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1. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth

Author

Kerstin Klinkert, Volker Haucke, Alessandra Bolino, Genaro Patino-Lopez, Linda Sawade, Francina Langa-Vives, Federica Grandi, Marianna Mignanelli, Roberta Di Guardo, Arnaud Echard, Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, IRCCS Ospedale San Raffaele [Milan, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Hospital Infantil de México Federico Gómez (HIMFG), Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Freie Universität Berlin, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Supported by grants from the German Research Foundation (DFG) (SFB958/A01 and HA2686/15-1 to V.H.), from Muscular Dystrophy Association (MDA574294) and AFM-Telethon France (#21528) to A.B., V.H. and A.B. are funded by E-Rare-3 JTC 2017 and are members of the eRARE Consortium 'Treat-MTMs'. Part of this work has been supported by Institut Pasteur and CNRS to A.E., K.K. was supported by the Pasteur - Paris University (PPU) International PhD Program and by and a fellowship from FRM (FDT20150532389)., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]

Subjects
0301 basic medicine, Myelin biology and repair, General Physics and Astronomy, GTPase, mTORC1, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Small GTPases, chemistry.chemical_compound, Myelin, 0302 clinical medicine, Charcot-Marie-Tooth Disease, Gene Knock-In Techniques, Lipid signalling, lcsh:Science, Myelin Sheath, Multidisciplinary, Hyperactivation, Chemistry, Protein Tyrosine Phosphatases, Non-Receptor, Phenotype, 3. Good health, Cell biology, medicine.anatomical_structure, Signal Transduction, congenital, hereditary, and neonatal diseases and abnormalities, Science, Primary Cell Culture, Down-Regulation, Mice, Transgenic, Mechanistic Target of Rapamycin Complex 1, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Animals, Humans, Phosphatidylinositol, Gene, General Chemistry, Nutrient signalling, Lipid Metabolism, nervous system diseases, 030104 developmental biology, HEK293 Cells, rab GTP-Binding Proteins, Astrocytes, Mutation, lcsh:Q, 030217 neurology & neurosurgery, Biogenesis, HeLa Cells
Abstract

Inherited peripheral neuropathies (IPNs) represent a broad group of disorders including Charcot-Marie-Tooth (CMT) neuropathies characterized by defects primarily arising in myelin, axons, or both. The molecular mechanisms by which mutations in nearly 100 identified IPN/CMT genes lead to neuropathies are poorly understood. Here we show that the Ras-related GTPase Rab35 controls myelin growth via complex formation with the myotubularin-related phosphatidylinositol (PI) 3-phosphatases MTMR13 and MTMR2, encoded by genes responsible for CMT-types 4B2 and B1 in humans, and found that it downregulates lipid-mediated mTORC1 activation, a pathway known to crucially regulate myelin biogenesis. Targeted disruption of Rab35 leads to hyperactivation of mTORC1 signaling caused by elevated levels of PI 3-phosphates and to focal hypermyelination in vivo. Pharmacological inhibition of phosphatidylinositol 3,5-bisphosphate synthesis or mTORC1 signaling ameliorates this phenotype. These findings reveal a crucial role for Rab35-regulated lipid turnover by myotubularins to repress mTORC1 activity and to control myelin growth., Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy. Here, the authors show that Rab35 forms a complex with genes implicated in CMT, MTMR13 and MTMR2, which regulates myelin growth by controlling mTORC1 signaling through lipid turnover.

Published
2020
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2. Penicillin Resistance Compromises Nod1-Dependent Proinflammatory Activity and Virulence Fitness of Neisseria meningitidis

Author

Francina Langa Vives, Aude Antignac, Muhamed-Kheir Taha, Ala-Eddine Deghmane, Anna Skoczynska, Faridabano Nato, Philippe J. Sansonetti, Stephen E. Girardin, Ivo G. Boneca, Lucie Peduto, Françoise Thouron, Martine Fanton d'Andon, Thierry Pedron, Meriem El Ghachi, Marek Szatanik, Dana J. Philpott, Catherine Werts, Lionel LeBourhis, Maria Leticia Zarantonelli, Céline Mulet, Gérard Eberl, Neisseria, Institut Pasteur [Paris], National Reference Centre for Bacterial Meningitis [Warsaw, Poland] (NRCBM), National Medicines Institute - Narodowy Instytut Leków [Warsaw] (NIL), Infections Bactériennes Invasives, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Production de Protéines Recombinantes et d'Anticorps (Plate-Forme), Immunité Innée et Signalisation, Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Our research is supported by Institut Pasteur grants (PTR153 and PTR187), an ACI 0321 (Action Concertée Incitative Intégrée Microbiology) Grant from the Ministère chargé de la Recherche (INSERM No. MIC 0321), and a European Research Council starting grant (202283-PGNfromSHAPEtoVIR). A.S. was supported by a Marie Curie Intra-European Fellowship (No. 23188) within the Sixth European Community Framework Programme and Marie Curie European Reintegration Grants (No. 234876) within the Seventh European Community Framework Programme. M.E.G. was supported by an Institut Pasteur Roux fellowship., European Project: 234876,EC:FP7:PEOPLE,FP7-PEOPLE-ERG-2008,NMEN-PBP(2009), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Collège de France - Chaire Microbiologie et Maladies infectieuses

Subjects
Cancer Research, Penicillin Resistance, Virulence, MESH: Nod1 Signaling Adaptor Protein, Biology, Neisseria meningitidis, medicine.disease_cause, Microbiology, MESH: Neisseria meningitidis, Proinflammatory cytokine, Sepsis, 03 medical and health sciences, chemistry.chemical_compound, Mice, MESH: Mutant Proteins, Antibiotic resistance, MESH: Cell Wall, Cell Wall, Virology, Nod1 Signaling Adaptor Protein, Immunology and Microbiology(all), medicine, Animals, Humans, Penicillin-Binding Proteins, MESH: Animals, Pathogen, MESH: Mice, Molecular Biology, 030304 developmental biology, 0303 health sciences, MESH: Penicillin-Binding Proteins, MESH: Humans, 030306 microbiology, medicine.disease, MESH: Penicillin Resistance, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Penicillin, chemistry, Parasitology, Mutant Proteins, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Peptidoglycan, medicine.drug
Abstract

International audience; Neisseria meningitidis is a life-threatening human bacterial pathogen responsible for pneumonia, sepsis, and meningitis. Meningococcal strains with reduced susceptibility to penicillin G (Pen(I)) carry a mutated penicillin-binding protein (PBP2) resulting in a modified peptidoglycan structure. Despite their antibiotic resistance, Pen(I) strains have failed to expand clonally. We analyzed the biological consequences of PBP2 alteration among clinical meningococcal strains and found that peptidoglycan modifications of the Pen(I) strain resulted in diminished in vitro Nod1-dependent proinflammatory activity. In an influenza virus-meningococcal sequential mouse model mimicking human disease, wild-type meningococci induced a Nod1-dependent inflammatory response, colonizing the lungs and surviving in the blood. In contrast, isogenic Pen(I) strains were attenuated for such response and were out-competed by meningococci sensitive to penicillin G. Our results suggest that antibiotic resistance imposes a cost to the success of the pathogen and may potentially explain the lack of clonal expansion of Pen(I) strains.

Published
2013
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3. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells

Author

Lucie Peduto, Marie Cherrier, Matthias Lochner, Francina Langa, Shinichiro Sawa, Mustapha Si-Tahar, James P. Di Santo, Gérard Eberl, Dieter Riethmacher, Rosa Varona, Hugot, Bérengère, Développement des Tissus Lymphoïdes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Department of Immunology and Oncology, Universidad Autónoma de Madrid (UAM)-Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Development and Regeneration, Human Genetics Division, University of Southampton, Défense innée et inflammation, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines et Développement Lymphoïde, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Universidad Autonoma de Madrid (UAM)-Centro Nacional de Biotecnologia, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Nuclear Receptor Subfamily 1, Group F, Member 3, MESH: Inflammation, MESH: Interleukin-10, Receptors, Retinoic Acid, MESH: Interleukin-17, T-Lymphocytes, MESH: Flow Cytometry, T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, MESH: Receptors, Interleukin-12, RAR-related orphan receptor gamma, Genes, Reporter, Immunology and Allergy, MESH: Animals, MESH: Genetic Variation, 0303 health sciences, education.field_of_study, Receptors, Thyroid Hormone, Interleukin-17, Receptors, Interleukin-12, FOXP3, hemic and immune systems, Forkhead Transcription Factors, Articles, Nuclear Receptor Subfamily 1, Group F, Member 3, Flow Cytometry, Interleukin-10, Interleukin 10, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 17, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, Immunology, Population, chemical and pharmacologic phenomena, Mice, Transgenic, Biology, Article, Proinflammatory cytokine, 03 medical and health sciences, MESH: Forkhead Transcription Factors, Internal medicine, medicine, Animals, MESH: Receptors, Thyroid Hormone, education, MESH: Mice, 030304 developmental biology, MESH: Receptors, Retinoic Acid, Inflammation, Interleukin-6, MESH: T-Lymphocytes, Regulatory, T-cell receptor, MESH: Genes, Reporter, Genetic Variation, Molecular biology, MESH: Interleukin-6, CCL20, Endocrinology, MESH: T-Lymphocytes, 030215 immunology
Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan receptor gamma t (RORgamma t) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORgamma t(+) T cells express IL-17. We report here that RORgamma t(+) T alphabeta cells include Foxp3(+) cells that coexist with IL-17-producing RORgamma t(+) T alphabeta cells in all tissues examined. The Foxp3(+) RORgamma t(+) T alphabeta express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3(+) to IL-17-producing RORgamma t(+) T alphabeta cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORgamma t(+) T cells express the gammadelta T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17-producing and regulatory Foxp3(+) RORgamma t(+) T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORgamma t(+) T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

Published
2008
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4. Conditional knock-out reveals that zygotic vezatin-null mouse embryos die at implantation

Author

Vincent Hyenne, Michel Cohen-Tannoudji, Francina Langa, Celine Souilhol, Christine Petit, Bernard Maro, Silvia Cereghini, Marie-Christine Simmler, Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), 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), Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique des Déficits Sensoriels, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris], Sackler Faculty of Medicine, Tel Aviv University [Tel Aviv], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was supported by research Grants R0375/38 and R0475/100 from the Ligue Contre le Cancer (BM). Vincent Hyenne was recipient of a fellowship from the Ministère de l’Education et de la Recherche Technologique (MENRT) and from the Fondation pour la Recherche Médicale (FRM). Céline Souilhol is recipient of a fellowship from the Centre National de la Recherche Scientfique (CNRS). We thank Aude Jobart (IJM/CNRS UMR 7592) for her help with confocal microscopy. We are grateful to Rémi Beau and Françoise Thouron (Centre Ingéniérie Génétique Murine/Institut Pasteur) and Mélanie Fabre (Organogenèse Précoce chez la Souris et Maladies Génétiques Associées/CNRS UMR 7622) for excellent technical support., We sincerely thank Drs. Thierry Galli and Sophie Louvet-Vallée for critical review. We are grateful to Drs. Isabelle Roux, Yvan Lallemand and Shahragim Tajbakhsh for generous support and encouragement, 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 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), Collège de France - Chaire Génétique et physiologie cellulaire, Institut Pasteur [Paris] (IP), Tel Aviv University (TAU), and Cohen-Tannoudji, Michel

Subjects
Embryology, Mouse, Zygote, Pgk-1-cre, Peri-implantation lethality, Mutant, MESH: Amino Acid Sequence, MESH: Mice, Knockout, Mice, MESH: Embryo Implantation, Vezatin, 0302 clinical medicine, Embryonic Structure, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Mice, Knockout, 0303 health sciences, Embryo, Adherens Junctions, Cell biology, medicine.anatomical_structure, Essential gene, MESH: Membrane Proteins, Molecular Sequence Data, Intercellular adhesion, MESH: Carrier Proteins, Biology, Adherens junction, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, Amino Acid Sequence, Embryo Implantation, Blastocyst, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Embryo, Mammalian, Membrane Proteins, Embryo, Mammalian, Embryonic stem cell, Molecular biology, Conditional vezatin knock-out, MESH: Adherens Junctions, Genes, Lethal, MESH: Zygote, MESH: Genes, Lethal, Carrier Proteins, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Vezatin, a protein associated to adherens junctions in epithelial cells, is already expressed in mouse oocytes and during pre-implantation development. Using a floxed strategy to generate a vezatin-null allele, we show that the lack of zygotic vezatin is embryonic lethal, indicating that vezatin is an essential gene. Homozygous null embryos are able to elicit a decidual response but as early as day 6.0 post-coitum mutant implantation sites are devoid of embryonic structures. Mutant blastocysts are morphologically normal, but only half of them are able to hatch upon in vitro culture and the blastocyst outgrowths formed after 3.5 days in culture exhibit severe abnormalities, in particular disrupted intercellular adhesion and clear signs of cellular degeneration. Notably, the junctional proteins E-cadherin and beta-catenin are delocalized and not observed at the plasma membrane anymore. These in vitro observations reinforce the idea that homozygous vezatin-null mutants die at the time of implantation because of a defect in intercellular adhesion. Together these results indicate that the absence of zygotic vezatin is deleterious for the implantation process, most likely because cadherin-dependent intercellular adhesion is impaired in late blastocysts when the maternal vezatin is lost.

Published
2007
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