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Interplay Between Autophagy and the Primary Cilium: Role in Mechanical Interplay between autophagy and the primary cilium : Role in mechanical stress integration Idil Orhon To cite this version: Idil Orhon. Interplay between autophagy and the primary cilium : Role in mechanical stress in- tegration. Cellular Biology. Université Pierre et Marie Curie - Paris VI, 2014. English. NNT : 2014PA066672. tel-01242554 HAL Id: tel-01242554 https://tel.archives-ouvertes.fr/tel-01242554 Submitted on 13 Dec 2015 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. Université Pierre et Marie Curie (Paris 6) Ecole doctorale Physiologie et Physiopathologie 2014 DOCTORAL THESIS for University Pierre et Marie Curie Paris 6 Public Defense : 11 December 2014 by Idil ORHON entitled INTERPLAY BETWEEN AUTOPHAGY AND THE PRIMARY CILIUM: ROLE IN MECHANICAL STRESS INTEGRATION Members of the Jury: Professor Joëlle SOBCZAK-THEPOT President Doctor Alexandre BENMERAH Reporter Professor Fulvio REGGIORI Reporter Doctor Vincent GALY Examinator Doctor Sophie PATTINGRE Examinator Doctor Isabelle BEAU Thesis Director Doctor Patrice CODOGNO Thesis Director Institut Necker-Enfants Malades (INEM) INSERM UMR 1151 -CNRS UMR 8253 Université Paris Descartes-Sorbonne Paris Cité Laboratoire de l’homéostasie cellulaire et signalisation en physiopathologie hépatique et rénale 2 ACKNOWLEDGMENTS Firstly, I would like to thank the members of the jury, to Alexandre Benmerah and Fulvio Reggiori for accepting to evaluate this manuscript, to Joelle Sobczak for accepting to be the president of the jury and to Sophie Pattingre and Vincent Galy for accepting to be examiner of this work. Foremost, I would like to express my gratitude to my thesis supervisors Patrice Codogno and Isabelle Beau for giving me the opportunity to work and learn from them. I am sincerely grateful to Patrice Codogno for his expertise, experience and confidence in me throughout these years. Without his extensive knowledge on autophagy but also on “the outside world”, I certainly could not evolve as a researcher during these years. I am deeply thankful for Isabelle Beau and her presence in my PhD journey starting from day one whether from the next door or in distance. She set an inspiring example for a woman in science with her passion of bench work and guidance. I am greatly thankful to Ana-Maria Cuervo for giving me the opportunity to be part of an inspiring collaboration that changed my perspective on many different levels. Working in her lab was a condensed learning experience with a very dynamic and kind group of people. That leads to a sincere thanks and gratitude to Olatz Pampliega, an amazing collaborator and scientist whom I feel lucky to have worked with, learnt from and hope to work with again. Without them this work could not have happened. I would also like to acknowledge Gerard Friedlander, for his support and contribution to this work. A very special thanks goes to the “primary” Nicolas Dupont. During the last year, his presence changed the dynamism of our lab and this project. Without our brainstorms, his motivation and his passion for pubmed search, I wouldn’t see the finish line. I would especially like to thank him for his input and time on this manuscript. I would like express my thanks to my chocolate loving group of colleagues with whom I feel very lucky to work with daily: Ahmeeeeeeed Hamai who was ready to answer all of my questions at any time with a smile, Joelle Botti and Chantal Bauvy for their kindness and 3 support and Etienne Morel who was a support even before joining the lab, Anna Chiara Nascimbeni and Maryam Mehrpour. I’d like to thank sincerely to the Chatenay-Malabry team with whom I started this journey: Lina Mouna for her friendship and the Turkish/Syrian coffee time, Francoise Magnin for her daily kindness, Mathieu Bertrand, Marion Lussignol, Audrey Esclatine, Marie-Francoise Bernet-Camard, Anne Greffard and Raymonde Amsellem. I want to thank everybody from Co-lander team “across the hall”, with a shout-out to Christine and Valérie for their management skills and not leaving us in chaos. I would also like to thank to Marie Courbebaisse and Dominique Prié for their insight on the kidney. I must acknowledge the platforms that helped me: Claudine from Trans-Prot of IPSIT, Nicolas and Raphaelle from IMAGINE. I must thank Philippe Cardot for his support, Chiara Maiuri, Ezgi Tasdemir and Devrim Gozuacik for their supervision during my ignorant years and for teaching me how to work on the bench, which I love. I would also like to thank Rosalind, Henrietta, Simone, Charles, Pablo, Samed, Halit Ziya and Yoda for the inspiration. Last but not least I have to thank my family and friends who make this journey worth sharing. I am grateful for the love and support of my brother, mother and father. Without the patience of my mom and dad, I could not have pursued an education in science so far. I am also thinking of my dear grandmother who passed away at the beginning of this craziness and who I wished could have seen the end of it all. I am very lucky and grateful to have too many friends to name here who shared this experience with me. However, I cannot fail to acknowledge these wonderful people for their love, jokes and support: Seray, Yasemin, Burge, Idil, Irem and especially Isil who supported my daily neurosis towards the end. I love them dearly. 4 TABLE OF CONTENT Abbreviations ………………………………………………………………………………….7 Table of Illustrations…………………………………………………………………………..9 Summary……………………………………………………………………………………...10 Résumé………………………………………………………………………………………..11 I. Introduction…………………………………………………………………………..12 1. Cilium: Structure and Signaling……………………………………………………...13 1.1. Structure ……………………………………………………………...13 1.1.1. Motile Cilia and Flagella ……………………………………..13 1.1.2. Primary Cilia…………………………………………………..14 1.1.3. Ciliogenesis and Ciliary Subdomains………………………..15 1.1.4. Intraflagellar Transport Mechanism………………………....18 1.2. Ciliary Signaling………………………………………………………20 1.2.1. Hedgehog Signaling…………………………………………...20 1.2.2. PDGF Pathway………………………………………………..23 1.2.3. Wnt Pathway…………………………………………………..23 1.2.4. Calcium Signaling……………………………………………..24 1.2.5. Fluid flow and Fluid Shear Stress………………………..…..25 2. Autophagy…………………………………………………………………………….30 2.1. Role of Autophagy………………………………………………...….30 2.2. Different Types of Autophagy…………………………………..…...30 2.2.1. Macroautophagy………………………………………………30 2.2.2. Chaperone-mediated Autophagy ……………………………..31 2.2.3. Microautophagy…………………………………………... ….34 2.3. Autophagosome Machinery and Biogenesis …………………………34 2.3.1. Initiation……………………………………………………….35 2.3.2. Elongation…………………………………………………..…40 2.3.3. Maturation……………………………………………………..41 2.3.4. The origin of the Autophagosome…………………………….42 2.4. Regulation of Autophagy …………………………………………….46 2.4.1. Diverse Regulatory Pathways…………………………………46 5 2.4.2. Post-translational Modifications of Autophagic Machinery…..50 2.4.3. Transcriptional and Epigenetic Regulations of Autophagy…...53 2.5. Physiological Role of Autophagy……………………………………..55 2.5.1. Selective Autophagy…………………………………………..56 2.5.2. Autophagy during pre- and post-natal state…………………...58 2.5.3. Autophagy in the liver………………………………………...58 2.5.4. Autophagy in the brain………………………………………..59 2.5.5. Autophagy in the muscle……………………………………...59 2.5.6. Autophagy in the intestine…………………………………….60 2.5.7. Autophagy in the pancreas……………………………………60 2.5.8. Autophagy in the lung…………………………………………61 2.5.9. Autophagy in innate and adaptive immunity………………….61 2.5.10. Pathophysiological Role of Autophagy……………………….63 2.6. The Role of Autophagy in Kidney Physiology and Physiopathology...67 2.6.1. Physiology of the Kidney: An Introduction…………………...67 2.6.2. Autophagy in the Kidney: Health and Disease………………..71 II. AIMS of the study…………………………………………………………………….77 III. Materials and Methods………………………………………………………………..80 IV. Results …………………...…………………………………………………………...86 1. Objective1:Study the functional interaction between autophagy and primary cilium..87 1.1.Results…………………………………………………………………….89 1.2. Discussion 1……………………………………………………………..90 2. Objective 2: Study the role of autophagy in integration of mechanical stress via primary cilium………………………………………………………………………………….94 2.1. Results……………………………………………………………………96 2.2. Discussion 2……………………………………………………………..106 V. General Discussion and Perspectives………………………………………………..111 BIBLIOGRAPHY………………………………………………………………………………….…119 ANNEXE…………………………………………………………………………………………..…139 6 Abbreviations GFP: green fluorescent protein 3-MA: 3-methyladenine Gli: glioma-associated oncogene family 4EBP-1: 4E binding protein-1 GPCRs: G-protein-coupled receptors ADPKD: autosomal dominant polycystic kidney disease HDAC6: histone deacetylase-6 aIFT : anterograde IFT Hh: Hedgehog AKI: acute kidney injury IFN: interferon AMPK: AMP-activated protein kinase IFT : Intraflagellar transport APC: adenomatosis polyposis complex IKK: IκB kinase AQP: aquaporin IPTG: Isopropyl β-D-1-thgalactopyranoside ATG: autophagy related JNK1: Jun NH2-terminal kinase 1 ATP: adenosine triphosphate KEC: Kidney epithelial cell BB : Basal body MAPK: mitogen-activated protein kinase BBS: Bardet–Biedl syndrome
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