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419 results on '"Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)"'

1. Tumor Stiffening, a Key Determinant of Tumor Progression, is Reversed by Nanomaterial-Induced Photothermal Therapy

Author: Marangon, Iris, Silva, Amanda, Guilbert, Thomas, Kolosnjaj-Tabi, Jelena, Marchiol, Carmen, Natkhunarajah, Sharuja, Chamming's, Foucault, Ménard-Moyon, Cécilia, Bianco, Alberto, Gennisson, Jean-Luc, Renault, Gilles, Gazeau, Florence, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunopathologie et chimie thérapeutique (ICT), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Langevin - Ondes et Images (UMR7587) (IL), Sorbonne Université (SU)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), ANR-10-NANO-0008,NANOTHER,Hybrides multifonctionnels à base de nanotubes de carbone et de nanoparticules d'oxyde de fer fonctionnalisés pour des applications en imagerie et en thérapie(2010), ANR-10-LABX-0096,SEAM,Science and Engineering for Advanced Materials and devices(2010), Bos, Mireille, NANOTECHNOLOGIES ET NANOSYSTEMES - Hybrides multifonctionnels à base de nanotubes de carbone et de nanoparticules d'oxyde de fer fonctionnalisés pour des applications en imagerie et en thérapie - - NANOTHER2010 - ANR-10-NANO-0008 - P2N - VALID, Science and Engineering for Advanced Materials and devices - - SEAM2010 - ANR-10-LABX-0096 - LABX - VALID, Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Matière et Systèmes Complexes ( MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Immunopathologie et chimie thérapeutique ( ICT ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Langevin ondes et images, Centre National de la Recherche Scientifique ( CNRS ) -ESPCI ParisTech-Université Paris Diderot - Paris 7 ( UPD7 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), ANR-10-NANO-0008,NANOTHER,Hybrides multifonctionnels à base de nanotubes de carbone et de nanoparticules d’oxyde de fer fonctionnalisés pour des applications en imagerie et en thérapie ( 2010 ), and ANR-11-LABX-086 - ANR-11-IDEX-05-02,LabEx SEAM,Science and Engineering for Advanced Materials and devices
Subjects: elastography, photothermal therapy, administration & dosage, Antineoplastic Agents, methods, Mice, pathology, therapy, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, cancer, tumor microenvironment, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, carbon nanotubes, Nanotubes, Carbon, Lasers, Hyperthermia, Induced, Nanostructures, Disease Models, Animal, Photochemotherapy, Carcinoma, Squamous Cell, Elasticity Imaging Techniques, Heterografts, Chimie/Chimie thérapeutique, Research Paper
Abstract: Tumor stiffening, stemming from aberrant production and organization of extracellular matrix (ECM), has been considered a predictive marker of tumor malignancy, non-invasively assessed by ultrasound shear wave elastography (SWE). Being more than a passive marker, tumor stiffening restricts the delivery of diagnostic and therapeutic agents to the tumor and per se could modulate cellular mechano-signaling, tissue inflammation and tumor progression. Current strategies to modify the tumor extracellular matrix are based on ECM-targeting chemical agents but also showed deleterious systemic effects. On-demand excitable nanomaterials have shown their ability to perturb the tumor microenvironment in a spatiotemporal-controlled manner and synergistically with chemotherapy. Here, we investigated the evolution of tumor stiffness as well as tumor integrity and progression, under the effect of mild hyperthermia and thermal ablation generated by light-exposed multi-walled carbon nanotubes (MWCNTs) in an epidermoid carcinoma mouse xenograft. SWE was used for real-time mapping of the tumor stiffness, both during the two near infrared irradiation sessions and over the days after the treatment. We observed a transient and reversible stiffening of the tumor tissue during laser irradiation, which was lowered at the second session of mild hyperthermia or photoablation. In contrast, over the days following photothermal treatment, the treated tumors exhibited a significant softening together with volume reduction, whereas non-treated growing tumors showed an increase of tumor rigidity. The organization of the collagen matrix and the distribution of CNTs revealed a spatio-temporal correlation between the presence of nanoheaters and the damages on collagen and cells. This study highlights nanohyperthermia as a promising adjuvant strategy to reverse tumor stiffening and normalize the mechanical tumor environment. journal article research support, non-u.s. gov't 2017 2017 01 01 imported
Published: 2017

2. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Christelle Delmas, Juliette Saillard, Aline Dechanet, Claire Fougerou, Minh-Patrick Lê, Gilles Peytavin, Noémie Mercier, Priyanka Velou, Sarah Tubiana, Xavier Lescure, Emmanuel Faure, Saad Nseir, Jean-Christophe Richard, Florent Wallet, François Goehringer, Benjamin Lefèvre, Antoine Kimmoun, François Raffi, Benjamin Gaborit, Jean Reignier, Jean-Philippe Lanoix, Claire Andrejak, Yoann Zerbib, Firouzé Bani-Sadr, Bruno Mourvilliers, François Danion, Yvon Ruch, Raphaël Clere-Jehl, Vincent Le Moing, Kada Klouche, Karine Lacombe, Guillaume Martin-Blondel, Fanny Vardon-Bounes, André Cabié, Jean-Marie Turmel, Lionel Piroth, Mathieu Blot, Élisabeth Botelho-Nevers, Amandine Gagneux-Brunon, Guillaume Thiery, François Bénézit, Rostane Gaci, Joy Mootien, Sébastien Gallien, Denis Garot, Kevin Bouiller, Loïc Epelboin, Stéphane Jauréguiberry, Alexandre Gaymard, Gil Verschelden, Sandra Braz, Joao Miguel Ferreira Ribeiro, Michael Joannidis, Thérèse Staub, Antoine Altdorfer, Richard Greil, Alexander Egle, Jérémie Guedj, Marion Noret, Roberto Roncon-Albuquerque, Jose-Artur Paiva, Bruno Lina, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Hospices Civils de Lyon (HCL), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle de Recherche Clinique [Paris] (PRC), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
Subjects: [SDV]Life Sciences [q-bio]
Abstract: BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.FundingEuropean Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.
Published: 2023

3. A homozygous mutation in the human selenocysteine tRNA gene impairs UGA recoding activity and selenoproteome regulation by selenium

Author: Caroline Vindry, Olivia Guillin, Philippe Wolff, Paul Marie, Franck Mortreux, Philippe E Mangeot, Théophile Ohlmann, Laurent Chavatte, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Abstract: The selenocysteine (Sec) tRNA (tRNA[Ser]Sec) governs Sec insertion into selenoproteins by the recoding of a UGA codon, typically used as a stop codon. A homozygous point mutation (C65G) in the human tRNA[Ser]Sec acceptor arm has been reported by two independent groups and was associated with symptoms such as thyroid dysfunction and low blood selenium levels; however, the extent of altered selenoprotein synthesis resulting from this mutation has yet to be comprehensively investigated. In this study, we used CRISPR/Cas9 technology to engineer homozygous and heterozygous mutant human cells, which we then compared with the parental cell lines. This C65G mutation affected many aspects of tRNA[Ser]Sec integrity and activity. Firstly, the expression level of tRNA[Ser]Sec was significantly reduced due to an altered recruitment of RNA polymerase III at the promoter. Secondly, selenoprotein expression was strongly altered, but, more surprisingly, it was no longer sensitive to selenium supplementation. Mass spectrometry analyses revealed a tRNA isoform with unmodified wobble nucleotide U34 in mutant cells that correlated with reduced UGA recoding activities. Overall, this study demonstrates the pleiotropic effect of a single C65G mutation on both tRNA phenotype and selenoproteome expression.
Published: 2023

4. An integrated, structure- and energy-based view of the genetic code

Author: Henri Grosjean, Eric Westhof, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), and Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Computational biology, Biology, Ribosome, Sense Codon, 03 medical and health sciences, RNA, Transfer, Genetics, Survey and Summary, Codon, chemistry.chemical_classification, [ SDV ] Life Sciences [q-bio], RNA, Genetic code, Amino acid, 030104 developmental biology, chemistry, Genetic Code, Transfer RNA, Nucleic Acid Conformation, Thermodynamics, Ribosomes, GC-content, Decoding methods
Abstract: International audience; The principles of mRNA decoding are conserved among all extant life forms. We present an integrative view of all the interaction networks between mRNA, tRNA and rRNA: the intrinsic stability of codon-anticodon duplex, the conformation of the anticodon hairpin, the presence of modified nucleotides, the occurrence of non-Watson-Crick pairs in the codon-anticodon helix and the interactions with bases of rRNA at the A-site decoding site. We derive a more information-rich, alternative representation of the genetic code, that is circular with an unsymmetrical distribution of codons leading to a clear segregation between GC-rich 4-codon boxes and AU-rich 2:2-codon and 3:1-codon boxes. All tRNA sequence variations can be visualized, within an internal structural and energy framework, for each organism, and each anticodon of the sense codons. The multiplicity and complexity of nucleotide modifications at positions 34 and 37 of the anticodon loop segregate meaningfully, and correlate well with the necessity to stabilize AU-rich codon-anticodon pairs and to avoid miscoding in split codon boxes. The evolution and expansion of the genetic code is viewed as being originally based on GC content with progressive introduction of A/U together with tRNA modifications. The representation we present should help the engineering of the genetic code to include non-natural amino acids.
Published: 2016

5. Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia

Author: Sandra T. Cooper, Minal Menezes, Joëlle Rudinger-Thirion, Lisa G. Riley, Rachael M. Duff, Mark R. Davis, Michel Tchan, Pascale de Lonlay, John Christodoulou, Agnès Rötig, Genetic Metabolic Disorders Research Unit, Westmead Hospital [Sydney]-Kids Research Institute, Discipline of Paediatrics & Child Health, The University of Sydney, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre for Medical Research, The University of Western Australia (UWA)-Western Australian Institute for Medical Research, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Genetic Medicine, Westmead Hospital [Sydney], Discipline of Genetic Medicine, Sydney Medical School-The University of Sydney, Diagnostic Genomics, QEII Medical Centre, Institute for Neuroscience and Muscle Research, Kids Research Institute-Westmead Hospital [Sydney], Western Sydney Genetics Program, This research was supported by a March of Dimes Research Grant, and National Health and Medical Research Council of Australia Project Grant 1026891. M.M. is an Australian Mitochondrial Diseases Foundation (AMDF) Postgraduate Research Scholar, and the AMDF also provided financial support to RD and MD., Sydney Medical School, March of Dimes Research Grant, National Health and Medical Research Council of Australia Project Grant 1026891. M.M. is an Australian Mitochondrial Diseases Foundation (AMDF) Postgraduate Research Scholar, and the AMDF also provided financial support to RD and MD., Children's Hospital at Westmead-Kids Research Institute, The University of Sydney [Sydney], Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), The University of Western Australia ( UWA ) -Western Australian Institute for Medical Research, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Westmead Hospital, Children's Hospital at Westmead, BMC, Ed., Architecture et Réactivité de l'ARN, Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), and Sydney Medical School-The University of Sydney [Sydney]
Subjects: Adult, Mitochondrial respiratory chain, Muscle diseases, Adolescent, Myopathy with lactic acidosis and sideroblastic anemia, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, DNA, Mitochondrial, Lactic acidaemia, 03 medical and health sciences, Young Adult, Mitochondrial myopathy, Tyrosine-tRNA Ligase, Aminoacyl tRNA-synthetase, medicine, Humans, Genetics(clinical), Pharmacology (medical), Myopathy, Child, Gene, Genetics (clinical), Hydro-Lyases, 030304 developmental biology, Acidosis, Medicine(all), Genetics, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Research, 030305 genetics & heredity, Infant, Newborn, Infant, General Medicine, Inborn error of metabolism, medicine.disease, Anemia, Sideroblastic, Lactic acidosis, Child, Preschool, Acidosis, Lactic, Female, medicine.symptom, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Mitochondrial myopathies
Abstract: Background Mutations in the mitochondrial tyrosyl-tRNA synthetase (YARS2) gene have previously been identified as a cause of the tissue specific mitochondrial respiratory chain (RC) disorder, Myopathy, Lactic Acidosis, Sideroblastic Anaemia (MLASA). In this study, a cohort of patients with a mitochondrial RC disorder for who anaemia was a feature, were screened for mutations in YARS2. Methods Twelve patients were screened for YARS2 mutations by Sanger sequencing. Clinical data were compared. Functional assays were performed to confirm the pathogenicity of the novel mutations and to investigate tissue specific effects. Results PathogenicYARS2 mutations were identified in three of twelve patients screened. Two patients were found to be homozygous for the previously reported p.Phe52Leu mutation, one severely and one mildly affected. These patients had different mtDNA haplogroups which may contribute to the observed phenotypic variability. A mildly affected patient was a compound heterozygote for two novel YARS2 mutations, p.Gly191Asp and p.Arg360X. The p.Gly191Asp mutation resulted in a 38-fold loss in YARS2 catalytic efficiency and the p.Arg360X mutation did not produce a stable protein. The p.Phe52Leu and p.Gly191Asp/p.Arg360X mutations resulted in more severe RC deficiency of complexes I, III and IV in muscle cells compared to fibroblasts, but had relatively normal YARS2 protein levels. The muscle-specific RC deficiency can be related to the increased requirement for RC complexes in muscle. There was also a failure of mtDNA proliferation upon myogenesis in patient cells which may compound the RC defect. Patient muscle had increased levels of PGC1-α and TFAM suggesting mitochondrial biogenesis was activated as a potential compensatory mechanism. Conclusion In this study we have identified novel YARS2 mutations and noted marked phenotypic variability among YARS2 MLASA patients, with phenotypes ranging from mild to lethal, and we suggest that the background mtDNA haplotype may be contributing to the phenotypic variability. These findings have implications for diagnosis and prognostication of the MLASA and related phenotypes.
Published: 2013

6. Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy

Author: Michael Fähling, Josué Feingold, Edgar Benko, Marc Bintner, Diana Rodriguez, Simonetta Bandiera, Sylvain Hanein, Patrick Munier, Pascale Krejbich-Trotot, Stanislas Lyonnet, Jeanine Vellayoudom, Arnold Munnich, Eric Westhof, Nathalie Boddaert, Alexandra Henrion-Caude, Muriel Girard, Michel Renouil, Magali Naville, Jean-Jacques Hoarau, Emmanuelle Génin, Isabelle Desguerre, Pascale de Lonlay, François Cartault, Alain Fourmaintraux, Service de génétique, Centre hospitalier Felix Guyon (Saint-Denis), Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groupe de Recherche en Immunopathologies et maladies infectueuses ( GRI ), Université de la Réunion ( UR ) -Centre hospitalier Régional Site Félix Guyon, Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Cités, Territoires, Environnement et Sociétés ( CITERES ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Variabilité Génétique et Maladies Humaines, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Groupe Hospitalier Sud Réunion ( GHSR ), CHR La réunion, Institut de génétique et microbiologie [Orsay] ( IGM ), Université Paris-Sud - Paris 11 ( UP11 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Maladies Rares ' malformations et maladies congénitales du cervelet ', Hospices Civils de Lyon ( HCL ) -CHU Trousseau [APHP]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de neuropédiatrie [Trousseau], Service de Génétique Médicale [CHU Necker], Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Cités, Territoires, Environnement et Sociétés (CITERES), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier Sud Réunion (GHSR), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Tours (UT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre National de la Recherche Scientifique (CNRS)-Université de Tours
Subjects: RNA, Untranslated, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Retrotransposon, 0302 clinical medicine, Chromosome Segregation, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Indian Ocean, Conserved Sequence, Genetics, 0303 health sciences, Brain Diseases, Multidisciplinary, Geography, Nucleotides, Chromosome Mapping, Biological Sciences, Non-coding RNA, Magnetic Resonance Imaging, Anorexia, Phenotype, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease Progression, medulla oblongata, Chromosomes, Human, Pair 8, Primates, Retroelements, pediatrics, Molecular Sequence Data, Genes, Recessive, Biology, 03 medical and health sciences, Young Adult, genetic disease, Animals, Humans, long noncoding RNA, Gene, 030304 developmental biology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Base Sequence, Point mutation, Intron, RNA, Infant, long interspersed element 1, Noncoding DNA, Introns, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Genetic Loci, Mutation, Nucleic Acid Conformation, Human genome, 030217 neurology & neurosurgery
Abstract: International audience; The human genome is densely populated with transposons and transposon-like repetitive elements. Although the impact of these transposons and elements on human genome evolution is recognized, the significance of subtle variations in their sequence remains mostly unexplored. Here we report homozygosity mapping of an infantile neurodegenerative disease locus in a genetic isolate. Complete DNA sequencing of the 400-kb linkage locus revealed a point mutation in a primate-specific retrotransposon that was transcribed as part of a unique noncoding RNA, which was expressed in the brain. In vitro knockdown of this RNA increased neuronal apoptosis, consistent with the inappropriate dosage of this RNA in vivo and with the phenotype. Moreover, structural analysis of the sequence revealed a small RNA-like hairpin that was consistent with the putative gain of a functional site when mutated. We show here that a mutation in a unique transposable element-containing RNA is associated with lethal encephalopathy, and we suggest that RNAs that harbor evolutionarily recent repetitive elements may play important roles in human brain development.
Published: 2012

7. Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency

Author: Valérie Allamand, Pascale Guicheney, Mathieu Rederstorff, Alain Lescure, Maud Beuvin, Guillaume Chazot, Norma B. Romero, Marie Castets, Fabien Le Grand, Arnaud Ferry, Alain Krol, Anne Bertrand, Perrine Castets, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, pharmacologie et physiopathologie des maladies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Biocenter, Section for Genomics and RNomics, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Innsbruck Medical University [Austria] (IMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Werling, Danièle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -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 Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Innsbruck Medical University [Austria] ( IMU ), Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Pitié-Salpêtrière [APHP], University of Basel (Unibas), Centre de recherche Médecine, Science, Santé et Société (CERMES), Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), U974, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en myologie, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]
Subjects: Programmed cell death, Satellite Cells, Skeletal Muscle, Cell Survival, Population, Cobra Cardiotoxin Proteins, Endogeny, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Muscular Diseases, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Regeneration, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Myopathy, education, Muscle, Skeletal, Selenoproteins, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics (clinical), Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Mice, Knockout, 0303 health sciences, education.field_of_study, Selenoprotein N, Ryanodine receptor, Regeneration (biology), General Medicine, Anatomy, Cell biology, Disease Models, Animal, Mutation, medicine.symptom, 030217 neurology & neurosurgery, Homeostasis
Abstract: International audience; Selenoprotein N (SelN) deficiency causes a group of inherited neuromuscular disorders termed SEPN1-related myopathies (SEPN1-RM). Although the function of SelN remains unknown, recent data demonstrated that it is dispensable for mouse embryogenesis and suggested its involvement in the regulation of ryanodine receptors and/or cellular redox homeostasis. Here, we investigate the role of SelN in satellite cell (SC) function and muscle regeneration, using the Sepn1(-/-) mouse model. Following cardiotoxin-induced injury, SelN expression was strongly up-regulated in wild-type muscles and, for the first time, we detected its endogenous expression in a subset of mononucleated cells by immunohistochemistry. We show that SelN deficiency results in a reduced basal SC pool in adult skeletal muscles and in an imperfect muscle restoration following a single injury. A dramatic depletion of the SC pool was detected after the first round of degeneration and regeneration that totally prevented subsequent regeneration of Sepn1(-/-) muscles. We demonstrate that SelN deficiency affects SC dynamics on isolated single fibres and increases the proliferation of Sepn1(-/-) muscle precursors in vivo and in vitro. Most importantly, exhaustion of the SC population was specifically identified in muscle biopsies from patients with mutations in the SEPN1 gene. In conclusion, we describe for the first time a major physiological function of SelN in skeletal muscles, as a key regulator of SC function, which likely plays a central role in the pathophysiological mechanism leading to SEPN1-RM.
Published: 2011

8. Neutrophils degranulate GAG-containing proteoglycofili, which block Shigella growth and degrade virulence factors

Author: Antonin C André, Marina Valente Barroso, Jurate Skerniskyte, Mélina Siegwald, Vanessa Paul, Lorine Debande, Caroline Ridley, Isabelle Svahn, Stéphane Rigaud, Jean-Yves Tinevez, Romain R Vivès, Philippe J Sansonetti, David J Thornton, Benoit S Marteyn, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPCité), University of Manchester [Manchester], Bordeaux Imaging Center (BIC), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagopole (CITECH), Institut Pasteur [Paris] (IP), CEA Grenoble (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Institut d’Etudes Avancées de l’Université de Strasbourg - Institute for Advanced Study (USIAS), Université de Strasbourg (UNISTRA), Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Tinevez, Jean-Yves
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: Summary paragraphNeutrophil degranulation plays a central role in their ability to kill pathogens but also to stimulate other immune cells1–3. Here we show that neutrophil degranulation, induced in hypoxia or upon Shigella infection in vitro and in vivo, leads to the release of polymers called neutrophil Proteoglycofili (PGF). PGF are mainly composed of granular proteins (myeloperoxidase, elastase, lactoferrin, cathelicidin, albumin) pre-stored in various types of granules, and chondroitin sulfate. PGF individual fibers have a diameter of 43.9 ± 20.3 nm and. They secreted by viable neutrophils and do not contain DNA, as opposed to NETs which contains also granular proteins, chondroitin sulfate in addition to chromatin, released upon neutrophil disintegration and cell death.We demonstrated that PGF block the growth of Shigella and other bacteria and degrade Shigella virulence factors. The degradation of the chondroitin sulfate polymers with testes hyaluronidases destabilizes PGF ultrastructure and abolishes its antimicrobial activity. Our results provide novel insights in the neutrophil degranulation process and open new doors for the investigation of PGF contribution to cytokines concentration gradient formation and adaptive immune cells activation. Further investigations are required to better appreciate the importance of this “sterile blaster” in infectious or inflammatory diseases.
Published: 2022

9. Phytobeneficial traits of rhizobacteria under the control of multiple molecular dialogues

Author: Arnaud Laveilhé, Sylvain Fochesato, David Lalaouna, Thierry Heulin, Wafa Achouak, Laboratoire d'Ecologie Microbienne de la Rhizosphère et d'Environnements Extrêmes (LEMIRE), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Bacteria, Iron, Rhizosphere, Fungi, food and beverages, Bioengineering, Applied Microbiology and Biotechnology, Biochemistry, Soil Microbiology, Biotechnology, Alphaproteobacteria, Plant Diseases
Abstract: International audience; Pseudomonads play crucial roles in plant growth promotion and control of plant diseases. However, under natural conditions, other microorganisms competing for the same nutrient resources in the rhizosphere may exert negative control over their phytobeneficial characteristics. We assessed the expression of phytobeneficial genes involved in biocontrol, biostimulation and iron regulation such as, phlD, hcnA, acdS, and iron-small regulatory RNAs prrF1 and prrF2 in Pseudomonas brassicacearum co-cultivated with three phytopathogenic fungi, and two rhizobacteria in the presence or absence of Brassica napus, and in relation to iron availability. We found that the antifungal activity of P. brassicacearum depends mostly on the production of DAPG and not on HCN whose production is suppressed by fungi. We have also shown that the twocompeting bacterial strains modulate the plant growth promotion activity of P. brassicacearum by modifying the expression of phlD, hcnA and acdS according to iron availability. Overall, it allows us to better understand the complexity of the multiple molecular dialogues that take place underground between microorganisms and between plants and its rhizosphere microbiota and to show that synergy in favour of phytobeneficial gene expression may exist between different bacterial species.
Published: 2022

10. In vitro characterization of naturally occurring influenza H3NA- viruses lacking the NA gene segment: toward a new mechanism of viral resistance?

Author: E. Fournier, Daniel Thomas, Matthieu Yver, C. Boule, Vincent Moules, Emmanuel Giudice, Manuel Rosa-Calatrava, Bruno Lina, Corinne Bergeron, Roland Marquet, Nadia Naffakh, Guy Schoehn, Yi Pu Lin, Alan Hay, Martine Valette, Aurélien Traversier, Olivier Ferraris, A. Rivoire, M. Bouscambert-Duchamp, Michèle Ottmann, Jean-Paul Rolland, Olivier Terrier, Virologie et Pathologie Humaine ( VirPath ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Interactions cellulaires et moléculaires ( ICM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique moléculaire des virus à ARN, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut de biologie structurale ( IBS - UMR 5075 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Virologie et Pathologie Humaine (VirPath), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie structurale (IBS - UMR 5075 ), 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), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and 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)
Subjects: Models, Molecular, viral resistance, Protein Conformation, viruses, neuraminidase, medicine.disease_cause, Virus Replication, Influenza A virus, Enzyme Inhibitors, chemistry.chemical_classification, 0303 health sciences, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], virus diseases, Orthomyxoviridae, 3. Good health, influenza, Gene Expression Regulation, Viral, Hemagglutinin (influenza), Antiviral Agents, Gene Expression Regulation, Enzymologic, Cell Line, 03 medical and health sciences, Dogs, Oseltamivir, Virology, Drug Resistance, Viral, medicine, Animals, Humans, Amino Acid Sequence, hemagglutinin, Gene, 030304 developmental biology, 030306 microbiology, Influenza A Virus, H3N2 Subtype, Cryoelectron Microscopy, Virion, biology.organism_classification, Reverse genetics, Viral replication, chemistry, biology.protein, cryo-EM, Glycoprotein, Neuraminidase, Sequence Alignment, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience; Among a panel of 788 clinical influenza H3N2 isolates, two isolates were characterized by an oseltamivir-resistant phenotype linked to the absence of any detectable NA activity. Here, we established that the two H3NA- isolates lack any detectable full-length NA segment, and one of these could be rescued by reverse genetics in the absence of any NA segment sequence. We found that the absence of NA segment induced a moderate growth defect of the H3NA- viruses as on cultured cells. The glycoproteins density at the surface of H3NA- virions was unchanged as compared to H3N2 virions. The HA protein as well as residues 188 and 617 of the PB1 protein were shown to be strong determinants of the ability of H3NA- viruses to grow in the absence of the NA segment. The significance of these findings about naturally occurring seven-segment influenza A viruses is discussed.
Published: 2010

11. Probing mRNA structure and sRNA-mRNA interactions in bacteria using enzymes and lead(II)

Author: Chevalier, Clément, Geissmann, Thomas, Helfer, Anne-Catherine, Romby, Pascale, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), and Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: Staphylococcus aureus, RNA, Untranslated, MESH : RNA, Messenger, MESH : RNA, Untranslated, MESH : Molecular Sequence Data, Molecular Sequence Data, MESH : Nucleic Acid Conformation, MESH: Enzymes, MESH : Enzymes, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Chemical Fractionation, MESH: Base Sequence, MESH: RNA, Untranslated, MESH: Chemical Fractionation, MESH : Hydrolysis, MESH: RNA, MESH : RNA, MESH: Staphylococcus aureus, RNA, Messenger, Molecular Biology, MESH: RNA, Messenger, MESH: Molecular Sequence Data, Base Sequence, MESH : Chemical Fractionation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Hydrolysis, MESH : Staphylococcus aureus, MESH: Molecular Biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH : Molecular Biology, MESH : RNA, Bacterial, Enzymes, RNA, Bacterial, MESH: Nucleic Acid Conformation, Lead, Nucleic Acid Conformation, RNA, MESH : Base Sequence, MESH : Lead, MESH: RNA, Bacterial, MESH: Hydrolysis, MESH: Lead
Abstract: International audience; Enzymatic probing and lead(II)-induced cleavages have been developed to study the secondary structure of RNA molecules either free or engaged in complex with different ligands. Using a combination of probes with different specificities (unpaired vs. paired regions), it is possible to get information on the accessibility of each nucleotide, on the binding site of a ligand (noncoding RNAs, protein, metabolites), and on RNA conformational changes that accompanied ligand binding or environmental conditions (temperature, pH, ions, etc.). The detection of the cleavages can be conducted by two different ways, which are chosen according to the length of the studied RNA. The first method uses end-labeled RNA molecules and the second one involves primer extension by reverse transcriptase. We provide here an experimental procedure that was designed to map the structure of mRNA and mRNA-sRNA interaction in vitro.
Published: 2009

12. HuR interacts with human immunodeficiency virus type 1 reverse transcriptase, and modulates reverse transcription in infected cells

Author: Julie Lemay, Richard Benarous, Jean-Christophe Rain, Eric Ennifar, Lang Xia Liu, Priscilla Maidou-Peindara, Thomas Bader, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AB Science, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Hybrigenics [Paris], Hybrigenics, CellVir, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Architecture et Réactivité de l'ARN ( ARN ), Institut de biologie moléculaire et cellulaire ( IBMC ), and Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre National de la Recherche Scientifique ( CNRS )
Subjects: MESH : Cell Line, Fluoroimmunoassay, RNA-binding protein, MESH : RNA, Small Interfering, Virus Replication, MESH: Fluoroimmunoassay, ELAV-Like Protein 1, MESH: HIV-1, MESH : Protein Interaction Mapping, Protein Interaction Mapping, MESH: RNA, Small Interfering, MESH : HIV Reverse Transcriptase, MESH: Gene Silencing, RNA, Small Interfering, MESH: Chromatin Immunoprecipitation, 0303 health sciences, 030302 biochemistry & molecular biology, RNA-Binding Proteins, HIV Reverse Transcriptase, 3. Good health, MESH : Virus Replication, Infectious Diseases, ELAV Proteins, MESH: RNA, Viral, Antigens, Surface, RNA, Viral, RIP-Chip, MESH : Antigens, Surface, MESH : HIV-1, Binding domain, lcsh:Immunologic diseases. Allergy, Chromatin Immunoprecipitation, MESH : Fluoroimmunoassay, MESH: Antigens, Surface, MESH: HIV Reverse Transcriptase, MESH : RNA-Binding Proteins, Biology, MESH: Two-Hybrid System Techniques, Cell Line, 03 medical and health sciences, MESH : Chromatin Immunoprecipitation, Virology, Two-Hybrid System Techniques, MESH : Gene Silencing, MESH : RNA, Viral, Humans, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, RNase H, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Protein Interaction Domains and Motifs, Binding Sites, MESH: Humans, Research, MESH : Humans, MESH: Protein Interaction Mapping, MESH: Virus Replication, RNA, Molecular biology, Reverse transcriptase, MESH: Cell Line, MESH: RNA-Binding Proteins, Viral replication, MESH : Two-Hybrid System Techniques, MESH: Binding Sites, biology.protein, HIV-1, lcsh:RC581-607, Chromatin immunoprecipitation, MESH : Binding Sites, MESH : Protein Interaction Domains and Motifs
Abstract: Reverse transcription of the genetic material of human immunodeficiency virus type 1 (HIV-1) is a critical step in the replication cycle of this virus. This process, catalyzed by reverse transcriptase (RT), is well characterized at the biochemical level. However, in infected cells, reverse transcription occurs in a multiprotein complex – the reverse transcription complex (RTC) – consisting of viral genomic RNA associated with viral proteins (including RT) and, presumably, as yet uncharacterized cellular proteins. Very little is known about the cellular proteins interacting with the RTC, and with reverse transcriptase in particular. We report here that HIV-1 reverse transcription is affected by the levels of a nucleocytoplasmic shuttling protein – the RNA-binding protein HuR. A direct protein-protein interaction between RT and HuR was observed in a yeast two-hybrid screen and confirmed in vitro by homogenous time-resolved fluorescence (HTRF). We mapped the domain interacting with HuR to the RNAse H domain of RT, and the binding domain for RT to the C-terminus of HuR, partially overlapping the third RRM RNA-binding domain of HuR. HuR silencing with specific siRNAs greatly impaired early and late steps of reverse transcription, significantly inhibiting HIV-1 infection. Moreover, by mutagenesis and immunoprecipitation studies, we could not detect the binding of HuR to the viral RNA. These results suggest that HuR may be involved in and may modulate the reverse transcription reaction of HIV-1, by an as yet unknown mechanism involving a protein-protein interaction with HIV-1 RT.
Published: 2008

13. CARD9 in neutrophils protects from colitis and controls mitochondrial metabolism and cell survival

Author: Camille Danne, Chloé Michaudel, Jurate Skerniskyte, Julien Planchais, Aurélie Magniez, Allison Agus, Marie-Laure Michel, Bruno Lamas, Gregory Da-Costa, Madeleine Spatz, Cyriane Oeuvray, Chloé Galbert, Maxime Poirier, Yazhou Wang, Alexia Lapiere, Nathalie Rolhion, Tatiana Ledent, Cédric Pionneau, Solenne Chardonnet, Floriant Bellvert, Edern Cahoreau, Amandine Rocher, Rafael Jose Argüello, Carole Peyssonnaux, Sabine Louis, Mathias L. Richard, Philippe Langella, Jamel El-Benna, Benoit Marteyn, Harry Sokol, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), 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-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), MetaToul FluxoMet (TBI-MetaToul), 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)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut d’Etudes Avancées de l’Université de Strasbourg - Institute for Advanced Study (USIAS), Université de Strasbourg (UNISTRA), Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Funding was provided by the ANR-17-CE15-0019-01 grant and a Marie Skłodowska-Curie Actions fellowship., ANR-17-CE15-0019,MARYLAND,Modulation par Card9 du microbiote intestinal et de sa production d'agonistes Aryl hydrocarbon receptor: mécanisme, potentiel thérapeutique et comme biomarqueur dans les maladies inflammatoires chroniques de l'intestin(2017), LAMAS, Bruno, Modulation par Card9 du microbiote intestinal et de sa production d'agonistes Aryl hydrocarbon receptor: mécanisme, potentiel thérapeutique et comme biomarqueur dans les maladies inflammatoires chroniques de l'intestin - - MARYLAND2017 - ANR-17-CE15-0019 - AAPG2017 - VALID, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-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 de Toulouse (UT)-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 de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MetaToul-MetaboHUB, Institut Cochin, INSERM, CNRS, Université de Paris, Laboratoire d'excellence GR-Ex, Institut Cochin, INSERM, CNRS, UNiversité de Paris, Laboratoire d'excellence GR-Ex, Institut Pasteur, Université de Paris, Inserm 1225 Unité de Pathogenèse des infections Vasculaires, Métabolomique et Fluxomique (MetaToul) (TBI-MetaToul), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Faculte de Medecine Xavier Bichat, Université Paris Diderot - Paris 7 (UPD7), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, IBD, Gastroenterology, Apoptosis, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, mitochondrial activity, Gastrointestinal immune response, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, neutrophils, [SDV.TOX.TCA] Life Sciences [q-bio]/Toxicology/Toxicology and food chain, [SDV.TOX]Life Sciences [q-bio]/Toxicology, IBD-Genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, gut inflammation, CARD9, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: ObjectivesInflammatory bowel disease (IBD) results from a combination of genetic predisposition, dysbiosis of the gut microbiota and environmental factors, leading to alterations in the gastrointestinal immune response and chronic inflammation. Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection. However, the cell types and mechanisms involved in the CARD9 protective role against inflammation remain unknown.DesignWe used dextran sulfate sodium (DSS)-induced and adoptive transfer colitis models in total and conditional CARD9 knock-out mice to uncover which cell types play a role in the CARD9 protective phenotype. The impact of Card9 deletion on neutrophil function was assessed by an in vivo model of fungal infection and various functional assays, including endpoint dilution assay, apoptosis assay by flow cytometry, proteomics and real time bioenergetic profile analysis (Seahorse).ResultsLymphocytes are not intrinsically involved in the CARD9 protective role against colitis. CARD9 expression in neutrophils, but not in epithelial or CD11c+ cells, protects against DSS-induced colitis. In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment. The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation.ConclusionThese results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation, paving the way for new therapeutic strategies targeting neutrophils.Summary boxWhat is already known about this subject?Inflammatory bowel disease (IBD) results from genetic predisposition, microbiota dysbiosis and environmental factors, but the alterations of the immune response leading to chronic intestinal inflammation are still not fully understood.Caspase recruitment domain 9 (Card9), one of the IBD susceptibility genes, has been shown to protect against intestinal inflammation and fungal infection.However, the cell types and cellular mechanisms involved in the CARD9 protective role against inflammation remain unknown.What are the new findings?CARD9 expression in neutrophils, but not in lymphocytes, epithelial cells or CD11c+ cells, protects against DSS-induced colitis.In the absence of CARD9, mitochondrial dysfunction in neutrophils leads to their premature death through apoptosis, especially in oxidative environment.The decrease of fonctional neutrophils in tissues could explain the impaired containment of fungi and increased susceptibility to intestinal inflammation.How might it impact on clinical practice in the foreseeable future?These results provide new insight into the role of CARD9 in neutrophil mitochondrial function and its involvement in intestinal inflammation.Understanding the role of neutrophils in chronic inflammation could lead to innovative therapeutic strategies targeting these key immune cells for various complex diseases.
Published: 2022

14. Stabilization of Ribosomal RNA of the Small Subunit by Spermidine in Staphylococcus aureus

Author: Margarita Belinite, Iskander Khusainov, Heddy Soufari, Stefano Marzi, Pascale Romby, Marat Yusupov, Yaser Hashem, 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), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Kazan Federal University (KFU)
Subjects: RNA Stability, Staphylococcus aureus, QH301-705.5, translation, Translation (biology), Ribosomal RNA, RNA stability, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Ribosome, Spermidine, chemistry.chemical_compound, Structural biology, chemistry, Protein biosynthesis, Molecular Biosciences, 30S, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biology (General), ribosomal RNA, Molecular Biology, ribosome 70 S, Original Research
Abstract: Cryo-electron microscopy is now used as a method of choice in structural biology for studying protein synthesis, a process mediated by the ribosome machinery. In order to achieve high-resolution structures using this approach, one needs to obtain homogeneous and stable samples, which requires optimization of ribosome purification in a species-dependent manner. This is especially critical for the bacterial small ribosomal subunit that tends to be unstable in the absence of ligands. Here, we report a protocol for purification of stable 30 S from the Gram-positive bacterium Staphylococcus aureus and its cryo-EM structures: in presence of spermidine at a resolution ranging between 3.4 and 3.6 Å and in its absence at 5.3 Å. Using biochemical characterization and cryo-EM, we demonstrate the importance of spermidine for stabilization of the 30 S via preserving favorable conformation of the helix 44.
Published: 2021

15. CCA-addition in the cold: Structural characterization of the psychrophilic CCA-adding enzyme from the permafrost bacterium Planococcus halocryophilus

Author: de Wijn, Raphaël, Rollet, Kévin, Ernst, Felix G.M., Wellner, Karolin, Betat, Heike, Mörl, Mario, Sauter, Claude, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cold adaptation, [SDV]Life Sciences [q-bio], CCA-adding enzyme, Psychrophilic protein, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, SAXS, tRNA, TP248.13-248.65, X-ray crystallography, Biotechnology
Abstract: International audience; CCA-adding enzymes are highly specific RNA polymerases that add and maintain the sequence CC A at tRNA 3'-ends. Recently, we could reveal that cold adaptation of such a polymerase is not only achieved at the expense of enzyme stability, but also at the cost of polymerization fidelity. Enzymes from psychrophilic organisms usually show an increased structural flexibility to enable catalysis at low temperatures. Here, polymerases face a dilemma, as there is a discrepancy between the need for a tightly controlled flexibility during polymerization and an increased flexibility as strategy for cold adaptation. Based on structural and biochemical analyses, we contribute to clarify the cold adaptation strategy of the psychrophilic CCA-adding enzyme from Planococcus halocryophilus, a gram-positive bacterium thriving in the arctic permafrost at low temperatures down to À15°C. A comparison with the closely related enzyme from the thermophilic bacterium Geobacillus stearothermophilus reveals several features of cold adaptation-a significantly reduced amount of alpha-helical elements in the C-terminal tRNA-binding region and a structural adaptation in one of the highly conserved catalytic core motifs located in the N-terminal catalytic core of the enzyme.
Published: 2021

16. A conserved uORF impacts APOBEC3G translation and is essential for translational inhibition by the HIV-1 Vif protein

Author: Libre, Camille, Seissler, Tanja, Guerrero, Santiago, Batisse, Julien, Verriez, Cédric, Stupfler, Benjamin, Gilmer, Orian, Weber, Melanie, Cimarelli, Andrea, Etienne, Lucie, Marquet, Roland, Paillart, Jean-Christophe, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MATHELIN, Sandra
Subjects: [SDV] Life Sciences [q-bio], viruses, [SDV]Life Sciences [q-bio], [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, virus diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, biochemical phenomena, metabolism, and nutrition, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Abstract: The HIV-1 Vif protein is essential for viral fitness and pathogenicity. Vif decreases expression of cellular cytosine deaminases APOBEC3G (A3G), A3F, A3D and A3H, which inhibit HIV-1 replication by inducing hypermutations during reverse transcription. Vif counteracts A3G by several non-redundant mechanisms (transcription, translation and protein degradation) that concur in reducing the levels of A3G in cell and in preventing its incorporation into viral particles. How Vif affects A3G translation remains unclear. Here, we uncovered the importance of a short conserved uORF (upstream ORF) located within two critical stem-loop structures of the 5′ untranslated region (5′UTR) of A3G mRNA. Extensive mutagenesis of A3G 5′-UTR, combined with an analysis of their translational effect in transfected cells, indicated that the uORF represses A3G translation and that A3G mRNA is translated through a dual leaky-scanning and re-initiation mechanism. Interestingly, the uORF is also mandatory for the Vif-mediated repression of A3G translation. Furthermore, we showed that the redirection of A3G mRNA into stress granules was dependent not only on Vif, but also on the uORF. Overall, we discovered that A3G translation is regulated by a small uORF conserved in the human population and that Vif uses this specific motif to repress its translation.
Published: 2021

17. Quelle taxonomie des maladies inflammatoires en rhumatologie ?: Le concept de psoutte

Author: Messer, Laurent, Felten, Renaud, Duret, Pierre-Marie, Gottenberg, Jacques Eric, Widawski, Laura, Meyer, Alain, Lomo Myazhiom, Aggée Célestin, Spielmann, Lionel, Sibilia, Jean, Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Dynamiques européennes (DynamE), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; La pratique clinique de la médecine nécessite la reconnaissance de la maladie dont souffre le patient par le médecin. Pour cela, celui-ci rationnalise les signes permettant d’isoler une entité réaliste et de la classer dans la nosologie de référence. Contrairement à d’autres pratiques, le modèle biomédical utilise la méthodologie scientifique du recensement, dans une logique de classification pour définir les maladies. Du fait de son processus de simplification, ce modèle néglige les cas de transition ou les cas complexes. En rhumatologie, ce raisonnement classifiant est mis à l’épreuve par le manque d’objectivité et de spécificité des éléments sur lesquels s’appuie le clinicien pour construire le diagnostic, mais aussi par la complexité des mécanismes physiopathologiques des maladies rhumatismales. Ces maladies peuvent en effet se confondre ou s’intriquer, pour aboutir alors à la description de nouvelles entités non envisagées dans les classifications. Nous présentons dans cette revue les difficultés rencontrées au cours de l’exercice de la médecine dans ces contextes, et comment, à partir d’un cas concret, vécu, celles-ci peuvent donner naissance à la proposition d’un nouveau taxon1.
Published: 2021

18. A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery

Author: Crouchet, Emilie, Bandiera, Simonetta, Fujiwara, Naoto, Li, Shen, El Saghire, Hussein, Fernández-Vaquero, Mirian, Riedl, Tobias, Sun, Xiaochen, Hirschfield, Hadassa, Jühling, Frank, Zhu, Shijia, Roehlen, Natascha, Ponsolles, Clara, Heydmann, Laura, Saviano, Antonio, Qian, Tongqi, Venkatesh, Anu, Lupberger, Joachim, Verrier, Eloi R., Sojoodi, Mozhdeh, Oudot, Marine A., Duong, François H. T., Masia, Ricard, Wei, Lan, Thumann, Christine, Durand, Sarah C., González-Motos, Victor, Heide, Danijela, Hetzer, Jenny, Nakagawa, Shigeki, Ono, Atsushi, Song, Won-Min, Higashi, Takaaki, Sanchez, Roberto, Kim, Rosa S., Bian, C. Billie, Kiani, Karun, Croonenborghs, Tom, Subramanian, Aravind, Chung, Raymond T., Straub, Beate K., Schuppan, Detlef, Ankavay, Maliki, Cocquerel, Laurence, Schaeffer, Evelyne, Goossens, Nicolas, Koh, Anna P., Mahajan, Milind, Nair, Venugopalan D., Gunasekaran, Ganesh, Schwartz, Myron E., Bardeesy, Nabeel, Shalek, Alex K., Rozenblatt-Rosen, Orit, Regev, Aviv, Felli, Emanuele, Pessaux, Patrick, Tanabe, Kenneth K., Heikenwälder, Mathias, Schuster, Catherine, Pochet, Nathalie, Zeisel, Mirjam B., Fuchs, Bryan C., Hoshida, Yujin, Baumert, Thomas F., Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Texas Southwestern Medical Center [Dallas], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Universität Heidelberg [Heidelberg] = Heidelberg University, Nouvel Hôpital Civil de Strasbourg, University Hospital Basel [Basel], Hiroshima University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Kumamoto University, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), University Medical Center of the Johannes Gutenberg-University Mainz, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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)-Centre National de la Recherche Scientifique (CNRS), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospital (HUG), Massachusetts Institute of Technology (MIT), Harvard University, This work was supported by ARC, Paris and Institut Hospitalo-Universitaire, Strasbourg (TheraHCC1.0 and 2.0 IHUARC IHU201301187 and IHUARC2019 to T.F.B.), the European Union (ERC-AdG-2014-671231-HEPCIR to T.F.B. and Y.H., EU H2020-667273-HEPCAR to T.F.B. and M.H., and INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2012 to T.F.B. and M.B.Z), ANRS, Paris (2013/108 and ECTZ103701 to T.F.B), NIH (DK099558 to Y. H., and CA233794 to Y.H. and T. F. B, CA140861 to B.C.F., and CA209940, R21CA209940, and R03AI131066 to N.P. and T.F.B.), Cancer Prevention and Research Institute of Texas (RR180016 to Y.H.), US Department of Defense (W81XWH-16-1-0363 to T.F.B. and Y.H.), the Irma T. Hirschl/Monique Weill-Caulier Trust (Y.H.), and the Foundation of the University of Strasbourg (HEPKIN to T. F. B. and Y. H.) and the Institut Universitaire de France (IUF, T.F.B.). M.H. is supported by an ERC CoG grant (HepatoMetaboPath) and EOS grant and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 272983813—TRR 179, and Project-ID 314905040 SFB TR209. This work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and Inserm Plan Cancer and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program., ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), Cocquerel, Laurence, Functional genomics of viral hepatitis and liver disease - - HepSys2010 - ANR-10-LABX-0028 - LABX - VALID, Cell circuits as targets and biomarkers for liver disease and cancer prevention - HEPCIR - - H20202016-01-01 - 2020-12-31 - 671231 - VALID, Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities. - HEP-CAR - - H20202016-01-01 - 2019-12-31 - 667273 - VALID, Universität Heidelberg [Heidelberg], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Harvard University [Cambridge], Johannes Gutenberg - Universität Mainz (JGU), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Subjects: Liver Cirrhosis, Male, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Carcinogenesis, Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Chemoprevention, Models, Biological, Article, Cohort Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Drug Discovery, Cancer genomics, Cyclic AMP, Animals, Humans, Cyclic AMP Response Element-Binding Protein, Immunologic Surveillance, Liver diseases, Nizatidine, Inflammation, Mice, Knockout, Macrophages, Liver Neoplasms, Prognosis, Hepatitis C, Computational biology and bioinformatics, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Mechanisms of disease, HEK293 Cells, Liver, Hepatocytes, Transcriptome, Signal Transduction
Abstract: Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention., Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.
Published: 2021

19. Correction to ‘ Cis regulation within a cluster of viral microRNAs’

Author: Sébastien Pfeffer, Päivi M. Ojala, Endrit Elbasani, Monika Vilimova, Maud Contrant, Ramy Randrianjafy, Aurélie Fender, Philippe Dumas, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, and univOAK, Archive ouverte
Subjects: Gene Expression Regulation, Viral, RNA Folding, 0303 health sciences, AcademicSubjects/SCI00010, Computational biology, Oligonucleotides, Antisense, Biology, Cell Line, MicroRNAs, 03 medical and health sciences, HEK293 Cells, 0302 clinical medicine, Herpesvirus 8, Human, microRNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, Cis regulation, Cluster (physics), Humans, RNA, Viral, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Erratum, RNA Processing, Post-Transcriptional, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although many of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher a regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi's sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor and found that pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs. A mutational analysis showed that, in addition to producing mature miRNAs, they are also important for the optimal expression of the whole set of miRNAs. We showed that this feature depends on the presence of a canonical pre-miRNA at this location since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we exploited this characteristic of the cluster to inhibit the expression of the whole set of miRNAs by targeting the pre-miR-K1 with LNA-based antisense oligonucleotides in cells either expressing a synthetic construct or latently infected with KSHV.
Published: 2021

20. Cis regulation within a cluster of viral microRNAs

Author: Aurélie Fender, Maud Contrant, Philippe Dumas, Sébastien Pfeffer, Monika Vilimova, Päivi M. Ojala, Endrit Elbasani, Ramy Randrianjafy, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-17-EURE-0023,IMCBio,Integrative Molecular and Cellular Biology(2017), ANR-10-LABX-0036,NetRNA,Network of regulatory RNAs across kingdoms and dynamical responses to biotic and abiotic stresses.(2010), European Project: 647455,H2020,ERC-2014-CoG,RegulRNA(2016), University of Helsinki, univOAK, Archive ouverte, CAN-PRO - Translational Cancer Medicine Program, Department of Pathology, Biosciences, and Medicum
Subjects: EXPRESSION, AcademicSubjects/SCI00010, BIOGENESIS, HERPESVIRUS, PROTEIN, Heterologous, Computational biology, Biology, Cleavage (embryo), PATHWAY, 03 medical and health sciences, microRNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, RNA and RNA-protein complexes, Cluster (physics), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Synthetic construct, 030304 developmental biology, 0303 health sciences, LATENCY, IDENTIFICATION, Mechanism (biology), 030302 biochemistry & molecular biology, TERTIARY STRUCTURE, In vitro, Cell biology, 3. Good health, Mutational analysis, TARGET, MIRNAS, Antisense oligonucleotides, Cis regulation, 1182 Biochemistry, cell and molecular biology, Cytokinesis
Abstract: MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although many of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher a regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi’s sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor and found that pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs. A mutational analysis showed that, in addition to producing mature miRNAs, they are also important for the optimal expression of the whole set of miRNAs. We showed that this feature depends on the presence of a canonical pre-miRNA at this location since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we exploited this characteristic of the cluster to inhibit the expression of the whole set of miRNAs by targeting the pre-miR-K1 with LNA-based antisense oligonucleotides in cells either expressing a synthetic construct or latently infected with KSHV.
Published: 2021

21. Importance of Viral Late Domains in Budding and Release of Enveloped RNA Viruses

Author: Jean-Christophe Paillart, Serena Bernacchi, Lisa Welker, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN
Subjects: ESCRT machinery, viruses, Review, budding, Biology, medicine.disease_cause, Virus Replication, Microbiology, ESCRT, Conserved sequence, viral assembly, 03 medical and health sciences, late assembly domains, Retrovirus, Membrane fission, RNA enveloped viruses, Virology, medicine, Humans, RNA Viruses, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Virus Release, 030304 developmental biology, 0303 health sciences, Budding, Mutation, Endosomal Sorting Complexes Required for Transport, Virus Assembly, 030302 biochemistry & molecular biology, Ubiquitination, Virion, RNA, biology.organism_classification, retroviral gag precursor, QR1-502, 3. Good health, Cell biology, structural viral proteins, retrovirus, Infectious Diseases, Viral replication, Protein Binding
Abstract: Late assembly (L) domains are conserved sequences that are necessary for the late steps of viral replication, acting like cellular adaptors to engage the ESCRT membrane fission machinery that promote virion release. These short sequences, whose mutation or deletion produce the accumulation of immature virions at the plasma membrane, were firstly identified within retroviral Gag precursors, and in a further step, also in structural proteins of many other enveloped RNA viruses including arenaviruses, filoviruses, rhabdoviruses, reoviruses, and paramyxoviruses. Three classes of L domains have been identified thus far (PT/SAP, YPXnL/LXXLF, and PPxY), even if it has recently been suggested that other motifs could act as L domains. Here, we summarize the current state of knowledge of the different types of L domains and their cellular partners in the budding events of RNA viruses, with a particular focus on retroviruses.
Published: 2021

22. Correction: Antibacterial activity of a dual peptide targeting the Escherichia coli sliding clamp and the ribosome

Author: Christophe André, Florian Veillard, Philippe Wolff, Anne-Marie Lobstein, Guillaume Compain, Clément Monsarrat, Jean-Marc Reichhart, Dominique Y. Burnouf, Gilles Guichard, Jérôme E. Wagner, Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, 010405 organic chemistry, [SDV]Life Sciences [q-bio], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 01 natural sciences, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, 0104 chemical sciences, 3. Good health, 03 medical and health sciences, Chemistry, Chemistry (miscellaneous), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, 030304 developmental biology
Abstract: Correction for ‘Antibacterial activity of a dual peptide targeting the Escherichia coli sliding clamp and the ribosome’ by Christophe André et al., RSC Chem. Biol., 2020, 1, 137–147, DOI: 10.1039/D0CB00060D.
Published: 2021

23. RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence

Author: Victor Loegler, Heemee Devi Bunwaree, Martin Gobry, Laura Antoine, Stefano Marzi, Pascale Romby, Roberto Bahena-Ceron, Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: mRNA, Virulence, host-adaptation, Review, Computational biology, QH426-470, Biology, Host Adaptation, 03 medical and health sciences, RNA modifications, 0302 clinical medicine, Genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA Processing, Post-Transcriptional, Nucleic acid structure, tRNA, Gene, Genetics (clinical), small non-coding RNA, 030304 developmental biology, 0303 health sciences, Messenger RNA, Bacteria, RNA, pathogenic bacteria, Ribosomal RNA, stress adaptation, RNA, Bacterial, Host-Pathogen Interactions, Transfer RNA, Host adaptation, ribosomal RNA, 030217 neurology & neurosurgery
Abstract: RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications.
Published: 2021

24. Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

Author: Pierre Duffau, Maya Saleh, Anne Garreau, Emmanuel Ribeiro, Isabelle Douchet, Lionel Couzi, Irène Machelart, Cécile Contin-Bordes, Marc Scherlinger, Patrick Blanco, Jean-Philippe Guegan, Vivien Guillotin, Thierry Schaeverbeke, Patrick Legembre, Marie-Elise Truchetet, Andrea Boizard-Moracchini, Agathe Vermorel, Nathalie Merillon, Jean-François Viallard, Estibaliz Lazaro, Vanja Sisirak, Christophe Richez, Thomas Barnetche, Pierre Vacher, Jean-Luc Pellegrin, Hélène Dumortier, Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), SISIRAK, VANJA, Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Regulatory T cell, [SDV]Life Sciences [q-bio], Syk, T-Lymphocytes, Regulatory, Mice, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, Interferon, immune system diseases, medicine, Animals, Humans, Lupus Erythematosus, Systemic, skin and connective tissue diseases, Lupus erythematosus, biology, business.industry, General Medicine, Transforming growth factor beta, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Immunology, Selectins, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antibody, business, Selectin, 030215 immunology, Transforming growth factor, medicine.drug
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor–β axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin–dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.
Published: 2021

25. Evolutionary history expands the range of signaling interactions in hybrid multikinase networks

Author: Anne-Florence Bitbol, Sylvain Fochesato, David E. Whitworth, Philippe Ortet, Thierry Heulin, David Lalaouna, Catherine Santaella, Mohamed Barakat, Wafa Achouak, Laboratoire d'Ecologie Microbienne de la Rhizosphère et d'Environnements Extrêmes (LEMIRE), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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 de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Jean Perrin (LJP), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Aberystwyth University, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-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)-Centre National de la Recherche Scientifique (CNRS), and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, sensor kinases, gaca, Science, [SDV]Life Sciences [q-bio], 030106 microbiology, specificity, Computational biology, Biology, Microbiology, Article, Gene regulatory networks, Bacterial evolution, 03 medical and health sciences, Bacterial Proteins, Pseudomonas, transduction systems, Protein Interaction Domains and Motifs, Phosphorylation, Gene, global control, Phylogeny, secondary metabolism, Multidisciplinary, Bacteria, Phylogenetic tree, Histidine kinase, Biological Evolution, Computational biology and bioinformatics, [SDV] Life Sciences [q-bio], Transplantation, Response regulator, Phenotype, 030104 developmental biology, motility, biofilm formation, Medicine, Signal transduction, Protein Kinases, p2cs, pseudomonas-brassicacearum, Protein Binding, Signal Transduction
Abstract: Two-component systems (TCSs) are ubiquitous signaling pathways, typically comprising a sensory histidine kinase (HK) and a response regulator, which communicate via intermolecular kinase-to-receiver domain phosphotransfer. Hybrid HKs constitute non-canonical TCS signaling pathways, with transmitter and receiver domains within a single protein communicating via intramolecular phosphotransfer. Here, we report how evolutionary relationships between hybrid HKs can be used as predictors of potential intermolecular and intramolecular interactions (‘phylogenetic promiscuity’). We used domain-swap genes chimeras to investigate the specificity of phosphotransfer within hybrid HKs of the GacS–GacA multikinase network of Pseudomonas brassicacearum. The receiver domain of GacS was replaced with those from nine donor hybrid HKs. Three chimeras with receivers from other hybrid HKs demonstrated correct functioning through complementation of a gacS mutant, which was dependent on strains having a functional gacA. Formation of functional chimeras was predictable on the basis of evolutionary heritage, and raises the possibility that HKs sharing a common ancestor with GacS might remain components of the contemporary GacS network. The results also demonstrate that understanding the evolutionary heritage of signaling domains in sophisticated networks allows their rational rewiring by simple domain transplantation, with implications for the creation of designer networks and inference of functional interactions.
Published: 2021

26. A glutathione responsive nanoplatform made of reduced graphene oxide and MnO 2 nanoparticles for photothermal and chemodynamic combined therapy

Author: Ma, Baojin, Nishina, Yuta, Bianco, Alberto, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Fenton reaction, Cancer therapy, GSH depletion, Drug delivery, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Reactive oxygen species
Abstract: International audience; Based on the specific tumor microenvironment, characterized by an overproduction of H2O2 and a high glutathione (GSH) concentration, the cascade reactions of nanomaterials, capable of mediating GSH depletion and reactive oxygen species (ROS) generation, have become a popular strategy to increase cancer therapy efficiency. In this study, we exploited reduced graphene oxide (rGO), one of the most promising graphene-based materials, in combination with manganese dioxide nanoparticles (MnO2 NPs) to design a multifunctional nanoplatform (rGO@MnO2) for efficient photothermal/chemodynamic combined therapies. MnO2 NPs were anchored onto the surface of rGO nanosheets (rGO NSs). MnO2 NPs oxidize intracellular GSH, and the generated Mn 2+ ions converted H2O2 into HO by Fenton reaction. Meanwhile, rGO NSs mediated photothermal therapy (PTT) could further kill cancer cells. High temperature caused by photothermal conversion increased Fenton reaction rate, which enhanced the efficiency of MnO2 NPs mediated chemodynamic therapy (CDT). Importantly, thanks to the enhanced cell uptake of MnO2 NPs favored by the delivery properties of rGO, rGO@MnO2 possessed higher lethality to cancer cells. The decrease in the nanomaterials' effective dose would further improve biosecurity and reduce cost. Therefore, rGO@MnO2 have great potential in cancer therapy by exploiting the synergistic effect of PTT and photothermal/delivery effect enhanced CDT.
Published: 2021

27. Granulomatous manifestations associated with COVID19 infection: Is there a link between these two diseases?

Author: Aurélien Guffroy, Anne Sophie Korganow, Jean-Christophe Weber, M. Rondeau-Lutz, Juliette Jeannel, Philippe Mertz, S. Lescuyer, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherches interdisciplinaires sur les sciences et la technologie (IRIST), Université de Strasbourg (UNISTRA), Archives Henri-Poincaré - Philosophie et Recherches sur les Sciences et les Technologies (AHP-PReST), Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré (LHSP), and Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Mucosal associated invariant T cells, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Sarcoidosis, COVID19, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Mucosal associated invariant T cell, Peptidyl-Dipeptidase A, Article, Angiotensin-converting enzyme II, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, 030304 developmental biology, 0303 health sciences, Granulomatous disease, business.industry, SARS-CoV-2, COVID-19, medicine.disease, Virology, 030220 oncology & carcinogenesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Published: 2021

28. The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination

Author: Jordi Del-Pozo-Rodríguez, Christophe Romier, Peggy Tilly, Elizabeth Ramos-Morales, Thalia Salinas-Giegé, Eric Ennifar, Efil Bayam, Edouard Troesch, Martin Marek, Philippe Wolff, Juliette D. Godin, Laurence Drouard, Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-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)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), univOAK, Archive ouverte, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Adenosine, Adenosine Deaminase, AcademicSubjects/SCI00010, Deamination, Crystallography, X-Ray, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, RNA, Transfer, Cell Movement, Structural Biology, Catalytic Domain, Cell Line, Tumor, Genetics, medicine, Animals, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, Inosine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Neurons, 0303 health sciences, Mutation, Messenger RNA, biology, Active site, TRNA binding, Biochemistry, CRYSTAL-STRUCTURE, INTELLECTUAL DISABILITY, ESCHERICHIA-COLI, TADA, ANTICODON, SPECIFICITY, POSITION, FEATURES, DATABASE, ENZYMES, Transfer RNA, biology.protein, Ferredoxins, 030217 neurology & neurosurgery, medicine.drug
Abstract: Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2., Graphical Abstract Graphical abstractADAT catalyses tRNAs wobble adenosine-to-inosine modification through ADAT3 recognition of tRNAs 3D structure and anticodon-loop presentation to ADAT2 catalytic subunit. ADAT3 V128M mutation hampers presentation, leading to neurodevelopmental disorders.
Published: 2021

29. Human DICER helicase domain recruits PKR and modulates its antiviral activity

Author: Philippe Hammann, Sébastien Pfeffer, Mathieu Lefèvre, Erika Girardi, Johana Chicher, Morgane Baldaccini, Mélanie Messmer, Thomas Montavon, Béatrice Chane-Woon-Ming, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte
Subjects: Ribonuclease III, Small interfering RNA, Physiology, viruses, Interaction Networks, RNA-binding protein, Virus Replication, Biochemistry, DEAD-box RNA Helicases, eIF-2 Kinase, RNA interference, 0302 clinical medicine, Interferon, Immune Physiology, Medicine and Health Sciences, Biology (General), 0303 health sciences, Immune System Proteins, biology, 030302 biochemistry & molecular biology, food and beverages, RNA Helicase A, Enzymes, Precipitation Techniques, 3. Good health, Cell biology, Nucleic acids, RNA silencing, Genetic interference, Interferon Type I, Helicases, Epigenetics, Research Article, medicine.drug, QH301-705.5, Immunology, Research and Analysis Methods, Transfection, Antiviral Agents, Microbiology, Antibodies, 03 medical and health sciences, Virology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Humans, Immunoprecipitation, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Non-coding RNA, Molecular Biology Techniques, Molecular Biology, 030304 developmental biology, Alphavirus Infections, fungi, Biology and Life Sciences, Proteins, Helicase, RC581-607, Semliki forest virus, Protein kinase R, Gene regulation, enzymes and coenzymes (carbohydrates), HEK293 Cells, Enzymology, biology.protein, RNA, Parasitology, Gene expression, Immunologic diseases. Allergy, 030217 neurology & neurosurgery, Cloning, Dicer
Abstract: The antiviral innate immune response mainly involves type I interferon (IFN) in mammalian cells. The contribution of the RNA silencing machinery remains to be established, but several recent studies indicate that the ribonuclease DICER can generate viral siRNAs in specific conditions. It has also been proposed that type I IFN and RNA silencing could be mutually exclusive antiviral responses. In order to decipher the implication of DICER during infection of human cells with alphaviruses such as the Sindbis virus and Semliki forest virus, we determined its interactome by proteomics analysis. We show that DICER specifically interacts with several double-stranded RNA binding proteins and RNA helicases during viral infection. In particular, proteins such as DHX9, ADAR-1 and the protein kinase RNA-activated (PKR) are enriched with DICER in virus-infected cells. We demonstrate that the helicase domain of DICER is essential for this interaction and that its deletion confers antiviral properties to this protein in an RNAi-independent, PKR-dependent, manner., Author summary While RNAi has been recognized as an efficient antiviral defense system in organisms such as plants and insects, its physiological importance in mammals remains to be determined. DICER is an enzyme involved in cleaving long double-stranded RNAs and is essential for RNAi induction. Using mass spectrometry analysis, we determined its interactome in human cells and showed that RNA binding proteins such as PKR are specifically enriched upon infection with the Sindbis virus or the Semliki forest virus. We determined that the N terminal helicase domain of the DICER protein acts as a platform to recruit these factors during infection and that its deletion confers an antiviral activity to DICER.
Published: 2021

30. µIVC-Useq: a microfluidic-assisted high-throughput functionnal screening in tandem with next generation sequencing and artificial neural network to rapidly characterize RNA molecules

Author: Michael Ryckelynck, Farah Bouhedda, Roger Cubi, Mayeul Collot, Andrey S. Klymchenko, Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biophotonique et Pharmacologie (CNRS UMR 7213), and Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Small RNA, In silico, High-throughput screening, Aptamer, 030302 biochemistry & molecular biology, Robustness (evolution), RNA, Computational biology, Biology, 03 medical and health sciences, In vitro compartmentalization, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Throughput (business), 030304 developmental biology
Abstract: The function of an RNA is intimately linked to its structure. Many approaches encompassing X-ray crystallography, NMR, structural probing, or in silico predictions have been developed to establish structural models, sometimes with a precision down to atomic resolution. Yet these models still require experimental validation through the preparation and functional assay of mutants, which can rapidly become time consuming and laborious. Such limitations can be overcome using high-throughput functional screenings that may not only help in validating the model, but also inform on the mutational robustness of a structural element and the extent to which a sequence can be modified without altering RNA function, an important set of information to assist RNA engineering. We introduced the microfluidic-assisted in vitro compartmentalization (µIVC), an efficient and cost-effective screening strategy in which reactions are performed in picoliter droplets at rates of several thousand per second. We later improved µIVC efficiency by using it in tandem with high-throughput sequencing, though a laborious bioinformatic step was still required at the end of the process. In the present work, we further increased the automation level of the pipeline by implementing an artificial neural network enabling unsupervised bioinformatic analysis. We demonstrate the efficiency of this “µIVC-Useq” technology by rapidly identifying a set of sequences readily accepted by a key domain of the light-up RNA aptamer SRB-2. This work not only shed some new light on the way this aptamer can be engineered, but it also allowed us to easily identify new variants with an up to 10-fold improved performance.
Published: 2021

31. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Author: Zhengshan Chen, Maike Buchner, Kadriye Nehir Cosgun, Pauline Soulas-Sprauel, Nora Heisterkamp, Veronika Ecker, Lars Klemm, Anne Marie Knapp, Joo Y. Song, Friedemann Kiefer, Supraja Saravanakumar, Markus Müschen, Thierry Martin, Mark Robinson, Hassan Jumaa, Vu N. Ngo, Dana Ghergus, Tanya Siddiqi, Kohei Kume, Laura Oksa, Mickaël Martin, Teresa Sadras, Jevon Cutler, Lili Wang, Janet Winchester, Eric Meffre, Gal Lenz, Wing C. Chan, Jürgen Ruland, Akhilesh Pandey, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tampere University, and Clinical Medicine
Subjects: Lymphoma, B-Cell, Chronic lymphocytic leukemia, B-cell receptor, Antigens, CD19, Syk, Receptors, Antigen, B-Cell, Autoimmunity, Biology, Article, 03 medical and health sciences, Negative selection, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Neoplasms, medicine, Immune Tolerance, Animals, Humans, Syk Kinase, Molecular Biology, B cell, 030304 developmental biology, 0303 health sciences, B-Lymphocytes, ZAP-70 Protein-Tyrosine Kinase, Models, Genetic, NFATC Transcription Factors, ZAP70, B cell selection, breakpoint cluster region, Cell Differentiation, Cell Biology, medicine.disease, Neoplasm Proteins, Enzyme Activation, medicine.anatomical_structure, Cell Transformation, Neoplastic, Cancer research, Calcium, 3111 Biomedicine, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Protein Binding, Signal Transduction
Abstract: Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies. acceptedVersion
Published: 2021

32. Prevalence of antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis and spatial association with quarries in a French Northeast region

Author: Giorgiutti, Stéphane, Dieudonné, Yannick, Hinschberger, Olivier, Nespola, Benoît, Campagne, Julien, Rakotoarivelo, Hanta Nirina, Hannedouch, Thierry, Moulin, Bruno, Blaison, Gilles, Weber, Jean-Christophe, Dalmas, Marie‐Caroline, De Blay De Gaix, Frederic, Lipsker, Dan, Chantrel, François, Gottenberg, Jacques Eric, Dimitrov, Yves, Imhoff, Olivier, Gavand, Pierre‐Edouard, Andres, Emmanuel, Debry, Christian, Hansmann, Yves, Klein, Alexandre, Lohmann, Caroline, Mathiaux, François, Guffroy, Aurélien, Poindron, Vincent, Martin, Thierry, Korganow, Anne-sophie, Arnaud, Laurent, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Archives Henri-Poincaré - Philosophie et Recherches sur les Sciences et les Technologies (AHP-PReST), Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré (LHSP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Mitochondrie, stress oxydant et protection musculaire (MSP), Université de Strasbourg (UNISTRA), Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-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), Virulence bactérienne précoce : fonctions cellulaires et contrôle de l'infection aiguë et subaiguë, Immuno-Rhumatologie Moléculaire, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
Subjects: [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Objective: Silica is one of the strongest environmental substances linked with autoimmunity. The aim of this study was to assess the prevalence of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and renal limited vasculitis (RLV) in a French northeast region, and their geospatial association with quarries. Methods: Potential ANCA-Associated Vasculitis (AAV) cases were identified using three sources: hospital records, immunology laboratories and the National Health Insurance System. Patients who resided in Alsace on January 1, 2016 and fulfilled ACR AAV criteria or Chapel Hill Consensus Conference 2012 definition were included. Incomplete case ascertainment was corrected using capture-recapture analysis. The spatial association between the number of cases and quarries in each administrative entity was assessed using geographical weighted regression (GWR). Results: From 910 potential AAV cases, we identified 185 patients meeting inclusion criteria: 120 GPA, 35 MPA, 30 RLV. The number of cases missed by any source was 6.4 (95%CI 3.6-11.5). Accordingly, the 2016 estimated prevalence in Alsace was 65.5 cases per million inhabitants (95%CI 47.3-93.0) for GPA, 19.1 (95%CI 11.3-34.3) for MPA, and 16.8 (95%CI 8.7-35.2) for RLV. The risk of AAV was significantly increased in communes with quarries (OR: 2.51 [95%CI: 1.66-3.80]) and GWR revealed a significant spatial association between quarries and GPA cases (p = 0.039), and, regarding ANCA serotype, between quarries and both PR3-AAV (p = 0.04) and MPO-AAV (p = 0.03)." Conclusion: In a region with a high density of quarries, the spatial association of AAV with quarries supports the role of silica as a specific environmental factor.
Published: 2021

33. Biophysical Studies of the Binding of Viral RNA with the 80S Using switchSENSE

Author: Schenckbecher, Emma, Bec, Guillaume, Sakamoto, Taiichi, Meyer, Benoit, Ennifar, Eric, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

34. Impact of 3-deazapurine nucleobases on RNA properties

Author: Bereiter, Raphael, Himmelstoß, Maximilian, Renard, Eva, Mairhofer, Elisabeth, Egger, Michaela, Breuker, Kathrin, Kreutz, Christoph, Ennifar, Eric, Micura, Ronald, Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Chemical Biology and Nucleic Acid Chemistry, AcademicSubjects/SCI00010, Mutagenesis, Purines, RNA Stability, RNA, Thermodynamics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Crystallography, X-Ray, Base Pairing, Tubercidin
Abstract: Deazapurine nucleosides such as 3-deazaadenosine (c3A) are crucial for atomic mutagenesis studies of functional RNAs. They were the key for our current mechanistic understanding of ribosomal peptide bond formation and of phosphodiester cleavage in recently discovered small ribozymes, such as twister and pistol RNAs. Here, we present a comprehensive study on the impact of c3A and the thus far underinvestigated 3-deazaguanosine (c3G) on RNA properties. We found that these nucleosides can decrease thermodynamic stability of base pairing to a significant extent. The effects are much more pronounced for 3-deazapurine nucleosides compared to their constitutional isomers of 7-deazapurine nucleosides (c7G, c7A). We furthermore investigated base pair opening dynamics by solution NMR spectroscopy and revealed significantly enhanced imino proton exchange rates. Additionally, we solved the X-ray structure of a c3A-modified RNA and visualized the hydration pattern of the minor groove. Importantly, the characteristic water molecule that is hydrogen-bonded to the purine N3 atom and always observed in a natural double helix is lacking in the 3-deazapurine-modified counterpart. Both, the findings by NMR and X-ray crystallographic methods hence provide a rationale for the reduced pairing strength. Taken together, our comparative study is a first major step towards a comprehensive understanding of this important class of nucleoside modifications.
Published: 2021

35. The 'French Germinal Center Club' of the French Society for Immunology

Author: Ame, Patricia, Dumortier, Helene, Espeli, Marion, Milpied, Pierre, Fazilleau, Nicolas, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), and Chard-Hutchinson, Xavier
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract: International audience; The antibody response and B cell memory development are major effector arms of the immune system. They both rely on the selection of B cells in specific anatomical structures called germinal centers (GC). GCs are not only sites for clonal B cell expansion but also the places where the antibody repertoire diversifies following somatic hypermutations and class switch recombination. CD4+ T cells that are present in GCs guide the stringent cell selection of high-affinity B cell variants. They can be divided in two functional cell subsets: T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Furthermore, follicular B and T cell subsets are in close contact with specialized stromal cells allowing cell migration, adhesion, and participating in B cell selection mechanisms. Importantly, on top of their essential role as orchestrators of protective immune responses against infections, GCs have also been involved in diverse pathological conditions including autoimmunity, allergy, and cancer. The great complexity of these structures means that GC aficionados encompass researchers working on a very large palette of topics including in depth analysis of the immune cell types cited above, characterization of cell interactions between GC immune and/or mesenchymal cell subsets, as well as deciphering disease physiopathology. The great versatility of these research foci means that the GC field is extremely dynamic and multidisciplinary. However, because there are many scientific topics addressed when studying GC and despite a consequent number of teams interested in this field, events centered only on GCs allowing researcher interactions are quite rare.
Published: 2021

36. The 'French Germinal Center Club' of the French Society for Immunology: a dynamic collaboration between researchers passionate about the germinal center reaction

Author: Hélène Dumortier, Marion Espéli, Patricia Amé, Pierre Milpied, Nicolas Fazilleau, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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 ), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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 Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), and 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)
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], Immunology, Library science, Germinal center, Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, Club, Intersectoral Collaboration, 030304 developmental biology, 030215 immunology
Abstract: International audience; The antibody response and B cell memory development are major effector arms of the immune system. They both rely on the selection of B cells in specific anatomical structures called germinal centers (GC). GCs are not only sites for clonal B cell expansion but also the places where the antibody repertoire diversifies following somatic hypermutations and class switch recombination. CD4+ T cells that are present in GCs guide the stringent cell selection of high-affinity B cell variants. They can be divided in two functional cell subsets: T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Furthermore, follicular B and T cell subsets are in close contact with specialized stromal cells allowing cell migration, adhesion, and participating in B cell selection mechanisms. Importantly, on top of their essential role as orchestrators of protective immune responses against infections, GCs have also been involved in diverse pathological conditions including autoimmunity, allergy, and cancer. The great complexity of these structures means that GC aficionados encompass researchers working on a very large palette of topics including in depth analysis of the immune cell types cited above, characterization of cell interactions between GC immune and/or mesenchymal cell subsets, as well as deciphering disease physiopathology. The great versatility of these research foci means that the GC field is extremely dynamic and multidisciplinary. However, because there are many scientific topics addressed when studying GC and despite a consequent number of teams interested in this field, events centered only on GCs allowing researcher interactions are quite rare.
Published: 2021

37. The 'French Germinal Center Club' of the French Society for Immunology: a dynamic collaboration between researchers passionate about the germinal center reaction

Author: Ame, Patricia, Dumortier, Helene, Espeli, Marion, Milpied, Pierre, Fazilleau, Nicolas, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; The antibody response and B cell memory development are major effector arms of the immune system. They both rely on the selection of B cells in specific anatomical structures called germinal centers (GC). GCs are not only sites for clonal B cell expansion but also the places where the antibody repertoire diversifies following somatic hypermutations and class switch recombination. CD4+ T cells that are present in GCs guide the stringent cell selection of high-affinity B cell variants. They can be divided in two functional cell subsets: T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Furthermore, follicular B and T cell subsets are in close contact with specialized stromal cells allowing cell migration, adhesion, and participating in B cell selection mechanisms. Importantly, on top of their essential role as orchestrators of protective immune responses against infections, GCs have also been involved in diverse pathological conditions including autoimmunity, allergy, and cancer. The great complexity of these structures means that GC aficionados encompass researchers working on a very large palette of topics including in depth analysis of the immune cell types cited above, characterization of cell interactions between GC immune and/or mesenchymal cell subsets, as well as deciphering disease physiopathology. The great versatility of these research foci means that the GC field is extremely dynamic and multidisciplinary. However, because there are many scientific topics addressed when studying GC and despite a consequent number of teams interested in this field, events centered only on GCs allowing researcher interactions are quite rare.
Published: 2021

38. Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease

Author: Xiao-Long Zhou, Guang Li, Gilbert Eriani, En-Duo Wang, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), State Key Laboratory of Molecular Biology, and The Chinese Academy of Sciences
Subjects: 0301 basic medicine, Pelizaeus Merzbacher like disease, protein biosynthesis, [SDV]Life Sciences [q-bio], Biology, medicine.disease_cause, translation initiation, General Biochemistry, Genetics and Molecular Biology, Pathogenesis, 03 medical and health sciences, central nervous system (CNS), 0302 clinical medicine, Eukaryotic translation, Upstream open reading frame, medicine, Gene, tRNA, General Environmental Science, Genetics, Mutation, Translation (biology), 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Transfer RNA, aminoacyl-tRNA synthetase (aaRS), General Agricultural and Biological Sciences
Abstract: International audience; Mutations of the genes encoding aminoacyl-tRNA synthetases are highly associated with various central nervous system disorders. Recurrent mutations, including c.[5A>G], p.[D2G]; c.[1367C>T], p.[S456L]; c.[1535G>A], p.[R512Q] and c.[1846_1847del], p.[Y616Lfs*6] of RARS1 gene, which encodes two forms of human cytoplasmic arginyl-tRNA synthetase (hArgRS), are linked to Pelizaeus-Merzbacher-like disease (PMLD) with unclear pathogenesis. Among these mutations, c.[5A>G] is the most extensively reported mutation, leading to a p.[D2G] mutation in the N-terminal extension of the long-form hArgRS. Here, we showed the detrimental effects of R512Q substitution and DC mutations on the structure and function of hArgRS, while the most frequent mutation c.[5A>G], p.[D2G] acted in a different manner without impairing hArgRS activity. The nucleotide substitution c.[5A>G] reduced translation of hArgRS mRNA, and an upstream open reading frame contributed to the suppressed translation of the downstream main ORF. Taken together, our results elucidated distinct pathogenic mechanisms of various RARS1 mutations in PMLD.
Published: 2021

39. HIV-1 Capsid Core: A Bullet to the Heart of the Target Cell

Author: Daniela Lener, Matteo Negroni, Elenia Toccafondi, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), viruses, Cell, lcsh:QR1-502, Review, nuclear transport, Biology, Microbiology, Genome, lcsh:Microbiology, 03 medical and health sciences, medicine, capsid, 030304 developmental biology, 0303 health sciences, 030302 biochemistry & molecular biology, cellular cofactors, reverse transcription, restriction factors, Reverse transcriptase, Cell biology, medicine.anatomical_structure, genetic fragility, Capsid, Cytoplasm, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, uncoating, Nuclear transport, Nucleus, Intracellular
Abstract: The first step of the intracellular phase of retroviral infection is the release of the viral capsid core in the cytoplasm. This structure contains the viral genetic material that will be reverse transcribed and integrated into the genome of infected cells. Up to recent times, the role of the capsid core was considered essentially to protect this genetic material during the earlier phases of this process. However, increasing evidence demonstrates that the permanence inside the cell of the capsid as an intact, or almost intact, structure is longer than thought. This suggests its involvement in more aspects of the infectious cycle than previously foreseen, particularly in the steps of viral genomic material translocation into the nucleus and in the phases preceding integration. During the trip across the infected cell, many host factors are brought to interact with the capsid, some possessing antiviral properties, others, serving as viral cofactors. All these interactions rely on the properties of the unique component of the capsid core, the capsid protein CA. Likely, the drawback of ensuring these multiple functions is the extreme genetic fragility that has been shown to characterize this protein. Here, we recapitulate the busy agenda of an HIV-1 capsid in the infectious process, in particular in the light of the most recent findings.
Published: 2021

40. Reducing neutrophil exposure to oxygen allows their basal state maintenance

Author: Benoit S. Marteyn, Véronique Witko-Sarsat, Louise Injarabian, Jurate Skerniskyte, Quentin Giai Gianetto, Giai Gianetto, Quentin, Effet de l'exposition des neutrophiles à l'oxygène sur leur activation et leur mort : une lame à double tranchant - - NEUTROXIA2017 - ANR-17-CE15-0012 - AAPG2017 - VALID, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), University Hospital of Cologne [Cologne], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Plateforme de Protéomique / Proteomics platform, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the ANR JCJC grant (ANR-17-CE15-0012) (BSM) and has benefitted from the support provided by the University for Advanced Study (USIAS) for a fellowship, within the French national program 'Investment for the futur (Idex-UNISTRA) (BSM), We thank Evangeline Bennana (sample preparation) and Morgan Le Gall (data processing) from the institut Cochin 3P5 Proteom'IC platform, ANR-17-CE15-0012,NEUTROXIA,Effet de l'exposition des neutrophiles à l'oxygène sur leur activation et leur mort : une lame à double tranchant(2017), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Short Communication, Immunology, chemistry.chemical_element, Oxygen, Extracellular Traps, Neutrophil Activation, 03 medical and health sciences, Basal (phylogenetics), chemistry.chemical_compound, Leukocyte Count, 0302 clinical medicine, neutrophils, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Immunology and Allergy, Glycolysis, DAPI, Hyperoxia, Innate immune system, viability, anoxia, Cell Biology, Neutrophil extracellular traps, Cell biology, Cytosol, 030104 developmental biology, chemistry, hyperoxia, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.IMM]Life Sciences [q-bio]/Immunology, activation, medicine.symptom, 030215 immunology
Abstract: Neutrophils are the most abundant circulating white blood cells and are the central players of the innate immune response. During their lifecycle, neutrophils mainly evolve under low oxygen conditions (0.1–4% O2), to which they are well adapted. Neutrophils are atypical cells since they are highly glycolytic and susceptible to oxygen exposure, which induces their activation and death through mechanisms that remain currently elusive. Nevertheless, nearly all studies conducted on neutrophils are carried out under atmospheric oxygen (21%), corresponding to hyperoxia. Here, we investigated the impact of hyperoxia during neutrophil purification and culture on neutrophil viability, activation and cytosolic protein content. We demonstrate that neutrophil hyper‐activation (CD62L shedding) is induced during culture under hyperoxic conditions (24 h), compared with neutrophils cultured under anoxic conditions. Spontaneous neutrophil extracellular trap (NET) formation is observed when neutrophils face hyperoxia during purification or culture. In addition, we show that maintaining neutrophils in autologous plasma is the preferred strategy to maintain their basal state. Our results show that manipulating neutrophils under hyperoxic conditions leads to the loss of 57 cytosolic proteins during purification, while it does not lead to an immediate impact on neutrophil activation (CD11bhigh, CD54high, CD62Lneg) or viability (DAPI+). We identified two clusters of proteins belonging to cholesterol metabolism and to the complement and coagulation cascade pathways, which are highly susceptible to neutrophil oxygen exposure during neutrophil purification. In conclusion, protecting neutrophil from oxygen during their purification and culture is recommended to avoid activation and to prevent the alteration of cytosolic protein composition., In this study, we demonstrate that preserving neutrophils from oxygen exposure during their purification and culture is recommended to avoid their activation and to prevent formation of spontaneous neutrophil extracellular traps. Studying neutrophils in vitro under controlled oxygen levels similar to those encountered in vivo is essential for a better comprehension of their physiology.
Published: 2021

41. RNA Secondary Structure Study by Chemical Probing Methods Using DMS and CMCT

Author: Alghoul, Fatima, Eriani, Gilbert, Martin, Franck, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: QuSHAPE, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], DMS, CMCT, capillary electrophoresis, Chemical probing, RNA secondary structure, primer extension
Abstract: RNA folds into secondary structures that can serve in understanding various RNA functions (Weeks KM. Curr Opin Struct Biol 20(3):295-304, 2010). Chemical probing is a method that enables the characterization of RNA secondary structures using chemical reagents that specifically modify RNA nucleotides that are located in single-stranded areas. In our protocol, we used Dimethyl Sulfate (DMS) and Cyclohexyl-3-(2-Morpholinoethyl) Carbodiimide metho-p-Toluene sulfonate (CMCT) that are both base-specific modifying reagents (Behm-Ansmant I, et al. J Nucleic Acids 2011:408053, 2011). These modifications are mapped by primer extension arrests using 5' fluorescently labeled primers. In this protocol, we show a comprehensive method to identify RNA secondary structures in vitro using fluorescently labeled oligos. To demonstrate the efficiency of the method, we give an example of a structure we have designed which corresponds to a part of the 5'-UTR regulatory element called Translation Inhibitory Element (TIE) from Hox a3 mRNA (Xue S, et al. Nature 517(7532):33-38, 2015).
Published: 2021

42. Refining 'Long-COVID' by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection

Author: Seiamak Bahram, Magali Perret, Jacques-Eric Gottenberg, Adrien Gras, Laurent Arnaud, Alexandre Belot, Renaud Felten, Luc Pijnenburg, Jean Sibilia, Sabrina Bibi-Triki, Sophie Trouillet-Assant, Raphael Carapito, Charlotte Nazon, Emmanuel Chatelus, Rachel Arnould-Michel, Floriane Gallais, Amaury C. Mengin, Pierre Vidailhet, Samira Fafi-Kremer, Marc Scherlinger, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunopathologie et chimie thérapeutique (ICT), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), medicine.medical_specialty, Visual analogue scale, Pain, Physical examination, Serology, Patient perspective, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Interquartile range, Internal medicine, Medicine, 030212 general & internal medicine, Prospective cohort study, Depression (differential diagnoses), Original Research, Disability, medicine.diagnostic_test, SARS-CoV-2, business.industry, Long-COVID, disability long-covid pain patient perspective sars-cov-2 consequences, 3. Good health, Infectious Diseases, Anxiety, medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Introduction COVID-19 long-haulers, also decribed as having “long-COVID” or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied. Methods In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group. Results The median age was 40 [interquartile range: 35–54] years and 18 (60%) were female. At a median time of 152 [102–164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5–8] and 5 [2–6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively. Conclusions Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00484-w.
Published: 2021

43. Current Clinical and Pre-Clinical Imaging Approaches to Study the Cancer-Associated Immune System

Author: Christopher G. Mueller, Christian Gaiddon, Aïna Venkatasamy, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Gaiddon, Christian, Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), 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), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-20-SFRI-0012,STRAT'US,Façonner les talents en formation et en recherche à l'Université de Strasbourg(2020), ANR-11-EQPX-0022,I2MC,Insectarium pour l'Infectiologie Moléculaire et Cellulaire(2011), ANR-20-CE93-0006,Lymphinnate,Analyse de l'interaction entre l'endothélium lymphatique et cellules immunitaires innées dans le ganglion lymphatique et son impact sur l'immunité adaptative(2020), ANR-19-CE14-0021,ANTIPODE,La spécificité tissulaire des effets paradoxaux de la thérapie anti-TNF dans les maladies inflammatoires de l'intestin(2019), ANR-10-IAHU-0002,MIX-Surg,Institut de Chirurgie Mini-Invasive guidée par l'Image(2010), Immunologie et chimie thérapeutiques (ICT), and Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS)
Subjects: Diagnostic Imaging, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV]Life Sciences [q-bio], Mini Review, Immunology, Cancer therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, Cellular level, Sciences du Vivant [q-bio]/Cancer, Multimodal Imaging, Standard procedure, 03 medical and health sciences, Immune system, immune cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Medicine, Immunology and Allergy, Animals, Humans, cancer, tertiary lymphoid structure, Clinical imaging, 030304 developmental biology, 0303 health sciences, business.industry, Non invasive, Cancer, imaging, RC581-607, lymph node, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Molecular Imaging, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Risk analysis (engineering), [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Immune System, Lymphatic Metastasis, Lymph Nodes, Immunologic diseases. Allergy, 0210 nano-technology, business, Biomarkers
Abstract: In the light of the success and the expected growth of its arsenal, immuno-therapy may become the standard neoadjuvant procedure for many cancers in the near future. However, aspects such as the identity, organization and the activation status of the peri- and intra-tumoral immune cells would represent important elements to weigh in the decision for the appropriate treatment. While important progress in non-invasive imaging of immune cells has been made over the last decades, it falls yet short of entering the clinics, let alone becoming a standard procedure. Here, we provide an overview of the different intra-vital imaging approaches in the clinics and in pre-clinical settings and discuss their benefits and drawbacks for assessing the activity of the immune system, globally and on a cellular level. Stimulated by further research, the future is likely to see many technological advances both on signal detection and emission as well as image specificity and resolution to tackle current hurdles. We anticipate that the ability to precisely determine an immune stage of cancer will capture the attention of the oncologist and will create a change in paradigm for cancer therapy. journal article review research support, non-u.s. gov't 2021 2021 09 03 imported
Published: 2021

44. Post-Translational Modifications of Retroviral HIV-1 Gag Precursors: An Overview of Their Biological Role

Author: Serena Bernacchi, Jean-Christophe Paillart, Charlotte Bussienne, Roland Marquet, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg, CNRS, Architecture et Réactivité de l'ARN
Subjects: 0301 basic medicine, Viral budding, viruses, Cell, SUMO protein, Pr55Gag precursor, Review, Virus Replication, gag Gene Products, Human Immunodeficiency Virus, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, Ubiquitin, medicine, post-translational modifications, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physical and Theoretical Chemistry, Protein Precursors, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Myristoylation, 030102 biochemistry & molecular biology, biology, Endosomal Sorting Complexes Required for Transport, Virus Assembly, Organic Chemistry, Cell Membrane, General Medicine, Methylation, retroviral Gag precursors, 3. Good health, Computer Science Applications, Cell biology, retroviral life cycle, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, Viral replication, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, HIV-1, Phosphorylation, RNA, Viral, Protein Processing, Post-Translational
Abstract: Protein post-translational modifications (PTMs) play key roles in eukaryotes since they finely regulate numerous mechanisms used to diversify the protein functions and to modulate their signaling networks. Besides, these chemical modifications also take part in the viral hijacking of the host, and also contribute to the cellular response to viral infections. All domains of the human immunodeficiency virus type 1 (HIV-1) Gag precursor of 55-kDa (Pr55Gag), which is the central actor for viral RNA specific recruitment and genome packaging, are post-translationally modified. In this review, we summarize the current knowledge about HIV-1 Pr55Gag PTMs such as myristoylation, phosphorylation, ubiquitination, sumoylation, methylation, and ISGylation in order to figure out how these modifications affect the precursor functions and viral replication. Indeed, in HIV-1, PTMs regulate the precursor trafficking between cell compartments and its anchoring at the plasma membrane, where viral assembly occurs. Interestingly, PTMs also allow Pr55Gag to hijack the cell machinery to achieve viral budding as they drive recognition between viral proteins or cellular components such as the ESCRT machinery. Finally, we will describe and compare PTMs of several other retroviral Gag proteins to give a global overview of their role in the retroviral life cycle.
Published: 2021

45. Implications of the nucleocapsid protein in the reverse transcription & genetic diversity of HIV-1

Author: Negroni, Matteo, Lener, Daniela, univOAK, Archive ouverte, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Structure des macromolécules biologiques et mécanismes de reconnaissance (SMBMR), and Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Published: 2021

46. Application of NMR Spectroscopy to Determine the 3D Structure of Small Non-Coding RNAs

Author: Isabelle Lebars, Marc Quinternet, Marie-Eve Chagot, Xavier Manival, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), 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), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Mathieu Rederstorff, univOAK, Archive ouverte, and Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Saccharomyces cerevisiae, Computational biology, 010402 general chemistry, 3D structure, 01 natural sciences, 03 medical and health sciences, Small nucleolar RNA, Nuclear Magnetic Resonance, Biomolecular, Regulation of gene expression, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, RNA, RNA, Fungal, Nuclear magnetic resonance spectroscopy, dynamics, Non-coding RNA, Small molecule, NMR, 0104 chemical sciences, 030104 developmental biology, Nucleic acid, Nucleic Acid Conformation, RNA, Small Untranslated
Abstract: Many RNA architectures were discovered to be involved in a wide range of essential biological processes in all organisms from carrying genetic information to gene expression regulation. The remarkable ability of RNAs to adopt various architectures depending on their environment enables the achievement of their myriads of biological functions. Nuclear Magnetic Resonance (NMR) is a powerful technique to investigate both their structure and dynamics. NMR is also a key tool for studying interactions between RNAs and their numerous partners such as small molecules, ions, proteins, or other nucleic acids. In this chapter, to illustrate the use of NMR for 3D structure determination of small noncoding RNA, we describe detailed methods that we used for the yeast C/D box small nucleolar RNA U14 from sample preparation to 3D structure calculation.
Published: 2021

47. Amplifying and Fine-Tuning Rsm sRNAs Expression and Stability to Optimize the Survival of Pseudomonas brassicacerum in Nutrient-Poor Environments

Author: Thierry Heulin, Sylvain Fochesato, Philippe Ortet, David Lalaouna, Mourad Harir, Wafa Achouak, Philippe Schmitt-Kopplin, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Microbienne de la Rhizosphère et d'Environnements Extrêmes (LEMIRE), Institut de Biosciences et Biotechnologies d'Aix-Marseille (ex-IBEB) (BIAM), 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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-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), and Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: Microbiology (medical), Stringent response, Rsm sRNAs, medicine.disease_cause, Microbiology, 03 medical and health sciences, Virology, sRNAs stability, Gene duplication, medicine, ddc:630, Gene, lcsh:QH301-705.5, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, biology, 030306 microbiology, Pseudomonas, Biofilm, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Pseudomonas brassicacearum, ddc, lcsh:Biology (General), nutritional stress, Transfer RNA, Gaca-dependent, Nutritional Stress, Pseudomonas Brassicacearum, Rsm Srnas, Srnas Stability, GacA-dependent, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: In the beneficial plant root-associated Pseudomonas brassicacearum strain NFM421, the GacS/GacA two-component system positively controls biofilm formation and the production of secondary metabolites through the synthesis of rsmX, rsmY and rsmZ. Here, we evidenced the genetic amplification of Rsm sRNAs by the discovery of a novel 110-nt long sRNA encoding gene, rsmX-2, generated by the duplication of rsmX-1 (formerly rsmX). Like the others rsm genes, its overexpression overrides the gacA mutation. We explored the expression and the stability of rsmX-1, rsmX-2, rsmY and rsmZ encoding genes under rich or nutrient-poor conditions, and showed that their amount is fine-tuned at the transcriptional and more interestingly at the post-transcriptional level. Unlike rsmY and rsmZ, we noticed that the expression of rsmX-1 and rsmX-2 genes was exclusively GacA-dependent. The highest expression level and longest half-life for each sRNA were correlated with the highest ppGpp and cyclic-di-GMP levels and were recorded under nutrient-poor conditions. Together, these data support the view that the Rsm system in P. brassicacearum is likely linked to the stringent response, and seems to be required for bacterial adaptation to nutritional stress.
Published: 2021

48. Cex1 is a component of the COPI intracellular trafficking machinery

Author: Ludovic Enkler, Bruno Rinaldi, Johan Owen de Craene, Philippe Hammann, Osamu Nureki, Bruno Senger, Sylvie Friant, Hubert D. Becker, Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Biomolécules et biotechnologies végétales (BBV EA 2106), Université de Tours, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), The University of Tokyo (UTokyo), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Université de Tours (UT)
Subjects: Proteomics, Nucleocytoplasmic Transport Proteins, QH301-705.5, Science, Intracellular Space, Golgi Apparatus, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Endoplasmic Reticulum, Mass Spectrometry, Coat Protein Complex I, Fungal Proteins, SCYL1, Biology (General), COPI coat, Trafficking, RNA-Binding Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Protein Transport, Mutation, Cex1, Arc1, Gene Deletion, Chromatography, Liquid, Protein Binding, Research Article
Abstract: COPI (coatomer complex I) coated vesicles are involved in Golgi-to-ER and intra-Golgi trafficking pathways, and mediate retrieval of ER resident proteins. Functions and components of the COPI-mediated trafficking pathways, beyond the canonical set of Sec/Arf proteins, are constantly increasing in number and complexity. In mammalian cells, GORAB, SCYL1 and SCYL3 proteins regulate Golgi morphology and protein glycosylation in concert with the COPI machinery. Here, we show that Cex1, homologous to the mammalian SCYL proteins, is a component of the yeast COPI machinery, by interacting with Sec27, Sec28 and Sec33 (Ret1/Cop1) proteins of the COPI coat. Cex1 was initially reported to mediate channeling of aminoacylated tRNA outside of the nucleus. Our data show that Cex1 localizes at membrane compartments, on structures positive for the Sec33 α-COP subunit. Moreover, the Wbp1 protein required for N-glycosylation and interacting via its di-lysine motif with the Sec27 β′-COP subunit is mis-targeted in cex1Δ deletion mutant cells. Our data point to the possibility of developing Cex1 yeast-based models to study neurodegenerative disorders linked to pathogenic mutations of its human homologue SCYL1., Summary: Cex1, the yeast homologue of mammalian SCYL1, interacts with COPI coat components and is recruited to the Golgi to regulate retrograde vesicular trafficking and sorting
Published: 2021

49. The viral protein NSP1 acts as a ribosome gatekeeper for shutting down host translation and fostering SARS-CoV-2 translation

Author: Franck Martin, Philippe Hammann, Eric Westhof, Gilbert Eriani, Antonin Tidu, Lauriane Kuhn, Laure Schaeffer, Aurélie Janvier, Piotr Sosnowski, univOAK, Archive ouverte, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Viral protein, viruses, Biology, medicine.disease_cause, Ribosome, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Molecular Biology, Letter to the Editor, 030304 developmental biology, Coronavirus, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, Messenger RNA, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 030302 biochemistry & molecular biology, Viral translation, RNA, virus diseases, Translation (biology), 3. Good health, Cell biology, Transplantation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030217 neurology & neurosurgery
Abstract: SARS-CoV-2 coronavirus is responsible for Covid-19 pandemic. In the early phase of infection, the single-strand positive RNA genome is translated into non-structural proteins (NSP). One of the first proteins produced during viral infection, NSP1, binds to the host ribosome and blocks the mRNA entry channel. This triggers translation inhibition of cellular translation. In spite of the presence of NSP1 on the ribosome, viral translation proceeds however. The molecular mechanism of the so-called viral evasion to NSP1 inhibition remains elusive. Here, we confirm that viral translation is maintained in the presence of NSP1. The evasion to NSP1-inhibition is mediated by thecis-acting RNA hairpin SL1 in the 5’UTR of SARS-CoV-2. NSP1-evasion can be transferred on a reporter transcript by SL1 transplantation. The apical part of SL1 is only required for viral translation. We show that NSP1 remains bound on the ribosome during viral translation. We suggest that the interaction between NSP1 and SL1 frees the mRNA accommodation channel while maintaining NSP1 bound to the ribosome. Thus, NSP1 acts as a ribosome gatekeeper, shutting down host translation or fostering SARS-CoV-2 translation depending on the presence of the SL1 5’UTR hairpin. SL1 is also present and necessary for translation of sub-genomic RNAs in the late phase of the infectious program. Consequently, therapeutic strategies targeting SL1 should affect viral translation at early and late stages of infection. Therefore, SL1 might be seen as a genuine ‘Achille heel’ of the virus.
Published: 2021

50. Structural Differences in Translation Initiation between Pathogenic Trypanosomatids and Their Mammalian Hosts

Author: Anthony Bochler, Jailson Brito Querido, Terezie Prilepskaja, Heddy Soufari, Angelita Simonetti, Mayara Lucia Del Cistia, Lauriane Kuhn, Aline Rimoldi Ribeiro, Leoš Shivaya Valášek, Yaser Hashem, Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Charles University [Prague] (CU), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institute of Microbiology of the Czech Academy of Sciences [Prague, Czech Republic] (MBU / CAS), Czech Academy of Sciences [Prague] (CAS), and CCSD, Accord Elsevier
Subjects: eIF5-CTD, Models, Molecular, Chagas disease, ES7S, ES9S, Trypanosoma cruzi, [SDV]Life Sciences [q-bio], initiation à la traduction, translation initiation, Article, 03 medical and health sciences, 0302 clinical medicine, Eukaryotic translation, Eukaryotic initiation factor, parasitic diseases, medicine, Animals, Parasite hosting, Eukaryotic Small Ribosomal Subunit, le complexe de pré-initiation 43S, ES6(S), 030304 developmental biology, Mammals, Genetics, 0303 health sciences, biology, ES6S, the 43S pre-initiation complex, Helicase, Ribosomal RNA, biology.organism_classification, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], k-DDX60, Protein Biosynthesis, biology.protein, cryo-EM, eIF2, Trypanosomatina, eIF1, eIF3, ES9(S), ES7(S), 030217 neurology & neurosurgery
Abstract: Summary Canonical mRNA translation in eukaryotes begins with the formation of the 43S pre-initiation complex (PIC). Its assembly requires binding of initiator Met-tRNAiMet and several eukaryotic initiation factors (eIFs) to the small ribosomal subunit (40S). Compared to their mammalian hosts, trypanosomatids present significant structural differences in their 40S, suggesting substantial variability in translation initiation. Here, we determine the structure of the 43S PIC from Trypanosoma cruzi, the parasite causing Chagas disease. Our structure shows numerous specific features, such as the variant eIF3 structure and its unique interactions with the large rRNA expansion segments (ESs) 9S, 7S, and 6S, and the association of a kinetoplastid-specific DDX60-like helicase. It also reveals the 40S-binding site of the eIF5 C-terminal domain and structures of key terminal tails of several conserved eIFs underlying their activities within the PIC. Our results are corroborated by glutathione S-transferase (GST) pull-down assays in both human and T. cruzi and mass spectrometry data., Graphical Abstract, Highlights • Structure of the 43S pre-initiation complex from Trypanosoma cruzi is solved at 3.33 Å • The kinetoplastids’ eIF3 core is a septamer that binds mainly the unique, extended ES7s • A kinetoplastid-specific DDX60-like helicase binds to the 43S PIC entry pore • The 40S positions of eIF5-CTD and key tails of several eIFs are determined, Trypanosoma cruzi, which causes Chagas disease, represents a serious health problem. Bochler et al. solve the structure of the 43S translation pre-initiation complex of this parasite, highlighting numerous features by which it differs from the mammalian complex to stimulate development of new drugs against trypanosomiasis and leishmaniasis.
Published: 2020

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