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THÈSE L’Obtention De Du Strasbourg Grade De ÉcoleU DoctoraleNIVERSITÉ des Sciences DE STRASBOURG de la Vie et de la Santé INCI – CNRS UPR 3212 DocteurPrésentée de Pour l’UniversitéTHÈSE l’obtention de du Strasbourg grade de : Discipline : Sciences du Vivant Spécialité : Aspects moléculaires et cellulaires de la biologie Q ili P WANGar Interaction entre la sous unité V0 de la V-ATPase et le facteur d'échange ARNO et son implication fonctionnelle dans l'exocytose régulée SoutenueDr. SIMONNEAUX mecredi le Valérie 18 septembre 2019 , devant Présidente le jury compos du juré dey : Dr. EL FAR Oussama Rapporteur externe Pr. OLIVIER Jean-Luc Rapporteur externe Dr. VITALE Nicolas Directeur de thèse Remerciements Dr. SIMONNEAUX JeValérie souhaiterais, Dr. EL toutFAR d’abordOussama remercier et Pr. OLIVIER les membres Jean de-Luc mon jury de thèse, , qui m’ont fait le grand honneur d’avoir accepté de lire, commenter et juger mon travail de thèse. Dr. VITALE Nicolas Je voudrais également remercier mon directeur de thèse . Tu m’as encadré pendant 4 ans et tu m’as suivi pas a pas dans mon apprentissage de la recherche avec tes qualités scientifiques et humaines. Je veux bien profiter de cette occasion pour t’exprimer mes sincères remerciements pour ta confiance et les libértés que tu m’as données dans la recherche. Merci pour tout. MesDr. Marieremerciements France vontBADER également à tous les membres de l’équipe pour leur aide : , pour m’avoir accueillie à l’INCI alors qu’elle en était la directrice.Dr. Stéphane GASMAN , co-responsable de l’équipe, pour tes remarques constructives et saDr. bonne Stéphane humeur ORY. , pour les discussions scientifiques et les conseils notamment en imagerie.Dr. Sylvette CHASSEROT-GOLAZ Tam THAHOULY , pour la formation à la microscopie confocale. , un grand merci pour les manips de biologie moléculaire et pour les culturesClaudine de BOISSIER chromaffines bovines. Anne-Marie HAEBERLE, pour ta serviabilité, et la gestion des stocks et commandes. , pour ton aide en microscopie électronique par transmission durantDr. Petra mon TOTH stage de master et le début de ma thèse. Sebahat OZKAN, pour les discussions scientifiques ou non-scientifiques. , plus récemment arrivée dans l’équipe, merci pour tes conseils de clonage.Valérie CALCO , pour ton aide à la culture des cellules PC12. Emeline Tanguy, Marion RAME, Marion GABEL Marion DeMILLET même, un grand merci à et pour tous les moments de discussion et les aides durant les 4 ans dans notre laboratoire. Merci aussi à Marion Millet, Laura et Margherita, je vous souhaite bonne chance pour la suite de votre thèse. Je souhaiterais remercier tous ma famille. Merci à mes parents pour votre soutiens sans ré serve depuis toujours. Merci à ma sœur pour toute son aide. Yidan Enfin, un grand merci pour ma femme . Sans ta patience et ton soutien tout au long de ma thèse, je n’aurais certainement pas réussi à la mener à bien. J’en profite pour t’exprimer mon grand amour et ma grande fierté. Abbreviations AD Alzheimer Disease ADHD Attention deficit/ hyperactivity disorder AL Autolysosomes AP Autophagosome APP Amyloid precursor protein ARF6 ADP-ribosylation factor 6 ARNO Cytohesin 2 ATP Adenosine Triphosphate ARCL Autosomal recessive cutis laxa α-SNAP NSF cofactor BoNT Botulinum neurotoxin CMA Chaperone-mediated autophagy c-AMP Cyclic adenosine monophosphate dRTA Distal renal tubular acidosis EE Early endosomes ER Endoplasmic reticulum F-ATPase ATP-synthase FLIM Fluorescence-lifetime imaging microscopy FRAP Fluorescence recovery after photobleaching FRET Förster resonance energy transfer GEF Guanine Nucleotide Exchange Factor GTP Guanosine-5'-triphosphate ISG Immature secretory granules LE Late endosomes MMs Matrix metalloproteinase isoforms MRXSH X-linked Mental Retardation Hedera type MSG Mature secretory granules Munc-18 Mammalian uncoordinated-18 MVB Multi+ -+vesicular bodies NHE3 Na -H exchanger isoform 3 NSF N-ethylmaleimide sensitive factor NTs Neurotransmitters PA Phosphatidic acid PAS Preautophagosomal structure PI-3 kinase Phosphatidylinositol 3-kinase PI(3)P Phosphatidylinositol-3-phosphate PI(4)P Phophatidylinositol-4-phosphate PI(3,5)P2 Phosphatidylinositol-3,5-bisphosphate PI(4,5)P2 Phosphatidylinositol-4,5-bisphosphate PLD Phospholipase D PS1 Presenilin-1 PS2 Presenilin-2 PUFA Polyunsaturated fatty acids Rab One of five families of small GTPases Ras cAMP-dependent protein kinase RAVE Regulator of acidification of vacuoles and endosomes RRP Readily releasable pool SM protein Sec1/Munc18 protein SNARE Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor SNAP-25 Q-SNARE protein synaptosome associated protein 25 t-SNARE Target SNARE TeNT Tetanus neurotoxin TGF-β Transforming growth factor beta TGM Triple glycosylation mutant TGN Trans-Golgi network TIRF Dynamic live imaging TMD Transmembrane domain TRACE/ADAM 17 Tumor necrosis factor-alpha converting enzyme TCSPC Time-correlated single-photon counting V-ATPase Vacuolar ATPases v-SNARE Vesicular SNARE V0 Transmembrane domain of V-ATPase V1 Peripheral domain of V-ATPase VACHT Vesicular acetylcholine transporter VAMP Vesicle-associated membrane proteins VGCC Voltage-gated calcium channel VGLUT Inhibitor of the glutamate vesicular transporter XMEA X-linked myopathy with excessive autophagy XPDS X-linked Parkinson Disease with Spasticity List of figures Figure 1: Physiological role of V-ATPase………………………………………………………………………….…………………3 Figure 2: Structure and function of the V-ATPase complex…………………………………………..……………………..4 Figure 3: Elasticity of Vma5p……………………………………………………………………………………..……………………..10 Figure 4: The Lysosomal System……………………………………………………………………………….………………….…..12 Figure 5: Regulation of the V-ATPase……………………………………………………………………………...…………………15 Figure 6: V-ATPase defects and associated neurodegenerative diseases………………………………………..…18 Figure 7: V-ATPase and cellular signaling…………………………………………………………………………………..……..24 Figure 8: Model of life cycle of secretory granule from biogenesis to fusion………………………………..……29 Figure 9: The different stages of exocytosis in secretory cells………………………………………………..…………30 Figure 10: The SNARE complex…………………………………………………………………………………………………..…….36 Figure 11: Structure of the neuronal SNARE complex………………………………………………………………..……..37 Figure 11: Structure of SNARE and SM proteins……………………………………………………………………………..…38 Figure 12: SNARE zippering model……………………………………………………………………………………………..…….41 Figure 13: Energetics of stalk formation……………………………………………………………………………………..……42 Figure14: Target SNARE proteins of botulinum neurotoxin (BoNT) and tetanus neurotoxin (TeNT) in the axon terminal…………………………………………………………………………………………..………..……47 Figure 15: Calibration curve of the EGFP fluorescence lifetimes in different pH……………………………....56 Figure 16: How V-ATPase regulate exocytosis…………………….……………………………...………………………….….61 Table of Contents Introduction Chapter 1: The V-ATPase 1.1 A short historical point on V-ATPase…………………………………………………………………1 1.2 Structure and function……………………………………………………………………………………..2 1.2.1 V0 domain………………………………………………………………………………………………………6 1.2.1.1 The a subunit…………………………………………………………………………………………...6 1.2.1.2 The c, c' and c” subunits…………………………………………………………………………….7 1.2.1.3 The d subunit……………………………………………………………………………………………8 1.2.1.4 The e subunit……………………………………………………………………………………………8 1.2.2 The V1 sub domain………………………………………………………………………………………….8 1.2.2.1 The A and B subunits………………………………………………………………………………...9 1.2.2.2 The C subunit……………………………………………………………………………………………9 1.2.2.3 The D and F subunits……………………………………………………………………………….10 1.2.2.4 The E and G subunits……………………………………………………………………………….10 1.2.2.5 The H subunit……………………………………………………………………………………….....11 1.3 V-ATPase and organelle function………………………………………………………………………...…11 1.4 Regulation of V-ATPase activity……………………………………………………………………..…13 1.4.1 Regulation of V-ATPase by reversible disulfide formation………………………..……....13 1.4.2 Regulation of V-ATPase by modification of density…………………………………………..14 1.4.3 Regulation of V-ATPase by reversible disulfide formation………………………………..14 1.4.4 Other regulatory mechanisms of V-ATPase activity………………………………………….17 1.5 Genetic diseases related to the V-ATPase…………………………….……………………………17 1.5.1 Osteopetrosis………………………………………………………………………………………………..18 1.5.2 Autosomal recessive cutis laxa (ARCL) type II…………………………………………………19 1.5.3 Distal renal tubular acidosis (dRTA)……………………………………………………………….19 1.5.4 X-linked myopathy with excessive autophagy (XMEA)……………………………………..20 1.6 Autophagy and V-ATPase: Aging and neurodegenerative disease………………………20 1.7 V-ATPase and regulation of signaling pathways………………………………………………..22 1.8Chapter V-ATPase 2: Regulated and cancer Exocytosis……………………………………………………………………………… ……….23 2.1 Exocytosis………………………………………………………………………………………………………26 2.1.1 Constitutive exocytosis…………………………………………………………………………………..26 2.1.2 Regulated exocytosis……………………………………………………………………………………...26 2.2 The life cycle of a secretory vesicle: from Golgi to plasma membrane……….………..27 2.3 The different steps of exocytosis………………………………………………………………….…..28 2.3.1 Production of secretory vesicles……………………………………………………………………..30 2.3.2 The docking of the vesicle………………………………………………………………………………31 2.3.3 Getting ready for secretion……………………………………………………………………………..31 2.3.4 Release of contents of vesicle………………………………………………………………………….32 2.4 Factors involved in membrane fusion…………………………………………………….………….33 2.4.1 Lipids……………………………………………………………………………………………………………..33 2.4.2 SNARE proteins………………………………………………………………………………………………34 2.4.2.1 Structure and interaction of SNAREs……………….…………………………………………34 2.4.3 SNAREs and membrane fusion…………………………………………………………………………35
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