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1. Comparative analysis of docetaxel: physical and chemical characterisation of Taxotère® and generics

Author

Da Costa Eloïse, Do Bernard, Solgadi Audrey, Lemare François, Le Guyader Guillaume, Delaloge Suzette, Annereau Maxime, Souquere Sylvie, Pierron Gérard, Paul Muriel, Viellard Victoire, Fleury Thomas, Roy Pétronille, Conq Jérôme, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Groupe matériaux et santé, Université Paris-Saclay, Service de pharmacologie clinique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre Hospitalier Intercommunal de Créteil (CHIC), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, Cancer Research, Drug Compounding, Polysorbates, Antineoplastic Agents, Docetaxel, Pharmacology, Bioequivalence, Vial, Micelle, Risk Assessment, Excipients, 03 medical and health sciences, 0302 clinical medicine, medicine, Drugs, Generic, Humans, In patient, Particle Size, Adverse effect, Micelles, Ethanol, business.industry, Enterocolitis, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Drug Liberation, Kinetics, 030104 developmental biology, Oncology, Therapeutic Equivalency, 030220 oncology & carcinogenesis, Patient Safety, business, medicine.drug
Abstract

Several cases of fatal enterocolitis have been described in association with the use of docetaxel (DTX), and this increase in adverse events has been concomitant with a change in formulation. Indeed in 2010, a new DTX-based presentation has been introduced in the form of a single ready-to-use vial by Sanofi-Aventis, presentation also used for generics. In this study, different available formulations were compared (Sanofi 2 vials, Sanofi 1 vial, Accord Healthcare, Kabi, Hospira) in terms of composition compliance with control specifications and simulated micelle behaviour to try to determine what could be the potential causes of this problem. This work had permitted to show that all the tested products complied with specifications in terms of dosage and purity. Variations in the composition of polysorbate 80 (PS80) have been observed but are probably too small to be responsible for the toxicity found in patients. However, we identified a difference in micelle size and release kinetics probably because of doubling concentration of ethanol in new formulation. As a result, we emphasised the importance in the case of DTX of conducting bioequivalence studies as expected in European Medicines Agency (EMA) guidance to ensure patient safety, even though these formulation changes might seem minor. Therefore, further studies are needed to explore the potential role of ethanol, PS80 and the unbound fraction of DTX in the development of enterocolitis in patients treated with DTX.

Published
2020
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2. Artificial tethering of LC3 or p62 to organelles is not sufficient to trigger autophagy

Author

Gérard Pierron, Maria Chiara Maiuri, Sylvie Souquere, José Manuel Bravo-San Pedro, Sylvie Lachkar, Guido Kroemer, Oliver Kepp, Ana Joaquina Jimenez, Wei Xie, Valentina Sica, Adriana Petrazzuolo, Franck Perez, Allan Sauvat, Friedemann Loos, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Physiopathologie orale moléculaire (CRC - Inserm U1138), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Mort cellulaire et résistance aux traitements dans les hémopathies malignes (CRC - Inserm U1138), University of Nottingham, UK (UON), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Loos, F., Xie, W., Sica, V., Bravo-San Pedro, J. M., Souquere, S., Pierron, G., Lachkar, S., Sauvat, A., Petrazzuolo, A., Jimenez, A. J., Perez, F., Maiuri, M. C., Kepp, O., Kroemer, G., and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, CELL-SURVIVAL, PROTEIN, Golgi Apparatus, RNA-Binding Protein, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Endoplasmic Reticulum, chemistry.chemical_compound, 0302 clinical medicine, Cytosol, Medicine and Health Sciences, 0303 health sciences, biology, lcsh:Cytology, RNA-Binding Proteins, Recombinant Protein, Recombinant Proteins, Cell biology, Protein Transport, symbols, TURNOVER, Target protein, MAP1LC3B, Microtubule-Associated Proteins, Human, Protein Binding, Streptavidin, Immunology, Green Fluorescent Proteins, Biotin, Golgi Apparatu, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Green Fluorescent Protein, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, symbols.namesake, Cell Line, Tumor, Macroautophagy, Autophagy, Humans, SELECTIVE AUTOPHAGY, lcsh:QH573-671, MODULATION, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Endoplasmic reticulum, Microtubule-Associated Protein, fungi, Biology and Life Sciences, Cell Biology, Golgi apparatus, DEGRADATION, Fusion protein, chemistry, biology.protein, Chemical tools, 030217 neurology & neurosurgery, SYSTEM, Avidin
Abstract

The retention using selective hooks (RUSH) system allows to retain a target protein fused to green fluorescent protein (GFP) and a streptavidin-binding peptide (SBP) due to the interaction with a molar excess of streptavidin molecules (“hooks”) targeted to selected subcellular compartments. Supplementation of biotin competitively disrupts the interaction between the SBP moiety and streptavidin, liberating the chimeric target protein from its hooks, while addition of avidin causes the removal of biotin from the system and reestablishes the interaction. Based on this principle, we engineered two chimeric proteins involved in autophagy, namely microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B, best known as LC3) and sequestosome-1 (SQSTM1, best known as p62) to move them as SBP–GFP–LC3 and p62–SBP–GFP at will between the cytosol and two different organelles, the endoplasmic reticulum (ER) and the Golgi apparatus. Although both proteins were functional in thus far that SBP–GFP–LC3 and p62–SBP–GFP could recruit their endogenous binding partners, p62 and LC3, respectively, their enforced relocation to the ER or Golgi failed to induce organelle-specific autophagy. Hence, artificial tethering of LC3 or p62 to the surface of the ER and the Golgi is not sufficient to trigger autophagy.

Published
2019
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3. Recruitment of LC3 to damaged Golgi apparatus

Author

Allan Sauvat, Wei Xie, Sylvie Souquere, Franck Perez, Ana Joaquina Jimenez, Guido Kroemer, Oliver Kepp, Séverine Divoux, Øystein Rekdal, Luis G. Arnaut, Lígia C. Gomes-da-Silva, Baldur Sveinbjørnsson, Marko Storch, Institut Gustave Roussy (IGR), Fudan University, Fudan University [Shanghai], Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Department of Life Sciences, Imperial College London, London, United Kingdom, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de Structure Subcellulaire et Dynamique Cellulaire [Paris], Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Rétrovirus endogènes et éléments rétroides des eucaryotes supérieurs (REERES (UMR 8122)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Université Paris Dauphine-PSL-Institut Curie-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Programmed cell death, Protein subunit, ATG5, Green Fluorescent Proteins, Golgi Apparatus, Antineoplastic Agents, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Article, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Tumor Cells, Cultured, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Phagosome, biology, Cell Death, Chemistry, Autophagy, Cell Biology, Golgi apparatus, Phenotype, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, biology.protein, beta-Alanine, Microtubule-Associated Proteins, Peroxidase, HeLa Cells
Abstract

LC3 is a protein that can associate with autophagosomes, autolysosomes, and phagosomes. Here, we show that LC3 can also redistribute toward the damaged Golgi apparatus where it clusters with SQSTM1/p62 and lysosomes. This organelle-specific relocation, which did not involve the generation of double-membraned autophagosomes, could be observed after Golgi damage was induced by various strategies, namely (i) laser-induced localized cellular damage, (ii) local expression of peroxidase and exposure to peroxide and diaminobenzidine, (iii) treatment with the Golgi-tropic photosensitizer redaporfin and light, (iv) or exposure to the Golgi-tropic anticancer peptidomimetic LTX-401. Mechanistic exploration led to the conclusion that both reactive oxygen species-dependent and -independent Golgi damage induces a similar phenotype that depended on ATG5 yet did not depend on phosphatidylinositol-3-kinase catalytic subunit type 3 and Beclin-1. Interestingly, knockout of ATG5 sensitized cells to Golgi damage-induced cell death, suggesting that the pathway culminating in the relocation of LC3 to the damaged Golgi may have a cytoprotective function.

Published
2019
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4. IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise

Author

Thierry Fournier, Caroline Manet, Kenzo-Hugo Hillion, Thérèse Couderc, Emeline Perthame, Julian Buchrieser, Françoise Porrot, Séverine A. Degrelle, Marc Lecuit, Olivier Schwartz, Daniel A. Donahue, Quentin Nevers, Anne Dupressoir, Sylvie Souquere, Olivier Disson, Thierry Heidmann, Marlene V. Arroyo, Katinka Ruigrok, Xavier Montagutelli, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inovarion [Paris], Biologie des Infections - Biology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique fonctionnelle de la Souris, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie Structurale - Structural Virology, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Work in the laboratory of O.S. is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro-Immuno' ANR-14-CE14-0015-01, CNRS and the Gilead HIV cure program. Work in the laboratory of M.L. is funded by Institut Pasteur, INSERM, ERC, Labex IBEID (ANR-10-LABX-62-IBEID), Institut Convergence, and Université Paris Descartes. C.M. was supported by a fellowship from grant no. ANR-10-LABX-62-IBEID. M.V.A. was supported by NSF GRFP grant no. 1644869., We thank members of the Virus and Immunity Unit for discussions and help, M. Maaran Rajah for critical reading of the manuscript. We thank patients who participated in the study. We also thank members of Embryology and Core Breeding teams (DTPS-C2RA-Central Animal Facility platform) for technical support with strain revivification, M. Cohen-Tannoudji for hosting mouse experiments. We thank the Cellular and Molecular Imaging facility of the Faculty of Pharmacy of Paris (UMS3612 CNRS/US25 INSERM), and the UtechS Photonic BioImaging (Imagopole)., ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), Virus et Immunité, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Howard Hughes Medical Institute [New York], New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Columbia University Irving Medical Center (CUIMC)-Rockefeller University [New York], Virologie Structurale, Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]-Institut des Maladies Génétiques Imagine [Paris], Institut des Maladies Génétiques Imagine [Paris], ANR-10-LABX-0077/10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, Fetal Resorption, [SDV]Life Sciences [q-bio], Endogeny, Pregnancy Proteins, Biology, Cell Fusion, Mice, 03 medical and health sciences, 0302 clinical medicine, Syncytiotrophoblast, Multinucleate, Pregnancy, Interferon, medicine, Animals, Humans, Fetal Death, Multidisciplinary, Cell fusion, Intracellular Signaling Peptides and Proteins, Gene Products, env, RNA-Binding Proteins, Trophoblast, Antigens, Differentiation, Transmembrane protein, Trophoblasts, 3. Good health, Cell biology, Poly I-C, 030104 developmental biology, medicine.anatomical_structure, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Interferon Type I, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Comment in Protecting fetal development. [Science. 2019]; International audience; Elevated levels of type I interferon (IFN) during pregnancy are associated with intrauterine growth retardation, preterm birth, and fetal demise through mechanisms that are not well understood. A critical step of placental development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast (ST) layer. Fusion is mediated by syncytins, proteins deriving from ancestral endogenous retroviral envelopes. Using cultures of human trophoblasts or mouse cells, we show that IFN-induced transmembrane proteins (IFITMs), a family of restriction factors blocking the entry step of many viruses, impair ST formation and inhibit syncytin-mediated fusion. Moreover, the IFN inducer polyinosinic:polycytidylic acid promotes fetal resorption and placental abnormalities in wild-type but not in Ifitm-deleted mice. Thus, excessive levels of IFITMs may mediate the pregnancy complications observed during congenital infections and other IFN-induced pathologies.

Published
2019
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5. RNA is a critical element for the sizing and the composition of phase-separated RNA–protein condensates

Author

Dominique Weil, Zoher Gueroui, Sylvie Souquere, Racha Chouaib, Marina Garcia-Jove Navarro, Shunnichi Kashida, Gérard Pierron, weil, dominique, Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement [IBPS] (LBD), 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), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Laboratoire de Biologie du Développement [Paris] (LBD)

Subjects
0301 basic medicine, Scaffold, Cell biology, Science, Nucleation, General Physics and Astronomy, Context (language use), 02 engineering and technology, Plasma protein binding, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Cytoplasmic Granules, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Microscopy, Electron, Transmission, Phase (matter), [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Protein Interaction Maps, Biopolymers in vivo, lcsh:Science, 030304 developmental biology, Organelles, 0303 health sciences, Multidisciplinary, Rna protein, Chemistry, RNA, RNA-Binding Proteins, General Chemistry, 021001 nanoscience & nanotechnology, In vitro, Kinetics, 030104 developmental biology, Ribonucleoproteins, Biophysics, lcsh:Q, 0210 nano-technology, 030217 neurology & neurosurgery, Intracellular, HeLa Cells, Protein Binding
Abstract

Liquid–liquid phase separation is thought to be a key organizing principle in eukaryotic cells to generate highly concentrated dynamic assemblies, such as the RNP granules. Numerous in vitro approaches have validated this model, yet a missing aspect is to take into consideration the complex molecular mixture and promiscuous interactions found in vivo. Here we report the versatile scaffold ArtiG to generate concentration-dependent RNA–protein condensates within living cells, as a bottom-up approach to study the impact of co-segregated endogenous components on phase separation. We demonstrate that intracellular RNA seeds the nucleation of the condensates, as it provides molecular cues to locally coordinate the formation of endogenous high-order RNP assemblies. Interestingly, the co-segregation of intracellular components ultimately impacts the size of the phase-separated condensates. Thus, RNA arises as an architectural element that can influence the composition and the morphological outcome of the condensate phases in an intracellular context., RNA promotes liquid-liquid phase separation and contributes to the ribonucleoprotein granule assembly. Here the authors employ the protein scaffold ArtiGranule and show the role of intracellular RNA in nucleation and sizing of the phase separated condensates.

Published
2019
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6. Identification of the Receptor Used by the Ecotropic Mouse GLN Endogenous Retrovirus

Author

Thierry Heidmann, Jhen Tsang, David Ribet, Marie Dewannieux, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Sud Orsay

Subjects
Env, Glycosylation, ERV, GLN, receptor, Immunology, Endogenous retrovirus, Virus Attachment, CHO Cells, Microbiology, Host Specificity, Cell Line, 03 medical and health sciences, Mice, Reduced Folate Carrier Protein, Retrovirus, Cricetulus, Viral Envelope Proteins, endogenous retrovirus, Virology, Cricetinae, Animals, Humans, Receptor, Gene, Peptide sequence, 030304 developmental biology, Gammaretrovirus, 0303 health sciences, Genome, biology, 030302 biochemistry & molecular biology, Gene Products, env, Provirus, biology.organism_classification, gammaretrovirus, 3. Good health, Cell biology, Solute carrier family, Virus-Cell Interactions, Rats, Mice, Inbred C57BL, HEK293 Cells, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Receptors, Virus, Retroviridae Infections
Abstract

Approximately 10% of the mouse genome is composed of endogenous retroviruses belonging to different families. In contrast to the situation in the human genome, several of these families correspond to recent, still-infectious elements capable of encoding complete viral particles. The mouse GLN endogenous retrovirus is one of these active families. We previously identified one fully functional provirus from the sequenced genome of the C57BL/6 mouse strain. The GLN envelope protein gives the infectious viral particles an ecotropic host range, and we had demonstrated that the receptor was neither CAT1 nor SMIT1, the two previously identified receptors for mouse ecotropic retroviral envelope proteins. In this study, we have identified SLC19A1, the reduced folate carrier, as the cellular protein used as a receptor by the GLN retrovirus. The ecotropic tropism exhibited by this envelope is due to the presence or absence of an N-linked glycosylation site in the first extracellular loop as well as the specific amino acid sequence of the extracellular domains of the receptor. Like all the other retroviral envelope proteins from the gammaretrovirus genus whose receptors have been identified, the GLN envelope protein uses a member of the solute carrier superfamily as a receptor. IMPORTANCE Endogenous retroviruses are genomic traces of past infections present in all vertebrates. Most of these elements degenerate over time and become nonfunctional, but the mouse genome still contains several families with full infection abilities. The GLN retrovirus is one of them, and its members encode particles that are able to infect only mouse cells. Here, we identified the cellular protein used as a receptor by GLN for cell entry. It is SLC19A1, the reduced folate carrier. We show that GLN infection is limited to mouse cells due to both a mutation in the mouse gene preventing the glycosylation of SLC19A1 and also other residues conserved within the rat but not in the hamster and human proteins. Like all other gammaretroviruses whose receptors have been identified, GLN uses a member of the solute carrier superfamily for cell entry, highlighting the role of these proteins for retroviral infection in mammals.

Published
2019
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7. Capture of a Hyena-Specific Retroviral Envelope Gene with Placental Expression Associated in Evolution with the Unique Emergence among Carnivorans of Hemochorial Placentation in Hyaenidae

Author

Odile Heidmann, Mathis Funk, Alan J Conley, Guillaume Cornelis, Thierry Heidmann, Stephen E. Glickman, Cécile Vernochet, Anne Dupressoir, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Simon, Viviana

Subjects
Candidate gene, Placenta, receptor, [SDV]Life Sciences [q-bio], Carnivora, Endogenous retrovirus, Medical and Health Sciences, 0302 clinical medicine, Viral Envelope Proteins, Pregnancy, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Phylogeny, hyena, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, biology, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Biological Sciences, syncytin, Hyena, medicine.anatomical_structure, Female, Sequence Analysis, Biotechnology, placenta, Immunology, Locus (genetics), [SDV.BID]Life Sciences [q-bio]/Biodiversity, Genes, env, Microbiology, 03 medical and health sciences, Dogs, endogenous retrovirus, Virology, biology.animal, Genetics, medicine, Animals, Amino Acid Sequence, Gene, 030304 developmental biology, env, Agricultural and Veterinary Sciences, Sequence Analysis, RNA, Gene Expression Profiling, Contraception/Reproduction, Endogenous Retroviruses, Placentation, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Evolution of mammals, envelope protein, Retroviridae, Genetic Diversity and Evolution, Genes, Evolutionary biology, Insect Science, Cats, RNA, endotheliochorial/hemochorial, Hyaenidae, RDR/ASCT2/SLC1A5, 030217 neurology & neurosurgery
Abstract

Capture of retroviral envelope genes from endogenous retroviruses has played a role in the evolution of mammals, with evidence for the involvement of these genes in the formation of the maternofetal interface of the placenta. It has been shown that the diversity of captured genes is likely to be responsible for the diversity of placental structures, ranging from poorly invasive (epitheliochorial) to highly invasive (hemochorial), with an intermediate state (endotheliochorial) as found in carnivorans. The latter recapitulate part of this evolution, with the hyena being the sole carnivoran with a hemochorial placenta. In this study, we performed RNA sequencing on hyena placental transcripts and searched for endogenous retroviral envelope genes that have been captured specifically in the Hyaenidae clade and are not found in any other carnivoran. We identified an envelope gene that is expressed in the placenta at the level of the maternofetal interface, as evidenced by in situ hybridization/immunohistochemistry. The gene entry is coincidental with the emergence of the Hyaenidae clade 30 million years ago (Mya), being found at the same genomic locus in all 4 extant hyena species. Its coding sequence has further been maintained during all of Hyaenidae evolution. It is not found in any of the 30 other carnivorans—both Felidae and Canidae—that we screened. This envelope protein does not disclose any fusogenic activity in ex vivo assays, at variance with the syncytin-Car1 gene, which is found in all carnivorans, including the hyena, in which it is still present, transcriptionally active in the placenta, and fusogenic. Together, the present results illustrate the permanent renewal of placenta-specific genes by retroviral capture and de facto provide a candidate gene for the endotheliochorial to hemochorial transition of Hyaenidae among carnivorans. IMPORTANCE The placenta is the most diverse organ among mammals, due in part to stochastic capture of retroviral envelope genes. In carnivorans, capture of syncytin-Car1 took place 80 Mya. It is fusogenic, expressed at the syncytialized placental maternofetal interface, and conserved among all carnivorans, consistent with their shared endotheliochorial placenta. Hyenas are a remarkable exception, with a highly invasive hemochorial placenta, as found in humans, where disruption of maternal blood vessels results in maternal blood bathing the syncytial maternofetal interface. In this study, we identified a retroviral envelope gene capture and exaptation that took place about 30 Mya and is coincident with the emergence of the Hyaenidae, being conserved in all extant hyena species. It is expressed at the maternofetal interface in addition to the shared syncytin-Car1 gene. This new env gene, not present in any other carnivoran, is a likely candidate to be responsible for the specific structure of the hyena placenta.

Published
2019
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8. Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate

Author

Sica V., Bravo-San Pedro J. M., Izzo V., Pol J., Pierredon S., Enot D., Durand S., Bossut N., Chery A., Souquere S., Pierron G., Vartholomaiou E., Zamzami N., Soussi T., Sauvat A., Mondragon L., Kepp O., Galluzzi L., Martinou J. -C., Hess-Stumpp H., Ziegelbauer K., Kroemer G., Maiuri M. C., Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Institut Gustave Roussy (IGR), University of Geneva [Switzerland], Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Cancer Center Karolinska [Karolinska Institutet] (CCK), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, Bayer Pharma AG [Berlin], 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), Gestionnaire, Hal Sorbonne Université, Université de Genève = University of Geneva (UNIGE), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Sica, V., Bravo-San Pedro, J. M., Izzo, V., Pol, J., Pierredon, S., Enot, D., Durand, S., Bossut, N., Chery, A., Souquere, S., Pierron, G., Vartholomaiou, E., Zamzami, N., Soussi, T., Sauvat, A., Mondragon, L., Kepp, O., Galluzzi, L., Martinou, J. -C., Hess-Stumpp, H., Ziegelbauer, K., Kroemer, G., and Maiuri, M. C.

Subjects
Glycolysi, parthanato, mitochondrial fragmentation, Poly (ADP-Ribose) Polymerase-1, Mice, Nude, cancer metabolism, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Oxadiazole, Oxidative Phosphorylation, Ketoglutaric Acid, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, MDM2, parthanatos, Cell Line, Tumor, Animals, Humans, RNA, Small Interfering, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, Oxadiazoles, Electron Transport Complex I, Animal, regulated cell death, Apoptosi, Apoptosis Inducing Factor, Proto-Oncogene Proteins c-mdm2, glycolysis, Isocitrate Dehydrogenase, Mitochondria, lcsh:Biology (General), Pyrazole, Ketoglutaric Acids, Pyrazoles, Female, RNA Interference, Tumor Suppressor Protein p53, Krebs cycle, Human
Abstract

Summary: Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens. : Sica et al. show that respiratory chain inhibition by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87) becomes lethal for cancer cells when glycolysis is simultaneously suppressed. When combined with B87, dimethyl α-ketoglutarate acquires the capacity to suppress glycolysis, thus lethally poisoning bioenergetics metabolism. This therapeutic combination effect relies on transcriptional reprogramming that can be reverted by pharmacological inhibition of MDM2. Keywords: MDM2, Krebs cycle, glycolysis, mitochondrial fragmentation, regulated cell death, parthanatos, cancer metabolism

Published
2019
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9. Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond–like syndrome

Author

Aline Schmidt, Felipe Suarez, Eric Oksenhendler, Barbara Schmaltz-Panneau, Philippe Bensaid, Jean Donadieu, Gérard Pierron, Yves Bertrand, Aurélie Docet, Blandine Beaupain, Vincent Barlogis, Frédéric Bauduer, Séverine Clauin, Christine Bellanné-Chantelot, Isabelle Plo, Isabelle Callebaut, Nathalie Aladjidi, Françoise Mazingue, Sylvie Souquere, Iléana Antony-Debré, Cécile Stoven, Thuan Chong Quah, Isabelle Pellier, Caroline Marty, Hubert Journel, Thierry Leblanc, Marie Ouachee, Gandhi-Laurent Damaj, Liana Carausu, Claire Fieschi, Odile Fenneteau, Véronique Saada, Claire Galambrun, Odile Boespflug-Tanguy, Marlène Pasquet, Brigitte Nelken, William Vainchenker, Claire Berger, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-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), Institut Gustave Roussy (IGR), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Hematology, Centre Hospitalier Universitaire (CHU), Faculté de Médecine, University of Normandie Caen, Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, Department of Pediatric Hematology, Immunology and Oncology, CHU, Angers, Department of Pediatrics, CHU La Réunion, Groupe Hospitalier Sud Réunion, Physiologie et physiopathologie des rétrovirus endogènes et infectieux (RETRO-ENDO), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Unit of Pediatric Hematology, Centre d'Investigation Clinique 1401INSERM Centre d'Investigation Clinique Plurithématique, CHU Bordeaux, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Côte Basque, Bayonne, Department of Pediatrics, Centre Hospitalier Argenteuil, Argenteuil, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Pediatric Hematology and Oncology, CHU, Saint-Etienne, Pediatric Hematology and Oncology Institute, Lyon, Department of Pediatric Hematology and Oncology, CHU Brest, Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, Paris, Service d'Hématologie pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Hematology, CHU, Angers, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatric Hematology and Oncology, CHRU, Lille, Department of Pediatrics, National University Hospital, Singapore, Service d'hématologie-oncologie adultes, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Institut of Pediatric Hematology and Oncology, Lyon, Hématologie pédiatrique, CHU Toulouse [Toulouse], Laboratory of Hematology, Gustave Roussy, Villejuif, Department of Hematology, Necker-Enfants Malades University Hospital, AP-HP, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Paris Descartes, CNRS UMR9196, Gustave Roussy, Villejuif, Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Département de biologie et pathologie médicales [Gustave Roussy], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Paris Descartes - Paris 5 (UPD5), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de la Côte Basque (CHCB), National University of Singapore (NUS), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Gene knockdown, Shwachman–Diamond syndrome, Mutation, business.industry, [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Neutropenia, medicine.disease, medicine.disease_cause, Biochemistry, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Membrane protein, Unfolded protein response, medicine, Cancer research, Congenital Neutropenia, business, Exocrine pancreatic insufficiency, ComputingMilieux_MISCELLANEOUS
Abstract

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

Published
2018
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10. Comparative ultrastructure of CRM1-Nucleolar bodies (CNoBs), Intranucleolar bodies (INBs) and hybrid PML/p62 bodies uncovers new facets of nuclear body dynamic and diversity

Author

Souquere, Sylvie, Weil, Dominique, Pierron, Gerard, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique, Fondation ARC pour la Recherche, Agence Nationale pour la Recherche [ANR-14-CE09-0013-01], Institut Gustave Roussy (IGR), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Compartimentation et trafic intracellulaire des mRNP = Compartmentation and intracellular traffic of mRNPs (LBD-E14), Laboratoire de Biologie du Développement [Paris] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), 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), Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie du Développement [IBPS] (LBD), 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)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
nuclear organization, [SDV]Life Sciences [q-bio], p62/SQSTM1, p62, Intranuclear Inclusion Bodies, SUMO-1 Protein, Active Transport, Cell Nucleus, Receptors, Cytoplasmic and Nuclear, nuclear bodies, Karyopherins, Chromatin, INB, PML bodies, immunoelectron microscopy, SUMO, CNoB, ubiquitin, Fatty Acids, Unsaturated, Humans, SQSTM1, nucleolus, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cell Nucleolus, Research Paper, HeLa Cells
Abstract

International audience; In order to gain insights on the nuclear organization in mammalian cells, we characterized ultrastructurally nuclear bodies (NBs) previously described as fluorescent foci. Using high resolution immunoelectron microscopy (I-EM), we provide evidence that CNoBs (CRM1-Nucleolar bodies) and INBs (Intranucleolar bodies) are distinct genuine nucleolar structures in untreated HeLa cells. INBs are fibrillar and concentrate the post-translational modifiers SUMO1 and SUMO-2/3 as strongly as PML bodies. In contrast, the smallest CRM1-labeled CNoBs are vitreous, preferentially located at the periphery of the nucleolus and, intricately linked to the chromatin network. Upon blockage of the CRM1-dependent nuclear export by leptomycin B (LMB), CNoBs disappear while p62/SQSTM1-containing fibrillar nuclear bodies are induced. These p62 bodies are enriched in ubiquitinated proteins. They progressively associate with PML bodies to form hybrid bodies of which PML decorates the periphery while p62/SQSTM1 is centrally-located. Our study is expanding the repertoire of nuclear bodies; revealing a previously unrecognized composite nucleolar landscape and a new mode of interactions between ubiquitous (PML) and stress-induced (p62) nuclear bodies, resulting in the formation of hybrid bodies.

Published
2015
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11. Humoral Responses Elicited by Adenovirus Displaying Epitopes Are Induced Independently of the Infection Process and Shaped by the Toll-Like Receptor/MyD88 Pathway

Author

Aleksandra, Anchim, Najat, Raddi, Lena, Zig, Patrick, Perrieau, Ronan, Le Goffic, Bernhard, Ryffel, Karim, Benihoud, Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Institut de Biologie Physico-Chimique, Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre National de la Recherche Scientifique, University Paris-Sud, Ministère de la Recherche et de la Technologie, Unité de recherche Virologie et Immunologie Moléculaires (VIM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Mice, Knockout, Ovalbumin, Adenoviridae Infections, [SDV]Life Sciences [q-bio], Toll-Like Receptors, Immunology, adenovirus, Antibodies, Viral, MyD88, Adenoviridae, Immunity, Humoral, Mice, Inbred C57BL, Epitopes, mitochondrial antiviral-signaling, Myeloid Differentiation Factor 88, Animals, Female, Antigens, antibody isotype, innate immunity, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Signal Transduction, Original Research, fiber
Abstract

International audience; The use of serotype 5 adenovirus (Ad)-derived vectors in vaccination is confronted to preexisting anti-Ad immunity. Epitope display on Ad capsid is currently being investigated as an alternative approach of vaccination. The present study seeks to better understand virus-and host-related factors controlling the efficacy of this new vaccination approach. In contrast to an Ad vector expressing ovalbumin as a transgene, Ad displaying an ovalbumin-derived B-cell epitope inserted into the fiber protein was able to elicit antibody responses in both Ad-naive and Ad-immune mice. Moreover, introduction of a set of mutations abrogating Ad interaction with its receptors did not modify the virus capacity to elicit a humoral response against the inserted epitope while reducing its capacity to mount antibody responses against the transgene product. Taken as a whole these data indicate that the efficacy of Ad displaying epitopes requires neither Ad binding to its receptors nor the infection process. In addition, the use of genetically deficient mice demonstrated that both toll-like receptor (TLR)/MyD88 and RIG-I/mitochondrial antiviral-signaling (MAVS) innate immunity pathways were dispensable to mount anti-epitope antibody responses. However, they also revealed that TLR/MyD88 pathway but not RIG-I/MAVS pathway controls the nature of antibodies directed against the displayed epitope.

Published
2018
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12. P-Body Purification Reveals the Condensation of Repressed mRNA Regulons

Author

Zhou Yi, Magali Fradet, Maïté Courel, Edouard Bertrand, Dominique Weil, Marianne Bénard, Michèle Ernoult-Lange, Sylvie Souquere, Racha Chouaib, Annie Munier, Julien Mozziconacci, Maëlle Daunesse, Jean-Baptiste Morlot, Arnaud Hubstenberger, Gérard Pierron, Michel Kress, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique de la Matière Condensée (LPTMC), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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 Pierre et Marie Curie - Paris 6 (UPMC)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)

Subjects
0301 basic medicine, Cytoplasm, Proteome, RNA Stability, [SDV]Life Sciences [q-bio], Biology, Cell Fractionation, Cytoplasmic Granules, Regulon, Phase Transition, 03 medical and health sciences, Stress granule, P-bodies, Humans, RNA, Messenger, Molecular Biology, Psychological repression, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, Messenger RNA, RNA, Molecular Sequence Annotation, Cell Biology, Molecular biology, Cell biology, Gene Ontology, HEK293 Cells, 030104 developmental biology, Gene Expression Regulation, Ribonucleoproteins, Protein Biosynthesis, Function (biology), HeLa Cells
Abstract

Summary Within cells, soluble RNPs can switch states to coassemble and condense into liquid or solid bodies. Although these phase transitions have been reconstituted in vitro, for endogenous bodies the diversity of the components, the specificity of the interaction networks, and the function of the coassemblies remain to be characterized. Here, by developing a fluorescence-activated particle sorting (FAPS) method to purify cytosolic processing bodies (P-bodies) from human epithelial cells, we identified hundreds of proteins and thousands of mRNAs that structure a dense network of interactions, separating P-body from non-P-body RNPs. mRNAs segregating into P-bodies are translationally repressed, but not decayed, and this repression explains part of the poor genome-wide correlation between RNA and protein abundance. P-bodies condense thousands of mRNAs that strikingly encode regulatory processes. Thus, we uncovered how P-bodies, by condensing and segregating repressed mRNAs, provide a physical substrate for the coordinated regulation of posttranscriptional mRNA regulons.

Published
2017
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13. Genetic Evidence That Captured Retroviral Envelope syncytins Contribute to Myoblast Fusion and Muscle Sexual Dimorphism in Mice

Author

Najat Raddi, Anne Dupressoir, Julie Dumonceaux, Stéphanie Charrin, Nicolas Blanchard-Gutton, Agathe Bacquin, Cécile Vernochet, Vincent Gache, Virginie Mariot, Thierry Heidmann, Laurent Tiret, François Redelsperger, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Institut de 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, École nationale vétérinaire d'Alfort (ENVA), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), 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) (AP-HP)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École nationale vétérinaire - Alfort (ENVA), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL UPMC, Gestionnaire

Subjects
Male, 0301 basic medicine, Cancer Research, Cellular differentiation, Endogenous retrovirus, Pregnancy Proteins, Muscle Development, Biochemistry, Myoblasts, Cell Fusion, Gene Knockout Techniques, Mice, Myoblast fusion, 0302 clinical medicine, Animal Cells, Morphogenesis, Myocyte, Small interfering RNAs, RNA, Small Interfering, Genetics (clinical), Mammals, Sex Characteristics, Syncytium, Cell fusion, Myogenesis, Stem Cells, Cell Differentiation, Animal Models, Muscle Analysis, Nucleic acids, Bioassays and Physiological Analysis, Vertebrates, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Cellular Types, Muscle Regeneration, Research Article, Cell Physiology, lcsh:QH426-470, Mouse Models, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Biology, Research and Analysis Methods, 03 medical and health sciences, Model Organisms, Dogs, Multinucleate, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Regeneration, Animals, Humans, Non-coding RNA, Muscle, Skeletal, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Endogenous Retroviruses, Organisms, Biology and Life Sciences, Gene Products, env, Cell Biology, Molecular biology, Gene regulation, lcsh:Genetics, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Amniotes, RNA, Gene expression, Organism Development, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Syncytins are envelope genes from endogenous retroviruses, “captured” for a role in placentation. They mediate cell-cell fusion, resulting in the formation of a syncytium (the syncytiotrophoblast) at the fetomaternal interface. These genes have been found in all placental mammals in which they have been searched for. Cell-cell fusion is also pivotal for muscle fiber formation and repair, where the myotubes are formed from the fusion of mononucleated myoblasts into large multinucleated structures. Here we show, taking advantage of mice knocked out for syncytins, that these captured genes contribute to myoblast fusion, with a >20% reduction in muscle mass, mean muscle fiber area and number of nuclei per fiber in knocked out mice for one of the two murine syncytin genes. Remarkably, this reduction is only observed in males, which subsequently show muscle quantitative traits more similar to those of females. In addition, we show that syncytins also contribute to muscle repair after cardiotoxin-induced injury, with again a male-specific effect on the rate and extent of regeneration. Finally, ex vivo experiments carried out on murine myoblasts demonstrate the direct involvement of syncytins in fusion, with a >40% reduction in fusion index upon addition of siRNA against both syncytins. Importantly, similar effects are observed with primary myoblasts from sheep, dog and human, with a 20–40% reduction upon addition of siRNA against the corresponding syncytins. Altogether, these results show a direct contribution of the fusogenic syncytins to myogenesis, with a demonstrated male-dependence of the effect in mice, suggesting that these captured genes could be responsible for the muscle sexual dimorphism observed in placental mammals., Author Summary Syncytins are “captured” genes of retroviral origin, corresponding to the fusogenic envelope gene of endogenized retroviruses. They are present in all placental mammals in which they have been searched for, where they play an essential role in placentation via their cell-cell fusion activity. Here we show that they also contribute to myoblast fusion and muscle formation in development and repair after injury, using both in vivo knock-out mouse models and ex vivo primary myoblast cell cultures from several mammals, including humans, carnivores and ruminants. Interestingly, the effects observed in mice are sex-dependent, thus suggesting that the added “collateral” effect of syncytins on myogenesis could be responsible for the muscle sexual dimorphism observed in placental mammals.

Published
2016
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14. Genome-Wide Screening of Retroviral Envelope Genes in the Nine-Banded Armadillo (Dasypus novemcinctus, Xenarthra) Reveals an Unfixed Chimeric Endogenous Betaretrovirus Using the ASCT2 Receptor

Author

Baptiste Mulot, Odile Heidmann, Anne Dupressoir, Cécile Vernochet, Sébastien Malicorne, Frédéric Delsuc, Thierry Heidmann, Guillaume Cornelis, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), ZooParc de Beauval, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)

Subjects
Amino Acid Transport System ASC, 0301 basic medicine, Armadillos, viruses, [SDV]Life Sciences [q-bio], 030106 microbiology, Immunology, Population, Endogenous retrovirus, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Biology, Betaretrovirus, Microbiology, Minor Histocompatibility Antigens, 03 medical and health sciences, Retrovirus, Proviruses, Viral Envelope Proteins, Viral envelope, Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Testing, education, Gene, Recombination, Genetic, Genetics, education.field_of_study, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BA]Life Sciences [q-bio]/Animal biology, Endogenous Retroviruses, Provirus, biology.organism_classification, 030104 developmental biology, Dasypus novemcinctus, Genetic Diversity and Evolution, Insect Science, Pseudotyping, Receptors, Virus
Abstract

Retroviruses enter host cells through the interaction of their envelope (Env) protein with a cell surface receptor, which triggers the fusion of viral and cellular membranes. The sodium-dependent neutral amino acid transporter ASCT2 is the common receptor of the large RD114 retrovirus interference group, whose members display frequent env recombination events. Germ line retrovirus infections have led to numerous inherited endogenous retroviruses (ERVs) in vertebrate genomes, which provide useful insights into the coevolutionary history of retroviruses and their hosts. Rare ERV-derived genes display conserved viral functions, as illustrated by the fusogenic syncytin env genes involved in placentation. Here, we searched for functional env genes in the nine-banded armadillo ( Dasypus novemcinctus ) genome and identified dasy-env1.1 , which clusters with RD114 interference group env genes and with two syncytin genes sharing ASCT2 receptor usage. Using ex vivo pseudotyping and cell-cell fusion assays, we demonstrated that the Dasy-Env1.1 protein is fusogenic and can use both human and armadillo ASCT2s as receptors. This gammaretroviral env gene belongs to a provirus with betaretrovirus-like features, suggesting acquisition through recombination. Provirus insertion was found in several Dasypus species, where it has not reached fixation, whereas related family members integrated before diversification of the genus Dasypus >12 million years ago (Mya). This newly described ERV lineage is potentially useful as a population genetic marker. Our results extend the usage of ASCT2 as a retrovirus receptor to the mammalian clade Xenarthra and suggest that the acquisition of an ASCT2-interacting env gene is a major selective force driving the emergence of numerous chimeric viruses in vertebrates. IMPORTANCE Retroviral infection is initiated by the binding of the viral envelope glycoprotein to a host cell receptor(s), triggering membrane fusion. Ancient germ line infections have generated numerous endogenous retroviruses (ERVs) in nearly all vertebrate genomes. Here, we report a previously uncharacterized ERV lineage from the genome of a xenarthran species, the nine-banded armadillo ( Dasypus novemcinctus ). It entered the Dasypus genus >12 Mya, with one element being inserted more recently in some Dasypus species, where it could serve as a useful marker for population genetics. This element exhibits an env gene, acquired by recombination events, with conserved viral fusogenic properties through binding to ASCT2, a receptor used by a wide range of recombinant retroviruses infecting other vertebrate orders. This specifies the ASCT2 transporter as a successful receptor for ERV endogenization and suggests that ASCT2-binding env acquisition events have favored the emergence of numerous chimeric viruses in a wide range of species.

Published
2016
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15. Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint

Author

Isabelle Plo, Sylvie Souquere, Hana Raslova, Valérie Lapierre, Larissa Lordier, William Vainchenker, Najet Debili, Catherine Pioche-Durieu, Anita Roy, Lydia Roy, Philippe Rameau, Eric Le Cam, Laboratoire Pierre Aigrain (LPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Technologies et systèmes d'information pour les agrosystèmes (UR TSCF), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institut Gustave Roussy (IGR), Signalisation, noyaux et innovations en cancérologie (UMR8126), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Blood Platelets, rho GTP-Binding Proteins, [SDV]Life Sciences [q-bio], Cellular differentiation, Gene Expression, Cell Cycle Proteins, Biology, Protein Serine-Threonine Kinases, Models, Biological, Thrombopoiesis, Polyploidy, 03 medical and health sciences, Megakaryocyte, Polyploid, medicine, Humans, Hippo Signaling Pathway, ComputingMilieux_MISCELLANEOUS, Genetics, Hippo signaling pathway, Gene knockdown, fungi, food and beverages, Nuclear Proteins, Cell Differentiation, Hematology, pathological conditions, signs and symptoms, Articles, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cell biology, Tetraploidy, 030104 developmental biology, medicine.anatomical_structure, Mitochondrial biogenesis, Gene Expression Regulation, Gene Knockdown Techniques, Ploidy, Tumor Suppressor Protein p53, Megakaryocytes, Biomarkers, Signal Transduction, Transcription Factors
Abstract

Megakaryocytes are naturally polyploid cells that increase their ploidy by endomitosis. However, very little is known regarding the mechanism by which they escape the tetraploid checkpoint to become polyploid. Recently, it has been shown that the tetraploid checkpoint was regulated by the Hippo-p53 pathway in response to a downregulation of Rho activity. We therefore analyzed the role of Hippo-p53 pathway in the regulation of human megakaryocyte polyploidy. Our results revealed that Hippo-p53 signaling pathway proteins are present and are functional in megakaryocytes. Although this pathway responds to the genotoxic stress agent etoposide, it is not activated in tetraploid or polyploid megakaryocytes. Furthermore, Hippo pathway was observed to be uncoupled from Rho activity. Additionally, polyploid megakaryocytes showed increased expression of YAP target genes when compared to diploid and tetraploid megakaryocytes. Although p53 knockdown increased both modal ploidy and proplatelet formation in megakaryocytes, YAP knockdown caused no significant change in ploidy while moderately affecting proplatelet formation. Interestingly, YAP knockdown reduced the mitochondrial mass in polyploid megakaryocytes and decreased expression of PGC1α, an important mitochondrial biogenesis regulator. Thus, the Hippo pathway is functional in megakaryocytes, but is not induced by tetraploidy. Additionally, YAP regulates the mitochondrial mass in polyploid megakaryocytes.

Published
2016
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16. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

Author

Guido Kroemer, Yuting Ma, Oliver Kepp, Sylvie Souquere, Allan Sauvat, Guo Chen, Heng Yang, Federico Pietrocola, Heng Zhou, Laurence Zitvogel, Takahiro Yamazaki, Erika Vacchelli, Christophe Klein, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tsinghua University [Beijing] (THU), Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École Pratique des Hautes Études (EPHE), Tsinghua University [Beijing], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, biology, Kinase, Necroptosis, [SDV]Life Sciences [q-bio], Immunology, HMGB1, 3. Good health, Cell biology, Immunosurveillance, 03 medical and health sciences, 030104 developmental biology, Immune system, Oncology, Cancer cell, Cancer research, biology.protein, Immunology and Allergy, Cytotoxic T cell, Immunogenic cell death, ComputingMilieux_MISCELLANEOUS, Original Research
Abstract

Chemotherapy can reinstate anticancer immunosurveillance through inducing tumor immunogenic cell death (ICD). Here, we show that anthracyclines and oxaliplatin can trigger necroptosis in murine cancer cell lines expressing receptor-interacting serine-threonine kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL). Necroptotic cells featured biochemical hallmarks of ICD and stimulated anticancer immune responses in vivo. Chemotherapy normally killed Rip3 (-/-) and Mlkl (-/-) tumor cells and normally induced caspase-3 activation in such cells, yet was unable to reduce their growth in vivo. RIP3 or MLKL deficiency abolished the capacity of dying cancer cells to elicit an immune response. This could be attributed to reduced release of ATP and high mobility group box 1 (HMGB1) by RIP3 and MLKL-deficient cells. Measures designed to compensate for deficient ATP and HMGB1 signaling restored the chemotherapeutic response of Rip3 (-/-) and Mlkl (-/-) cancers. Altogether, these results suggest that RIP3 and MLKL can contribute to ICD signaling and tumor immunogenicity.

Published
2016
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17. Retroviral envelope gene captures and syncytin exaptation for placentation in marsupials

Author

Ulrich Zeller, Cécile Vernochet, Baptiste Mulot, François Catzeflis, Brandon R. Menzies, Anne Dupressoir, Maria Nilsson, Guillaume Cornelis, Gérard Pierron, Thierry Heidmann, Marilyn B. Renfree, Sylvie Souquere, Odile Heidmann, Quentin Carradec, Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Institut de Biologie François JACOB (JACOB), 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), ZooParc de Beauval, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, and Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)

Subjects
Transcription, Genetic, Placenta, [SDV]Life Sciences [q-bio], Molecular Sequence Data, Endogenous retrovirus, Pregnancy Proteins, Genes, env, Monodelphis domestica, Viral Envelope Proteins, Pregnancy, Opossum, Animals, Gene, In Situ Hybridization, Phylogeny, ComputingMilieux_MISCELLANEOUS, Marsupial, Genetics, Multidisciplinary, biology, Gene Expression Profiling, Gene Products, env, Placentation, Exaptation, biology.organism_classification, Gene expression profiling, Marsupialia, Retroviridae, PNAS Plus, Female
Abstract

Syncytins are genes of retroviral origin captured by eutherian mammals, with a role in placentation. Here we show that some marsupials—which are the closest living relatives to eutherian mammals, although they diverged from the latter ∼190 Mya—also possess a syncytin gene. The gene identified in the South American marsupial opossum and dubbed syncytin-Opo1 has all of the characteristic features of a bona fide syncytin gene: It is fusogenic in an ex vivo cell–cell fusion assay; it is specifically expressed in the short-lived placenta at the level of the syncytial feto–maternal interface; and it is conserved in a functional state in a series of Monodelphis species. We further identify a nonfusogenic retroviral envelope gene that has been conserved for >80 My of evolution among all marsupials (including the opossum and the Australian tammar wallaby), with evidence for purifying selection and conservation of a canonical immunosuppressive domain, but with only limited expression in the placenta. This unusual captured gene, together with a third class of envelope genes from recently endogenized retroviruses—displaying strong expression in the uterine glands where retroviral particles can be detected—plausibly correspond to the different evolutionary statuses of a captured retroviral envelope gene, with only syncytin-Opo1 being the present-day bona fide syncytin active in the opossum and related species. This study would accordingly recapitulate the natural history of syncytin exaptation and evolution in a single species, and definitely extends the presence of such genes to all major placental mammalian clades.

Published
2015
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18. Control of Acute Arboviral Infection by Natural Killer Cells

Author

Christopher Maucourant, Caroline Petitdemange, Hans Yssel, Vincent Vieillard, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), and Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
natural killer cells, Host Microbial Interactions, Coinfection, Zika Virus Infection, viruses, lcsh:QR1-502, virus diseases, Review, Arbovirus Infections, biochemical phenomena, metabolism, and nutrition, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, lcsh:Microbiology, Immunity, Innate, Dengue, Killer Cells, Natural, Mice, arboviruses, interferon-γ, Animals, Chikungunya Fever, Humans, cytotoxicity, Chikungunya virus
Abstract

International audience; The recent explosive pandemic of chikungunya virus (CHIKV) followed by Zika (ZIKV) virus infections occurring throughout many countries represents the most unexpected arrival of arthropod-borne viral diseases in the past 20 years. Transmitted through the bite of Aedes mosquitoes, the clinical picture associated with these acute arbovirus infections, including Dengue (DENV), CHIKV and ZIKV, ranges from classical febrile illness to life-threatening disease. Whereas ZIKV and CHIKV-mediated infections have previously been recognized as relatively benign diseases, in contrast to Dengue fever, recent epidemic events have brought waves of increased morbidity and mortality leading to a serious public health problem. Although the host immune response plays a crucial role in controlling infections, it may also promote viral spread and immunopathology. Here, we review recent developments in our understanding of the immune response, with an emphasis on the early antiviral immune response mediated by natural killer cells and emphasize their Janus-faced effects in the control of arbovirus infection and pathogenesis. Improving our understanding knowledge on of the mechanisms that control viral infection is crucial in the current race against the globalization of arbovirus epidemics.

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