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Role of the Clathrin Adaptor Complex AP1 and the Small Gtpase Rab11a in Anterograde Trafficking in Toxoplasma Gondii Kannan Venugopal

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Role of the Clathrin Adaptor Complex AP1 and the Small Gtpase Rab11a in Anterograde Trafficking in Toxoplasma Gondii Kannan Venugopal Role of the clathrin adaptor complex AP1 and the small GTPase Rab11A in anterograde trafficking in Toxoplasma gondii Kannan Venugopal To cite this version: Kannan Venugopal. Role of the clathrin adaptor complex AP1 and the small GTPase Rab11A in anterograde trafficking in Toxoplasma gondii. Human health and pathology. Université du Droitet de la Santé - Lille II, 2016. English. NNT : 2016LIL2S055. tel-01617170 HAL Id: tel-01617170 https://tel.archives-ouvertes.fr/tel-01617170 Submitted on 16 Oct 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE LILLE NORD DE FRANCE ECOLE DOCTORALE BIOLOGIE – SANTE DE LILLE THESE Pour l’Obtention du grade de: DOCTEUR en Biologie et Santé de l’Université de Lille Nord de France Spécialité : Parasitologie Présentée par VENUGOPAL Kannan Role of the Clathrin Adaptor Complex AP1 and the small GTPase Rab11A in Anterograde Trafficking in Toxoplasma gondii Soutenue le 21 Décembre 2016 Composition du jury: Madame le Docteur LEBRUN Maryse, Rapporteur Monsieur le Docteur SILVIE Olivier, Rapporteur Madame le Docteur SOLDATI-Favré Dominique, Examinateur Monsieur le Docteur MEISSNER Markus, Examinateur Monsieur le Docteur DELEVOYE Cedric, Examinateur Madame le Docteur MARION Sabrina, Directeur de Thése Laboratoire de Biologie Cellulaire et Moleculaire du Toxoplasme Centre d’Infection et d’Immunité de Lille, Institut Pasteur de Lille CNRS UMR 8204 – INSERM U1019 1 Contents Résumé ............................................................................................ 6 Summary ........................................................................................ 7 Acknowledgements ....................................................................... 8 Scientific output ........................................................................... 10 List of Abbreviations .................................................................. 11 Chapter I. Introduction ............................................................... 14 1. The Apicomplexa ...................................................................... 14 2. Toxoplasma gondii .................................................................... 15 2.1 Classification ........................................................................... 15 2.2 Life cycle ................................................................................. 16 2.3 Toxoplasmosis ......................................................................... 19 2.3.1 Modes of transmission .......................................................... 19 2.3.2 Dissemination and Pathogenesis .......................................... 20 2.3.3 Diagnosis and Treatment ...................................................... 22 2.3.4 Prophylaxis ........................................................................... 23 3. Parasite Architecture and ultrastructural organization ......... 24 3.1 Intracellular organelles ............................................................ 25 3.1.1 The apicoplast ....................................................................... 26 3.1.2 Micronemes .......................................................................... 26 3.1.3 Rhoptries ............................................................................... 28 3.1.4 Dense Granules ..................................................................... 30 3.1.4.1 Dense granule proteins localization and function ............. 30 3.1.4.2 Dense granule proteins structure and secretion ................. 32 2 3.2 The cytoskeleton ...................................................................... 33 3.2.1 The pellicle ........................................................................... 33 3.2.2 The microtubule network ..................................................... 35 3.2.3 The conoid ............................................................................ 35 4. The Lytic Cycle .......................................................................... 38 4.1Gliding motility and adhesion .................................................. 39 4.1.1 Microneme secretion ............................................................ 39 4.1.2 The glideosome ..................................................................... 40 4.1.3 Actin dynamics ..................................................................... 41 4.2 Invasion .................................................................................... 43 4.2.1 Formation of the Moving Junction ....................................... 43 4.2.2 PVM formation ..................................................................... 46 4.3 Intracellular parasite replication .............................................. 46 4.3.1 A modified cell cycle ............................................................ 46 4.3.2 Centrosome initiated division process .................................. 47 4.4 Egress ....................................................................................... 50 5. Eukaryotic protein trafficking .................................................. 51 5.1 The anterograde trafficking pathway ...................................... 52 5.1.1 Vesicle budding at the TGN ................................................. 53 5.1.2 Membrane tubulation, scission and transport ....................... 54 5.1.3 Vesicular tethering, docking and fusion ............................... 56 5.2 The Adaptor Protein complexes ............................................. 57 5.2.1 AP1 ....................................................................................... 60 5.3 Epsins ....................................................................................... 61 3 5.4 Rabs ......................................................................................... 62 5.5 Rab11 ....................................................................................... 65 5.5.1 Rab11 and motor proteins .................................................... 67 5.5.2 Rab11 regulators ................................................................... 68 5.5.3 Rab11 in disease ................................................................... 68 5.6 Hook1 ....................................................................................... 68 6. Protein trafficking in T.gondii ................................................. 70 6.1 The T. gondii plant-like endosomal system ............................ 71 6.2 T.gondii Rab11 ........................................................................ 73 6.3 Microneme protein trafficking in the secretory pathway ........ 74 6.4 Rhoptry protein trafficking in the secretory pathway and the role played by TgAP1 ....................................................... 77 6.5 TgSORTLR a unique receptor for MIC and ROP transport ... 80 6.6 Dense granule biogenesis ........................................................ 81 6.7 Concluding Remarks ............................................................... 82 7. Objectives ................................................................................. 83 Chapter II Materials and Methods ........................................... 85 1. Cell culture ................................................................................ 85 2. Molecular Biology ..................................................................... 85 3. Cell Biology ............................................................................... 93 4. Biochemistry .............................................................................. 97 Chapter III Results ................................................................... 101 1. Dual role of the Toxoplasma gondii clathrin adaptor AP1 in the differential sorting of rhoptry and microneme proteins and in parasite division ........................................................................... 101 4 2. Toxoplasma gondii Rab11A regulates surface membrane proteins and dense granule secretion during host invasion and parasite replication ....................................................................... 155 Chapter IV Discussion and Perspectives ................................ 176 Bibliography ............................................................................... 184 Resume Detaille des Travaux de These (Français) ................ 215 5 Résumé Toxoplasma gondii, l'agent causal de la toxoplasmose appartient au phylum des Apicomplexes. Comme son nom l'indique, le parasite possède un complexe unique d'organites sécrétoires apicaux, les micronèmes, rhoptries et le conoïde, qui jouent un rôle essentiel pour l’invasion de la cellule hôte et la survie du parasite dans la vacuole parasitophore. T. gondii est devenu un modèle populaire de biologie cellulaire et aussi un outil de référence pour l'étude de l’organisation ultra-structurale et des différentes fonctions des autres parasites du phylum Apicomplexa tel que Plasmodium, l’agent causal de la malaria. Des progrès récents dans la dissection des différentes voies du trafic intracellulaire ont conduit à une meilleure
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