Saïda, Pichereaux, Carole, Garnerone, A. Marie, Zou, Lan, Soni, Badrish, Carpéné, Marie-Anne, Gargaros, Audrey, Maillet, Fabienne, Burlet-Schiltz, Odile, Poinsot, Verena, Polard, Patrice, Gough, Clare, Batut, Jacques, Erist, Montpellier, Autoregulation de l'infection dans la symbiose rhizobium-legumineuses - - AOI2015 - ANR-15-CE20-0004 - AAPG2015 - VALID, BLANC - Signalisation par l'AMP cyclique et contrôle de l'infection chez Sinorhizobium meliloti, le symbiote de Medicago - - RhizocAMP2010 - ANR-10-BLAN-1719 - BLANC - VALID, Towards a Unified theory of biotic Interactions: the roLe of environmental - - TULIP2010 - ANR-10-LABX-0041 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Laboratoire des Interactions Plantes Microbes Environnement (LIPME), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de microbiologie et génétique moléculaires - UMR5100 (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Fédération de Recherche Agrobiosciences, Interactions et Biodiversité (FR AIB), Institut de pharmacologie et de biologie structurale (IPBS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Post-doctoral AGREENSKILLS fellowship, CSC PhD scholarship, INRA SPE post-doctoral fellowship, French Ministere de l'Enseignement superieur et de la Recherche, Agri Sud Ouest Innovation, European Union (EU), Toulouse Metropole, Region Occitanie, ANR-15-CE20-0004,AOI,Autoregulation de l'infection dans la symbiose rhizobium-legumineuses(2015), ANR-10-BLAN-1719,RhizocAMP,Signalisation par l'AMP cyclique et contrôle de l'infection chez Sinorhizobium meliloti, le symbiote de Medicago(2010), ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Laboratoire de microbiologie et génétique moléculaires (LMGM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: Protein Extraction, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, Plant Root Nodulation, Plant Roots, Cell Signaling, Gene Expression Regulation, Plant, Medicago, Medicine and Health Sciences, Plant Immunity, Post-Translational Modification, Flowering Plants, Plant Proteins, Extraction Techniques, Coinfection, Eukaryota, food and beverages, Fabaceae, Plants, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, Legumes, Signaling Cascades, Ethylene Signaling Cascade, Experimental Organism Systems, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cellular Structures and Organelles, Root Nodules, Plant, Signal Peptides, Research Article, Signal Transduction, Ribosomal Proteins, Science, Research and Analysis Methods, Genes, Plant, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, Model Organisms, Plant and Algal Models, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicago truncatula, Symbiosis, Organisms, Biology and Life Sciences, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Ethylenes, biochemical phenomena, metabolism, and nutrition, Health Care, Species Interactions, Animal Studies, Ribosomes, Sinorhizobium meliloti
Abstract: We recently described a regulatory loop, which we termed autoregulation of infection (AOI), by which Sinorhizobium meliloti, a Medicago endosymbiont, downregulates the root susceptibility to secondary infection events via ethylene. AOI is initially triggered by so-far unidentified Medicago nodule signals named signal 1 and signal 1’ whose transduction in bacteroids requires the S. meliloti outer-membrane-associated NsrA receptor protein and the cognate inner-membrane-associated adenylate cyclases, CyaK and CyaD1/D2, respectively. Here, we report on advances in signal 1 identification. Signal 1 activity is widespread as we robustly detected it in Medicago nodule extracts as well as in yeast and bacteria cell extracts. Biochemical analyses indicated a peptidic nature for signal 1 and, together with proteomic analyses, a universally conserved Medicago ribosomal protein of the uL2 family was identified as a candidate signal 1. Specifically, MtRPuL2A (MtrunA17Chr7g0247311) displays a strong signal activity that requires S. meliloti NsrA and CyaK, as endogenous signal 1. We have shown that MtRPuL2A is active in signaling only in a non-ribosomal form. A Medicago truncatula mutant in the major symbiotic transcriptional regulator MtNF-YA1 lacked most signal 1 activity, suggesting that signal 1 is under developmental control. Altogether, our results point to the MtRPuL2A ribosomal protein as the candidate for signal 1. Based on the Mtnf-ya1 mutant, we suggest a link between root infectiveness and nodule development. We discuss our findings in the context of ribosomal protein moonlighting. Copyright: © 2020 Sorroche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Published: 2020
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30. Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics

Author: Guillaume Voisinne, Bernard Malissen, Laura Girard, Odile Burlet-Schiltz, Daiki Mori, Javier Celis-Gutierrez, Yunhao Zhai, Anne Gonzalez de Peredo, Romain Roncagalli, Malissen, Bernard, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Decoding at systems-level the crosstalk between the T cell antigen receptor, the CD28 costimulator and the PD-1 coinhibitor under physiological and pathological conditions - BASILIC - 787300 - INCOMING, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), European Project: 787300,BASILIC, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Adaptive immunity, Receptors, Antigen, T-Cell, Mice, Transgenic, Signal transduction, HAVCR2, 03 medical and health sciences, 0302 clinical medicine, Correspondence, Immunology and Allergy, Animals, Hepatitis A Virus Cellular Receptor 2, biology, Cell adhesion molecule, Chemistry, Effector, Mucin, Acquired immune system, 3. Good health, Cell biology, 030104 developmental biology, Infectious Diseases, Cytoplasm, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, 030215 immunology, Protein Binding
Abstract: International audience; Deciphering how T-cell antigen receptor signals are modulated by coinhibitors is a fundamental goal in immunology and of considerable clinical interest because blocking coinhibitory signals via therapeutic antibodies have become a standard cancer immunotherapeutic strategy. Most of the attention devoted to T-cell immunoglobulin and mucin domain-3 (TIM3; also known as HAVCR2 or CD366) molecules stems from their expression on exhausted T cells in settings of chronic viral infection and tumors. Moreover, T cells expressing high levels of both PD-1 and TIM3 coinhibitors appear more dysfunctional than those expressing PD-1 alone. Combination therapies intending to block both PD-1 and TIM3 are thus actively being explored in the cancer treatment setting. Upon interaction with Galectin-9 (GAL-9) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), the tyrosines found in the TIM3 cytoplasmic tail are phosphorylated.1 Because these conserved tyrosines do not form a recognizable inhibitory signaling motif, the mechanism by which TIM3 transmits inhibitory signals has not been elucidated. Paradoxically, TIM3 also has costimulatory activity in T cells.2,3 Published biochemical studies attempting to unveil the mode of action of TIM3 have relied on approaches addressing one candidate effector at a time with limited quantitative insight, and most used transformed cells. Using mice expressing an affinity Twin-Strep-tag (OST) at the TIM3-protein C-terminus (TIM3OST mice) (Figs. 1a and S1a) and affinity purification coupled with mass spectrometry (AP-MS), we herein defined the composition and dynamics of the signaling protein complex (signalosome) used by TIM3 in primary effector T cells. These results provide a more complete model of TIM3 signaling and explain its paradoxical coinhibitory and costimulatory functions
Published: 2020
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31. Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling

Author: Jean C Shih, Yohan Santin, Damien Maggiorani, Olivier Lairez, Marlène Marcellin, Florence Tortosa, Pierre Sicard, Odile Burlet-Schiltz, Yannis Sainte-Marie, Jeanne Mialet-Perez, Loubina Fazal, Lise Teyssedre, Cécile Vindis, Angelo Parini, Jacques Rouquette, Yasemin Yücel Yücel, Frank Lezoualc'h, Mialet-Perez, Jeanne, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, EPAC1 : Une nouvelle cible thérapeutique dans les maladies rénales chroniques - - EPACK2017 - ANR-17-CE14-0014 - AAPG2017 - VALID, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement of Biochemistry [Istanbul, Turkey] (School of Pharmacy), Altinbas University [Istanbul, Turkey], Institut des Technologies Avancées en sciences du Vivant (ITAV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), University of Southern California (USC), This work was supported by grants from Agence Nationale pour la Recherche referenced as 'ANRJCJC CARDIOMAO', 'ProFIANR-10-INBS-08', 'ANR-17-CE14-0014-01', grants from European funds (FEDER), Fondazione Cariplo (2014-0672), Fondation pour la Recherche Médicale (équipe FRM2016, DEQ20160334892) and Région Occitanie., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-CE14-0014,EPACK,EPAC1 : Une nouvelle cible thérapeutique dans les maladies rénales chroniques(2017), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Southern California [Los Angeles, CA, USA], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), School of Pharmacy, Altinbas University, Istanbul, Turkey., University of Southern California, Los Angeles, CA, USA, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Yücel, Yasemin, Analytic and Computational Research, Inc. - Earth Sciences (ACRI-ST), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Mitochondrial ROS, [SDV]Life Sciences [q-bio], Myocardial Ischemia, Myocardial Infarction, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, Mitochondria, Heart, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cardiolipin, Myocytes, Cardiac, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Ventricular Remodeling, Chemistry, Whole Heart Imaging, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], Echocardiography, 030220 oncology & carcinogenesis, Monoamine oxidase A, Voltage-dependent anion channel, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Human Heart Tissues, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, Humans, Molecular Biology, Monoamine Oxidase, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ALDH2, Heart Failure, Aldehydes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Rats, Mice, Inbred C57BL, 030104 developmental biology, Monoamine neurotransmitter, Heart failure, biology.protein, Calcium, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: MIALET-PEREZ, Jeanne/0000-0002-1765-0283; O, Lairez/0000-0001-8141-6582; Sicard, Pierre/0000-0001-5837-3916; Vindis, Cecile/0000-0003-2421-1155; Schiltz, Odile/0000-0002-3606-2356; Santin, Yohan/0000-0002-9229-1161 WOS:000534930000012 PubMed: 31819159 Chronic remodeling postmyocardial infarction consists in various maladaptive changes including interstitial fibrosis, cardiomyocyte death and mitochondrial dysfunction that lead to heart failure (HF). Reactive aldehydes such as 4-hydroxynonenal (4-HNE) are critical mediators of mitochondrial dysfunction but the sources of mitochondrial 4-HNE in cardiac diseases together with its mechanisms of action remain poorly understood. Here, we evaluated whether the mitochondrial enzyme monoamine oxidase-A (MAO-A), which generates H2O2 as a by-product of catecholamine metabolism, is a source of deleterious 4-HNE in HF. We found that MAO-A activation increased mitochondrial ROS and promoted local 4-HNE production inside the mitochondria through cardiolipin peroxidation in primary cardiomyocytes. Deleterious effects of MAO-A/4-HNE on cardiac dysfunction were prevented by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), the main enzyme for 4-HNE metabolism. Mechanistically, MAO-A-derived 4-HNE bound to newly identified targets VDAC and MCU to promote ER-mitochondria contact sites and MCU higher-order complex formation. The resulting mitochondrial Ca2+ accumulation participated in mitochondrial respiratory dysfunction and loss of membrane potential, as shown with the protective effects of the MCU inhibitor, RU360. Most interestingly, these findings were recapitulated in a chronic model of ischemic remodeling where pharmacological or genetic inhibition of MAO-A protected the mice from 4-HNE accumulation, MCU oligomer formation and Ca2+ overload, thus mitigating ventricular dysfunction. To our knowledge, these are the first evidences linking MAO-A activation to mitoCa(2+) mishandling through local 4-HNE production, contributing to energetic failure and postischemic remodeling.
Published: 2020
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32. Pandoravirus Celtis Illustrates the Microevolution Processes at Work in the Giant Pandoraviridae Genomes

Author: Sandra Jeudy, Matthieu Legendre, Jean-Marie Alempic, Olivier Poirot, Sebastien Nin, Nadège Philippe, Audrey Lartigue, Chantal Abergel, Ngan Thi Ta, Jean-Michel Claverie, Yohann Couté, Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), This work was partially supported by the French National Research Agency (ANR-14-CE14-0023-01), France Genomique (ANR-10-INSB-01-01), Institut Français de Bioinformatique (ANR–11–INSB–0013), the Fondation Bettencourt-Schueller (OTP51251), by a DGA-MRIS scholarship, and by the Provence-Alpes-Côte-d’Azur région (2010 12125). Proteomic experiments were partly supported by the Proteomics French Infrastructure (ANR-10-INBS-08-01) and Labex GRAL (ANR-10-LABX-49-01). We thank the support of the discovery platform and informatics group at EDyP and the PACA-Bioinfo platform., ANR-14-CE14-0023,Pandoravirus,Caractérisation fonctionnelle et moléculaire des Pandoravirus(2014), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-11-INBS-0013,IFB (ex Renabi-IFB),Institut français de bioinformatique(2011), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Couté, Yohann, Appel à projets générique - Caractérisation fonctionnelle et moléculaire des Pandoravirus - - Pandoravirus2014 - ANR-14-CE14-0023 - Appel à projets générique - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Infrastructures - Institut français de bioinformatique - - IFB (ex Renabi-IFB)2011 - ANR-11-INBS-0013 - INBS - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID
Subjects: Microbiology (medical), lcsh:QR1-502, Acanthamoeba, comparative genomics, Microbiology, Genome, lcsh:Microbiology, 03 medical and health sciences, Intergenic region, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Giant Virus, giant viruses, Gene, Transposase, 030304 developmental biology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Comparative genomics, hAT transposase, 0303 health sciences, Pandoravirus, biology, 030306 microbiology, soil viruses, Microevolution, de novo gene creation, biology.organism_classification, Evolutionary biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pandoraviridae
Abstract: With genomes of up to 2.7 Mb propagated in µm-long oblong particles and initially predicted to encode more than 2000 proteins, members of the Pandoraviridae family display the most extreme features of the known viral world. The mere existence of such giant viruses raises fundamental questions about their origin and the processes governing their evolution. A previous analysis of six newly available isolates, independently confirmed by a study including 3 others, established that the Pandoraviridae pan-genome is open, meaning that each new strain exhibits protein-coding genes not previously identified in other family members. With an average increment of about 60 proteins, the gene repertoire shows no sign of reaching a limit and remains largely coding for proteins without recognizable homologs in other viruses or cells (ORFans). To explain these results, we proposed that most new protein-coding genes were created de novo, from pre-existing non-coding regions of the G+C rich pandoravirus genomes. The comparison of the gene content of a new isolate, P. celtis, closely related (96% identical genome) to the previously described P. quercus is now used to test this hypothesis by studying genomic changes in a microevolution range. Our results confirm that the differences between these two similar gene contents mostly consist of protein-coding genes without known homologs (ORFans), with statistical signatures close to that of intergenic regions. These newborn proteins are under slight negative selection, perhaps to maintain stable folds and prevent protein aggregation pending the eventual emergence of fitness-increasing functions. Our study also unraveled several insertion events mediated by a transposase of the hAT family, 3 copies of which are found in P. celtis and are presumably active. Members of the Pandoraviridae are presently the first viruses known to encode this type of transposase.
Published: 2019
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33. Five simple yet essential steps to correctly estimate the rate of false differentially abundant proteins in mass spectrometry analyses

Author: Thomas Burger, Quentin Giai Gianetto, Samuel Wieczorek, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the French National Research Agency: ProFI project (ANR-10-INBS-08), GRAL project (ANR-10-LABX-49-01) and SYMER project (ANR-15-IDEX-02), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Burger, Thomas, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: Proteomics, 0301 basic medicine, False discovery rate, Proteome, Computer science, Process (engineering), Quantitative proteomics, Biophysics, Machine learning, computer.software_genre, Biochemistry, Mass Spectrometry, 03 medical and health sciences, Software, Simple (abstract algebra), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], False Positive Reactions, Selection (genetic algorithm), Data processing, 030102 biochemistry & molecular biology, business.industry, Experimental data, Models, Theoretical, 030104 developmental biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Artificial intelligence, business, computer
Abstract: International audience; Results from mass spectrometry based quantitative proteomics analysis correspond to a subset of proteins which are considered differentially abundant relative to a control. Their selection is delicate and often requires some statistical expertise in addition to a refined knowledge of the experimental data. To facilitate the selection process, we have considered differential analysis as a five-step process, and here we present the practical aspects of the different steps. Prostar software is used throughout this article for illustration, but the general methodology is applicable with many other tools. By applying the approach detailed here, researchers who may be less familiar with statistical considerations can be more confident in the results they present.
Published: 2019
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34. The architecture of lipid droplets in the diatom Phaeodactylum tricornutum

Author: Khawla Seddiki, Juliette Salvaing, Fabrice Rébeillé, Juliette Jouhet, Denis Falconet, Sabine Brugière, Yohann Couté, Eric Maréchal, Marcel Kuntz, Pierre-Henri Jouneau, Hubert Schaller, Antoine Jaussaud, Josselin Lupette, Marianne Tardif, Christian Morabito, Jean-Luc Putaux, LIPID, Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Dynamique du protéome et biogenèse du chloroplaste (ChloroGenesis), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire d'Etude des Matériaux par Microscopie Avancée (LEMMA ), Modélisation et Exploration des Matériaux (MEM), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Flagship program from the CEA High Commissioner, French National Research Agency (ANR) ANR-11-BTBR-0008 ANR-15-IDEX-02 ANR-10-INBS-08, ANR-11-BTBR-0008,OCEANOMICS,Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques(2011), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Etude de la dynamique des protéomes (EDyP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire d'Etude des Matériaux par Microscopie Avancée (LEMMA), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), ANR-11-BTBR-0008/11-BTBR-0008,OCEANOMICS,Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques(2011), ANR-15-IDEX-02,DATA@UGA,Grenoble Alpes Data Institute(2016), ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Jouneau, Pierre-Henri, Biotech - Bioressources - Biotechnologies et bioressources pour la valorisation des écosystèmes marins planctoniques - - OCEANOMICS2011 - ANR-11-BTBR-0008 - BTBR - VALID, IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: 0106 biological sciences, 0301 basic medicine, Betaine lipid, Phaeodactylum, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 01 natural sciences, Ribosome, Triacylglycerol, [SDV.BV.BOT] Life Sciences [q-bio]/Vegetal Biology/Botanics, Histones, 03 medical and health sciences, Lipid droplet, Protein biosynthesis, ERAD pathway, Phaeodactylum tricornutum, Plastid, Secondary plastid, ComputingMilieux_MISCELLANEOUS, Diatoms, biology, Chemistry, Endoplasmic reticulum, fungi, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, Lipid droplets, Carotenoids, 030104 developmental biology, Biochemistry, Proteome, Agronomy and Crop Science, 010606 plant biology & botany
Abstract: International audience; Diatoms are a major phylum of phytoplankton biodiversity and a resource considered for biotechnological developments, as feedstock for biofuels and applications ranging from food, human health or green chemistry. They contain a secondary plastid limited by four membranes, the outermost one being connected with the endoplasmic reticulum (ER). Upon nitrogen stress, diatoms reallocate carbon to triacylglycerol storage inside lipid droplets (LDs). The comprehensive glycerolipid and sterol composition and the architecture of diatom LDs are unknown. In Phaeodactylum tricornutum, LDs are in contact with plastid, mitochondria and uncharacterized endomembranes. We purified LDs from nitrogen-starved P. tricornutum cells to high purity level (99 mol% triacylglycerol of total glycerolipids). We used the Stramenopile Lipid Droplet Protein (StLDP) as a previously validated marker for the identity of P. tricornutum LD. Amphipathic lipids surrounding LDs consist of a betaine lipid, diacylglycerylhydroxymethyltrimethyl-beta-alanine (0.4 mol%); sulfoquinovosyldiacylglycerol (0.35 mol%); phosphatidylcholine (0.15 mol%) and one sterol, brassicasterol. By contrast with whole cell extracts, the betaine lipid from LDs only contains eicosapentaenoic acid paired with palmitoleic or palmitolenic acids. This polar lipid composition suggests a budding of LDs from the cytosolic leaflet of the plastid outermost membrane. LD pigments reveal a specific accumulation of beta-carotene. The LD proteome obtained from three independent biological replicates, based on stringent filtering of extracted data, and following subtraction of proteins downregulated by nitrogen starvation, highlights a core proteome of 86 proteins, including StLDP. LD-associated proteins suggest connections with vesicular trafficking (coatomer, clathrin), cytoskeleton, plastid and mitochondria. Unsuspected LD-associated function includes protein synthesis (ribosomes), folding (chaperones), posttranslational modifications and quality control (ubiquitination and ERAD pathway), possibly preparing translation of specific mRNAs. The detection of histone proteins, as previously demonstrated in drosophila embryo LDs, also suggests the storage of nucleosome components, preparing cell division and chromatin packaging, when cells are not stressed anymore.
Published: 2019
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35. Diversity and evolution of the emerging $Pandoraviridae$ family

Author: Legendre, Matthieu, Fabre, Elisabeth, Poirot, Olivier, Jeudy, Sandra, Lartigue, Audrey, Alempic, Jean-Marie, Beucher, Laure, Philippe, Nadège, Bertaux, Lionel, Christo-Foroux, Eugène, Labadie, Karine, Couté, Yohann, Abergel, Chantal, Claverie, Jean-Michel, Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), This work was partially supported by the French National Research Agency (ANR-14-CE14-0023-01), France Genomique (ANR-10-INSB-01-01), Institut Français de Bioinformatique (ANR–11–INSB–0013), the Fondation Bettencourt-Schueller (OTP51251), by a DGA-MRIS scholarship, and by the Provence-Alpes-Côte-d’Azur région (2010 12125)., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Etude de la dynamique des protéomes (EDyP), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Laboratoire Adaptation et pathogénie des micro-organismes [Grenoble] (LAPM), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-49-01,Labex GRAL, Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Équipe Services et Architectures pour Réseaux Avancés (LAAS-SARA), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] (LAAS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées, Poirot, Olivier, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Proteomics, Gene Transfer, Horizontal, Science, [SDV]Life Sciences [q-bio], DNA Viruses, Virion, Genetic Variation, Acanthamoeba, Molecular Sequence Annotation, Genome, Viral, Sequence Analysis, DNA, Virus Replication, Article, Evolution, Molecular, Gene Duplication, DNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Environmental Microbiology, lcsh:Q, lcsh:Science, human activities, Phylogeny, ComputingMilieux_MISCELLANEOUS
Abstract: With DNA genomes reaching 2.5 Mb packed in particles of bacterium-like shape and dimension, the first two Acanthamoeba-infecting pandoraviruses remained up to now the most complex viruses since their discovery in 2013. Our isolation of three new strains from distant locations and environments is now used to perform the first comparative genomics analysis of the emerging worldwide-distributed Pandoraviridae family. Thorough annotation of the genomes combining transcriptomic, proteomic, and bioinformatic analyses reveals many non-coding transcripts and significantly reduces the former set of predicted protein-coding genes. Here we show that the pandoraviruses exhibit an open pan-genome, the enormous size of which is not adequately explained by gene duplications or horizontal transfers. As most of the strain-specific genes have no extant homolog and exhibit statistical features comparable to intergenic regions, we suggest that de novo gene creation could contribute to the evolution of the giant pandoravirus genomes., Giant viruses are visible by light microscopy and have unusually long genomes. Here, the authors report three new members of the Pandoraviridae family and investigate their evolution and diversity.
Published: 2018
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36. CD5, an Undercover Regulator of TCR Signaling

Author: Guillaume, Voisinne, Anne, Gonzalez de Peredo, Romain, Roncagalli, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ANR-17-CE15-0008,LYMPHOSCAN,Stucture et dynamique des reseaux de signalisation qui controllent la différentiation et les fonctionnalités des lymphocytes T primaires(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), DUMENIL, Anita, Stucture et dynamique des reseaux de signalisation qui controllent la différentiation et les fonctionnalités des lymphocytes T primaires - - LYMPHOSCAN2017 - ANR-17-CE15-0008 - AAPG2017 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Infrastructures - INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS - - PHENOMIN2010 - ANR-10-INBS-0007 - INBS - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: lcsh:Immunologic diseases. Allergy, [SDV.IMM] Life Sciences [q-bio]/Immunology, T-Lymphocytes, Immunology, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, TCR-T cell receptor, CD5 Antigens, Lymphocyte Activation, coreceptor, inhibition, CD5, Mice, signaling/signaling pathways, Models, Animal, Perspective, Animals, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:RC581-607
Abstract: International audience; T cells are critical components of adaptive immunity. As such, their activation is regulated by the T cell receptor (TCR) that constantly scan peptides associated with major histocompatibility complexes (MHC). TCR engagement initiates a series of molecular events leading to cytokine secretion, proliferation, and differentiation of T cells. As a second coincident event, activation of co-stimulatory molecules, such as CD28, synergize with the TCR in order to prolong and/or amplify intracellular signals. With the recent advances in immunotherapies targeting T cells, co-inhibitory receptors are of growing interest for immunologists due to their potential modulatory properties on T cell functions. However, special attention should be dedicated to avoid unwanted clinical outcomes (1). In particular, Manichean categorization of receptors based on incomplete functional knowledge can lead to an over-simplistic view of complex cellular regulations. Thus, analysis of the functions that characterize these receptors in diverse physiological contexts remains essential for their rational use in therapeutic protocols. Here we focus on CD5, a transmembrane receptor that regulates T cell functions and development but remains poorly characterized at the molecular level. We will review its roles in physiological conditions and suggest potential molecular effectors that could account for CD5-dependent regulation of TCR signaling.
Published: 2018
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37. Validating Missing Proteins in Human Sperm Cells by Targeted Mass-Spectrometry- and Antibody-based Methods

Author: Yves Vandenbrouck, Charlotte Macron, Thomas Fréour, Lydie Lane, Karine Rondel, Charles Pineau, Paula D. Duek, François Delalande, Christine Carapito, Marine Seffals, Cecilia Lindskog, Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Swiss Institute of Bioinformatics [Genève] (SIB), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Uppsala University, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), French National Agency for Research (ANR) [ANR-10-INBS-08], Biogenouest, Infrastructures en Biologie Sante et Agronomie (IBiSA), Conseil Regional de Bretagne, ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Lausanne (UNIL), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Equipe Direction scientifique, Sciences et Technologies de la Musique et du Son (STMS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-IRCAM-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Département de science des protéines humaines [Genève], Université de Genève (UNIGE)-Faculté de médecine [Genève], Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: 0301 basic medicine, Male, Proteome, [SDV]Life Sciences [q-bio], Tandem mass spectrometry, Biochemistry, immunocytochemistry, Tandem Mass Spectrometry, Testis, Human proteome project, ComputingMilieux_MISCELLANEOUS, ddc:616, biology, Histocytochemistry, bioinformatics, Immunohistochemistry, Spermatozoa, [SDV] Life Sciences [q-bio], spermatozoon, Chromosomes, Human, Pair 2, immunohistochemistry, Antibody, missing proteins, Human, human proteome project, targeted proteomics, Octoxynol, Human Protein Atlas, Context (language use), Computational biology, Chromosomes, Antibodies, 03 medical and health sciences, Spermatozoa/chemistry, Proteome/analysis, Humans, Chromosomes, Human, Pair 14, 030102 biochemistry & molecular biology, Testis/chemistry, General Chemistry, data mining, Sperm, Molecular biology, parallel reaction monitoring, 030104 developmental biology, Targeted mass spectrometry, biology.protein, Pair 14/genetics, Pair 2/genetics
Abstract: The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the 50 most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass-spectrometry-based strategy consisting of the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used. Out of the 38 selected MPs, 12 were identified with two or more peptides and 3 with one peptide after extensive SDS-PAGE fractionation of the two samples and with overall low-intensity signals. The PRM data are available via ProteomeXchange in PASSEL (PASS01013). Further validation by immunohistochemistry on human testes sections and cytochemistry on sperm smears was performed for eight MPs with antibodies available from the Human Protein Atlas. Deep analysis of human sperm still allows the validation of MPs and therefore contributes to the C-HPP worldwide effort. We anticipate that our results will be of interest to the reproductive biology community because an in-depth analysis of these MPs may identify potential new candidates in the context of human idiopathic infertilities.
Published: 2017
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38. Looking for Missing Proteins in the Proteome of Human Spermatozoa: An Update

Author: Yves Vandenbrouck, Marlène Marcellin, Thomas Fréour, Anne-Marie Hesse, Karima Chaoui, Christine Carapito, Christophe Bruley, Anne Gonzalez de Peredo, Karine Rondel, Emmanuelle Mouton-Barbosa, Thibault Robin, Jérôme Garin, Charlotte Macron, Charles Pineau, Lydie Lane, Sarah Cianférani, Paula D. Duek, Loren Méar, Cecilia Lindskog, Myriam Ferro, Emmanuelle Com, Alain Gateau, Yohann Couté, Odile Burlet-Schiltz, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de science des protéines humaines [Genève], Université de Genève = University of Geneva (UNIGE)-Faculté de médecine [Genève], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Swiss Institute of Bioinformatics [Genève] (SIB), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Proteomics Core Facility (Protim), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Uppsala University, ANR-10-INBS-08, Agence Nationale de la Recherche, Conseil Régional de Bretagne, Biogenouest, ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève (UNIGE)-Faculté de médecine [Genève], Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Bertacchi Griffi, Nathalie, and Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID
Subjects: Male, Proteomics, 0301 basic medicine, human proteome project, Proteome, [SDV]Life Sciences [q-bio], Peptide, Computational biology, Biology, Bioinformatics, Biochemistry, 03 medical and health sciences, Expression pattern, Tandem Mass Spectrometry, Testis, Protein purification, Human proteome project, Humans, ddc:576, Databases, Protein, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 030102 biochemistry & molecular biology, NeXtProt, cilia, General Chemistry, data mining, bioinformatics, Spermatozoa, mass spectrometry proteomics, [SDV] Life Sciences [q-bio], 030104 developmental biology, chemistry, spermatozoon, immunohistochemistry, Human testis, missing proteins, Chromatography, Liquid
Abstract: The Chromosome-Centric Human Proteome Project aims to identify proteins classed as « missing » in the neXtProt knowledgebase. In this article, we present an in-depth proteomics analysis of the human sperm proteome to identify testis-enriched missing proteins. Using a range of protein extraction procedures and LC-MS/MS analysis, we detected a total of 235 proteins (PE2-PE4) for which no previous evidence of protein expression was annotated. Through a combination of LC-MS/MS and LC-PRM analysis, data mining and immunohistochemistry, we were able to confirm the expression of 206 missing proteins (PE2-4) in line with current HPP guidelines (version 2.0). Parallel Reaction Monitoring (PRM) acquisition combined with synthetic heavy labeled peptides was used to target 36 « one-hit wonder » candidates selected on the basis of prior PSM assessment. Of this subset of candidates, 24 were validated with additional predicted and specifically targeted peptides. Evidence was found for a further 16 missing proteins using immunohistochemistry on human testis sections. The expression pattern for some of these proteins was specific to the testis, and they could potentially be valuable markers with applications in fertility assessment. Strong evidence was also found for the existence of 4 proteins labeled as "uncertain" (PE5); the status of these proteins should therefore be re-examined. Our results show how the use of a range of sample preparation techniques combined with MS-based analysis, expert knowledge and complementary antibody-based techniques can produce data of interest to the community. All MS/MS data are available via ProteomeXchange under identifier PXD003947. In addition to contributing to the Chromosome-Centric Human Proteome Project, we hope the availability of these data will stimulate the continued exploration of the sperm proteome.
Published: 2016
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39. Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation

Author: Voisinne, Guillaume, García-Blesa, Antonio, Chaoui, Karima, Fiore, Frédéric, Bergot, Elise, Girard, Laura, Malissen, Marie, Burlet-Schiltz, Odile, Gonzalez de Peredo, Anne, Malissen, Bernard, Roncagalli, Romain, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by CNRS, INSERM, European Research Council (FP7/2007–2013 grant no. 322465 ('Integrate') to B.M), Agence Nationale de la Recherche (PHENOMIN project to B.M. and Basilic project to M.M.), the Investissement d’Avenir program ProFI (Proteomics French Infrastructure project, ANR-10-INBS-08) and PHENOMIN (French National Infrastructure for Mouse Phenogenomics), Région Midi-Pyrénées, and by fellowships from the Integrate project (G.V. and E.B.), the NANOASIT Euronanomed project (A.G.B.), and the PHENOMIN project (L.G.)., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: grant no. 322465,' Integrate ', Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Roncagalli, Romain, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, European Research Council - FP 7 / 2007 – 2013 - ' Integrate ' - grant no. 322465 - INCOMING, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: CBL, [SDV.IMM] Life Sciences [q-bio]/Immunology, hemic and lymphatic diseases, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Proteolysis & Proteomics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ubiquitylation Subject Categories Immunology, CD5, Post-translational Modifications, CBLB, Signal Transduction
Abstract: International audience; T-cell receptor (TCR) signaling is essential for the function of T cells and negatively regulated by the E3 ubiquitin–protein ligases CBL and CBLB. Here, we combined mouse genetics and affinity purification coupled to quantitative mass spectrometry to monitor the dynamics of the CBL and CBLB signaling complexes that assemble in normal T cells over 600 seconds of TCR stimulation. We identify most previously known CBL and CBLB interacting partners, as well as a majority of proteins that have not yet been implicated in those signaling complexes. We exploit correlations in protein association with CBL and CBLB as a function of time of TCR stimulation for predicting the occurrence of direct physical association between them. By combining co-recruitment analysis with biochemical analysis, we demonstrated that the CD5 transmem-brane receptor constitutes a key scaffold for CBL-and CBLB-mediated ubiquitylation following TCR engagement. Our results offer an integrated view of the CBL and CBLB signaling complexes induced by TCR stimulation and provide a molecular basis for their negative regulatory function in normal T cells.
Published: 2016
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40. No plastidial calmodulin-like proteins detected by two targeted mass-spectrometry approaches and GFP fusion proteins

Author: Daniel Salvi, Mathieu Baudet, Martine Neveu, Elisa Dell’Aglio, Myriam Ferro, Alexandra Kraut, David Macherel, Norbert Rolland, Gilles Curien, Martin-Laffon, Jacqueline, BLANC - Régulation de la dynamique du protéome chloroplastique - - Chloro-Pro2010 - ANR-10-BLAN-1610 - BLANC - VALID, Mediterranean Center for Environment and Biodiversity - - CeMEB2010 - ANR-10-LABX-0004 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, ANR [ANR-2010-BLAN-1610-01 Chloro-Pro], Labex GRAL (Alliance Grenobloise pour la Biologie Structurale et Cellulaire Integrées : [ANR-10-LABEX-04], [ANR10-INSB-08 ProFI, Proteomics French Infrastructure], CEA DSV (IRTELIS International Program)., ANR-10-BLAN-1610,Chloro-Pro,Régulation de la dynamique du protéome chloroplastique(2010), ANR-10-LABX-0004,CeMEB,Mediterranean Center for Environment and Biodiversity(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Etude de la dynamique des protéomes (EDyP), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), ANR–10–LABEX–04 ,GRAL,Labex, ANR10-INSB-08,ProFI,Proteomics French Infrastructure, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: 0301 basic medicine, Proteomics, Calmodulin, Arabidopsis thaliana, Plastid, Plant Science, Vacuole, Mitochondrion, plastide, Biochemistry, Chloroplast, CaM-like protein, Purification protocol, 03 medical and health sciences, Cytosol, GFP fusion, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, calmoduline, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, protéomique, Molecular Biology, biology, chloroplaste, Mass spectrometry, Subcellular localization, Protein, Plant, Peroxisome, Cell biology, 030104 developmental biology, Targeted mass spectrometry, biology.protein, Calcium regulation, CaM-like proteins
Abstract: Supplementary data: http://dx.doi.org/10.1016/j.neps.2016.08.001; International audience; Background: CaM-like proteins (CMLs) are localized in the cytosol and others in organelles such as the mitochondria, the peroxisomes and the vacuole. To date, although several plastidial proteins were identified as CaM/CML interactors, no CMLs were assigned to the chloroplast. Absence of clues about the genetic identity of plastidial CMLs prevents investigating their regulatory role. Results: To improve our understanding of plastidial Ca2+ regulation, we attempted to identify plastidial CMLs with two large scale, CaM-specific proteomic approaches, and GFP-fusions. Conclusions: Despite the use of several different approaches no plastidial CML could be identified. GFP fusion of CML 35 CML36 and CML41 indicate a cytosolic localization.
Published: 2016
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41. A Receptor Pair with an Integrated Decoy Converts Pathogen Disabling of Transcription Factors to Immunity

Author: Hiroaki Adachi, Hirofumi Yoshioka, Marie Levaillant, Jane E. Parker, Binbin Zhou, Laurent Deslandes, Clémentine Le Roux, Alain Jauneau, Dominique Tremousaygue, Alexandra Kraut, Sylvain Raffaele, Gaëlle Huet, Yohann Couté, Laurent Camborde, Richard Berthomé, Laboratoire des interactions plantes micro-organismes (LIPM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Department of Plant Microbe Interactions, Max Planck Institute for Plant Breeding Research (MPIPZ), Plateforme Imagerie [Castanet-Tolosan] (IFR 3450 - Pôle de Biotechnologie Végétale), Institut Fédératif de Recherche, Laboratoire de Recherche en Sciences Végétales (LRSV), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Etude de la dynamique des protéomes (EDyP), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Defense in Plant-Pathogen Interactions [Nagoya, Japan], Nagoya University-Graduate School of Bioagricultural Sciences [Nagoya, Japan], L.D. and G.H. were supported by a research grant from the Agence Nationale pour la Recherche (ANR, ANR-10-JCJC-1706). C.L.R. was funded by fellowships from INRA Contrat Jeune Scientifique and the Max Planck Society. This work was supported by the French Laboratory of Excellence project ‘‘TULIP’’ (ANR-10-LABX-41, ANR-11-IDEX-0002-02). A.K. and Y.C. were supported by the CNRS, INSERM, CEA, and ANR (Investissement d’Avenir Infrastructures, ProFi project ANR-10-INBS-08-01). H.Y. is supported by Grant-in-Aid from Japan Society of the Promotion of Science (26292023). S.R. is supported by a Starting Grant of the European Research Council (ERC-StG 336808 project VariWhim). J.E.P. is supported by the Max-Planck Society, DFG SFB grant 670, and the Cluster of Excellence on Plant Sciences (CEPLAS)., ANR-10-JCJC-1706,PERCEPtome,Identification des cibles de l'effecteur de type III PopP2, impliquées dans un complexe de perception R/Avr(2010), ANR-11-IDEX-0002-02/10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2011), ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 336808,EC:FP7:ERC,ERC-2013-StG,VARIWHIM(2013), Couté, Yohann, Jeunes Chercheuses et Jeunes Chercheurs - Identification des cibles de l'effecteur de type III PopP2, impliquées dans un complexe de perception R/Avr - - PERCEPtome2010 - ANR-10-JCJC-1706 - JCJC - VALID, Initiative d'excellence - Université Fédérale de Toulouse - - UNITI2011 - ANR-11-IDEX-0002 - IDEX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Understanding White Mold disease quantitative resistance using natural variation - VARIWHIM - - EC:FP7:ERC2013-11-01 - 2018-10-31 - 336808 - VALID, Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Interactions Microbiennes dans la Rhizosphère et les Racines, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-11-IDEX-0002,UNITI,Université Fédérale de Toulouse(2011), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, 0106 biological sciences, [SDV]Life Sciences [q-bio], Arabidopsis, Virulence, Biology, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, chemistry.chemical_compound, Acetyltransferases, Gene expression, Gene, Transcription factor, Plant Proteins, 030304 developmental biology, Genetics, Regulation of gene expression, 0303 health sciences, Arabidopsis Proteins, Effector, Biochemistry, Genetics and Molecular Biology(all), DNA, WRKY protein domain, Cell biology, [SDV] Life Sciences [q-bio], chemistry, Ralstonia solanacearum, Transcription Factors, 010606 plant biology & botany
Abstract: Comment in Treasure your exceptions: unusual domains in immune receptors reveal host virulence targets. [Cell. 2015]; International audience; Microbial pathogens infect host cells by delivering virulence factors (effectors) that interfere with defenses. In plants, intracellular nucleotide-binding/leucine-rich repeat receptors (NLRs) detect specific effector interference and trigger immunity by an unknown mechanism. The Arabidopsis-interacting NLR pair, RRS1-R with RPS4, confers resistance to different pathogens, including Ralstonia solanacearum bacteria expressing the acetyltransferase effector PopP2. We show that PopP2 directly acetylates a key lysine within an additional C-terminal WRKY transcription factor domain of RRS1-R that binds DNA. This disrupts RRS1-R DNA association and activates RPS4-dependent immunity. PopP2 uses the same lysine acetylation strategy to target multiple defense-promoting WRKY transcription factors, causing loss of WRKY-DNA binding and transactivating functions needed for defense gene expression and disease resistance. Thus, RRS1-R integrates an effector target with an NLR complex at the DNA to switch a potent bacterial virulence activity into defense gene activation.
Published: 2015
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42. Selective BET bromodomain inhibition as an antifungal therapeutic strategy

Author: Marie Courçon, Charles E. McKenna, Murielle Chauvel, Jérôme Govin, Morgane Champleboux, Danièle Maubon, Flore Mietton, Didier Spittler, Christophe d'Enfert, Ninon Zala, Boris A. Kashemirov, Cécile Garnaud, Carlo Petosa, Muriel Cornet, Michael B. Harbut, Yingsheng Zhou, Mitchell V. Hull, Elena Ferri, Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Chemistry, University of Southern California (USC), Institut de Biologie et Pathologie, CHU Grenoble, California Institute for Biomedical Research - calibr, Scripps Research Institute, Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), This work used the platforms of the Grenoble Instruct Center (ISBG: UMS 3518 CNRS-CEA-UJF-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01) within the Grenoble Partnership for Structural Biology. We acknowledge the European Synchrotron Radiation Facility for provision of synchrotron radiation facilities and thank EMBL and ESRF staff for assistance at beamlines ID23-2, ID29 and ID30A-1, particularly M. Bowler and D. de Sanctis. We thank Myriam Ferro and Christophe Bruley for their general support, Sandrine Miesch-Fremy and Marie Arlotto for technical support, Joanna Timmins for access to and help with the CLARIOstar plate reader, Inah Kang for administrative support and EDyP team members for scientific discussions. This work was supported by grants from the FACE foundation (Partner University Fund to C.E.M. and C.P.), the National Institutes of Health (1R21AI113704 to C.E.M.), the Agence Nationale de Recherche (ANR-14-CE16-0027-01 (FungiBET) to C.P., J.G. and M.Co., ANR-11-PDOC-011-01 (EpiGam) to J.G., ANR-10-INBS-08 (ProFI) to J.G., ANR-10-LABX-62-IBEID to C.D.), the EU FP7 Marie Curie Action (Career Integration Grant 304003 to J.G.) aswell as by the USC Dornsife College of Letters, Arts and Sciences (E.F. and C.E.M.), a Chateaubriand Fellowship (E.F.) and a FINOVI fellowship from the Region Rhone Alpes, France (M.Cham.)., ANR-14-CE16-0027,FungiBET,Etude d'une nouvelle cible thérapeutique anti-fongique potentielle: structure, fonction et inhibition des bromodomaines BET fongiques(2014), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-11-PDOC-0011,EpiGam,Epigénétique et dynamique chromatinienne des gamètes : modèle 'spores de levure' et protéomique(2011), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), The Scripps Research Institute [La Jolla, San Diego], Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), ANR: FungiBET,ANR-14-CE16-0027-01, ANR-10-INBS-05-01/10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049/10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-11-PDOC-0011,EpiGam,Epigénétique et dynamique chromatinienne des gamètes : modèle spores de levure et protéomique(2011), ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0062/10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Etude de la dynamique des protéomes (EDyP), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-VetAgro Sup (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-VetAgro Sup (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), This work was supported by grants from the FACE foundation (Partner University Fund to C.E.M. and C.P.), the National Institutes of Health (1R21AI113704 to C.E.M.), the Agence Nationale de Recherche (ANR-14-CE16-0027-01 (FungiBET) to C.P., J.G. and M.Co., ANR-10-LABX-62-IBEID to C.D.), the EU FP7 Marie Curie Action (Career Integration Grant 304003 to J.G.) as well as by the USC Dornsife College of Letters, Arts and Sciences (E.F. and C.E.M.), a Chateaubriand Fellowship (E.F.) and a FINOVI fellowship from the Région Rhône Alpes, France (M.Cham.)., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), European Project: 304003,EC:FP7:PEOPLE,FP7-PEOPLE-2011-CIG,EPIGAM2(2012), McKenna, Charles E., Govin, Jérôme, Petosa, Carlo, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Thomas, Frank, Appel à projets générique - Etude d'une nouvelle cible thérapeutique anti-fongique potentielle: structure, fonction et inhibition des bromodomaines BET fongiques - - FungiBET2014 - ANR-14-CE16-0027 - Appel à projets générique - VALID, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Retour Post-Doctorants - Epigénétique et dynamique chromatinienne des gamètes : modèle 'spores de levure' et protéomique - - EpiGam2011 - ANR-11-PDOC-0011 - RPDOC - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID
Subjects: 0301 basic medicine, Models, Molecular, Antifungal Agents, Pyridines, Antifungal drug, General Physics and Astronomy, Gene Expression, Protein-Degradation, Plasma protein binding, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Crystallography, X-Ray, Salt Stress, Protein Structure, Secondary, Benzodiazepines, Mice, Small-Molecule Inhibitors, Candida albicans, Validation, Molecular Targeted Therapy, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Fungal protein, Multidisciplinary, Crystallography, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Candidiasis, hemic and immune systems, Acetylation, Azepines, Corpus albicans, Recombinant Proteins, Chromatin, 3. Good health, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Protein Binding, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Science, 030106 microbiology, Virulence, chemical and pharmacologic phenomena, General Biochemistry, Genetics and Molecular Biology, Histone Deacetylases, Fungal Proteins, 03 medical and health sciences, Species Specificity, Candida-Albicans, Animals, Humans, Saccharomyces-Cerevisiae, Protein Interaction Domains and Motifs, Amino Acid Sequence, Binding Sites, Sequence Homology, Amino Acid, General Chemistry, Triazoles, biology.organism_classification, In vitro, Bromodomain, 030104 developmental biology, Immunology, Azabicyclo Compounds, Sequence Alignment, Transcription Factors
Abstract: Invasive fungal infections cause significant morbidity and mortality among immunocompromised individuals, posing an urgent need for new antifungal therapeutic strategies. Here we investigate a chromatin-interacting module, the bromodomain (BD) from the BET family of proteins, as a potential antifungal target in Candida albicans, a major human fungal pathogen. We show that the BET protein Bdf1 is essential in C. albicans and that mutations inactivating its two BDs result in a loss of viability in vitro and decreased virulence in mice. We report small-molecule compounds that inhibit C. albicans Bdf1 with high selectivity over human BDs. Crystal structures of the Bdf1 BDs reveal binding modes for these inhibitors that are sterically incompatible with the human BET-binding pockets. Furthermore, we report a dibenzothiazepinone compound that phenocopies the effects of a Bdf1 BD-inactivating mutation on C. albicans viability. These findings establish BET inhibition as a promising antifungal therapeutic strategy and identify Bdf1 as an antifungal drug target that can be selectively inhibited without antagonizing human BET function.
Published: 2017
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43. Pandoraviruses: Amoeba Viruses with Genomes Up to 2.5 Mb Reaching That of Parasitic Eukaryotes

Author: Nadège Philippe, Lionel Bertaux, Chantal Abergel, Christophe Bruley, Virginie Seltzer, Defne Arslan, Matthieu Legendre, Olivier Poirot, Yohann Couté, Gabriel Doutre, Magali Lescot, Jean-Michel Claverie, Jérôme Garin, Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes (UGA), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), ANR-08-BLAN-0089,MIMIVIRUS,Etude de la relation hôte pathogène du système Acanthamoeba/Mimivirus(2008), ANR-09-GENM-0032,TARA-GIRUS(2009), ANR-10-INBS-08-01/10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), European Project: 227799,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2008-1,ASSEMBLE(2009), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), ANR-09-GENM-0032,TARA-GIRUS,Inventaire et ressources génétiques de virus géants à ADN dans les milieux marins sur Tara-Oceans(2009), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Savelli, Bruno, Blanc - Etude de la relation hôte pathogène du système Acanthamoeba/Mimivirus - - MIMIVIRUS2008 - ANR-08-BLAN-0089 - BLANC - VALID, Génomique et biotechnologies végétales - Inventaire et ressources génétiques de virus géants à ADN dans les milieux marins sur Tara-Oceans - - TARA-GIRUS2009 - ANR-09-GENM-0032 - GENOM-BTV - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, Association of European Marine Biological Laboratories - ASSEMBLE - - EC:FP7:INFRA2009-03-01 - 2014-10-31 - 227799 - VALID, and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: Proteomics, Marseilleviridae, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Fresh Water, [SDV.GEN] Life Sciences [q-bio]/Genetics, Genome, Viral, Nucleocytoplasmic large DNA viruses, Pithovirus, Evolution, Molecular, 03 medical and health sciences, Megaviridae, Giant Virus, Seawater, Amoeba, Phylogeny, 030304 developmental biology, Genetics, 0303 health sciences, Mimivirus, [SDV.GEN]Life Sciences [q-bio]/Genetics, Multidisciplinary, biology, Pandoravirus, Base Sequence, 030306 microbiology, Virophage, biology.organism_classification, [SDV] Life Sciences [q-bio], Mimiviridae
Abstract: Zeus' Revenge Sediment-dwelling amoebae appear to have an unhappy affinity for huge viruses. Giant icosahedral Mimiviruses with genomes of the order of 1 megabase (Mb) were first identified in Acanthamoeba. Digging into antipodean sediments has once again been fruitful where Philippe et al. (p. 281 ; see the cover) discovered some enormous viruses in Acanthamoeba, visible by light microscopy and having genomes up to 2.5 Mb. The Pandoraviruses are phagocytosed by target cells and, after fusing with the phagosome membrane, their contents are released into the cytoplasm where they wreak terrible havoc on its nucleus. These viruses are encased into a tegument-like envelope and lack genes for capsid proteins, and there are no genes for protein translation, adenosine triphosphate generation, or binary fission—confirming their classification as viruses.
Published: 2013
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