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Alturki Norah Abdullah 2020 T NECROSOME ACTIVATION AND DEGRADATION IN MACROPHAGES By Norah Abdullah Alturki A Thesis Submitted to The Faculty of Graduate and Postdoctoral Studies In Partial Fulfillment of the Requirements for the PhD degree in Microbiology and Immunology Department of Biochemistry, Microbiology and Immunology Faculty of Medicine University of Ottawa © Norah Abdullah Alturki, Ottawa, Canada, 2020 PREFACE CONTRIBUTION OF COLLABORATORS • Dr. Katey Rayner’s laboratory (University of Ottawa Heart Institute) provided all the reagents and plates used for preparing and mounting the cells for the confocal microscopy, and images were captured using a ZEISS LSM 880 with Airyscan in their lab. • Dr. Alexandre Blais’s laboratory (University of Ottawa) performed and provided all the reagents and microarray slides used for gene expression profiling, and raw data were filtered and normalized using Expander 6.5. APPROVALS The experimental protocols used were approved by the University of Ottawa Animal Care Committee and include the protocols BMI1638 and BMI1639. A Biohazardous Materials Use Certificate was obtained from the University of Ottawa Office of Risk Management, Environmental Health and Safety. ii ABSTRACT Necroptosis is a recently discovered form of cell death that is distinct from apoptosis that promotes inflammation. Necroptosis is induced upon engagement of various classical death receptors such as tumor necrotic factor receptor (TNFR) and Fas ligand, and also by engagement of toll like receptors involved in recognition of various pathogen associated molecular patterns such as lipopolysaccharide (LPS) and polyinosinic: polycytidylic acid (poly I:C). Necroptosis is induced by the activation of receptor-interacting protein kinase-1 (RipK1) and receptor-interacting protein kinase-3 (RipK3) that leads to phosphorylation-driven trimerization and consequent translocation of the mixed lineage kinase domain-like (MLKL) protein to the cell membrane, resulting in cell rupture. The formation of this necrosome complex is highly regulated by phosphorylation and ubiquitination. The precise mechanisms through which members of the necrosome assemble sequentially in macrophages are not clear. Herein I have evaluated the mechanisms that promote the assembly and degradation of the necrosome in macrophages. In the first aim of my thesis I revealed that during early necrosome formation RipK3 destabilizes the complex by promoting degradation of interacting proteins. RipK3 promoted K48-ubiquitin dependent proteasomal degradation of various necrosome interacting proteins such as RipK1, CASPASE-8, and FADD. This degradation event occurred independently of other ubiquitin editing enzymes such as cIAP1/2, A20 and CYLD that are known to edit RipK1. I further show that this degradation of early necrosomal proteins is mediated by the E3-ubiquiting ligase Triad3a (RNF216). Knocking-down Triad3a prevented degradation of necrosome proteins, enhanced necroptosis and production of inflammatory cytokines. In the second section of my thesis, I evaluated the mechanisms responsible for necrosome signalling following engagement of type-I interferon receptor. I show that the downstream Janus kinase (JAKs) kinases (TYK2 and JAK1) are required for necroptosis in macrophages. My results indicate that IFNAR1 signalling promotes phosphorylation of RipK3 and MLKL, the two events that are required for necroptosis. Furthermore, I observed that type-I interferon signalling promotes the transcription of MLKL and the phosphorylation driven oligomerization of MLKL which is necessary for pore formation in cells. Finally, inhibition of the p38MAPK pathway abrogated the resistance of Ifnar1-/- macrophages. The results presented in this thesis reveal mechanisms that regulate necrosome signalling and will help identify potential therapeutic targets that could be exploited in chronic inflammatory conditions. iii ACKNOWLEDGMENTS First and foremost, I would like to thank Allah (SWT) who made this thesis possible and gave me the faith that I could do it and the strength and perseverance to finish this PhD thesis. This thesis would never have been completed or have seen the light of day without the help and advice of my supervisor, Dr. Subash Sad. I still remember when we met for the first time in the elevator, in November 2013. That day you listened to me and accepted me as a PhD candidate, and I am very thankful to you that you allowed me to work and achieve my dream under your supervision. My profound appreciation to you for your patience, your advice, your wisdom and the friendship that you built with us in our lab. I will transfer what you taught me, and like you, I will always keep my door open. Thanks for guiding me during my PhD journey, thanks for believing in me, and thanks for developing my knowledge and skills and pushing me to challenge my limits and go beyond them. You helped me to grow with your advice, your constant meetings, your constructive critiques. Dr. Subash, thanks for the opportunity to work in your lab, with an amazing team, under your vision. I would also like to extend my gratitude to my thesis advisory committee members, Dr. Daniel Figeys, Dr. Alexandre Blais, and Dr. Robert Korneluk. Thanks for valuable discussions, constructive criticism and useful recommendations during our annual meeting. I owe my gratitude to all the members of the Sad lab, former and current, for their support and encouragement during my PhD. Thank you Dr. Bojan, Dr. Rajen, Erin, Dr. Julie, David, Dikchha, Emmanuelle, Naveen, Dr. Laila, Melisa, Palavi and Parva. Special thanks Ms. Kim Kwangsin for providing technical assistance during my studies. Thanks to Dr. Ardeshir Aryana, our idea maker, for his assistance and support during my PhD. I also thank Stephanie Hajjar for her emotional support and her encouragement words. I thank Ms. Mufida and her husband Mr. Mohammed for the unconditional love and endless support. I also thank the Animal Care and Veterinary Service (ACVS) team who trained me in the essential, practical skills I needed to perform my animal experiments. I thank Dr. Katey Rayner and Dr. Anne-Claire from the Ottawa Heart Institute for allowing me to perform immunofluorescence experiments. iv My deepest gratitude to Dr. Lionel Filion (my beloved Canadian father) for his valuable advice, unlimited support, encouragement from when I was doing my master’s degree to now. Your words are always in my mind and you are not comparable to anyone. I would like to thank Ms. Fay Draper and everyone at the graduate office for the help, flexibility and continuous support during the difficult time I have been through. Thank you very much. Special thanks to my soul mate Dr. Afaf Tawfiq for the unconditional love you gave, for relentless support, and for treating me as a daughter. I am very thankful that through my PhD experience I met you and know someone like you. I learned a lot from you. Thank you. I would like to extend my gratitude to King Saud University for their financial support and scholarship. Thank you for your generosity all these years, and for funding my masters and doctoral studies in Canada. Also, I thank Saudi cultural bureau in Canada especially Ms. Saly Michael. I thank my friends from my PhD journey, Abeer Zakariyah, Esraa Baitalmal and Roza, Albakri for been together all these years. I am blessed to have you as friends and I really appreciate your unlimited support and endless encouragement. Special thanks to my lovely friend Dr. Hilary Phenix for taking the time to help revise this thesis; her presence and assistance have been irreplaceable. Lastly, I owe my deepest gratitude to my family. To my ever-loving parents (Abdullah and Fatmah), you are the best parents in the world, and I owe my success to you. Thanks for the faith and for believing in me, that I would achieve my dreams. Thanks for the prayers over the years and the infinite love. Thanks for tolerating my absence over 10 years. I also thank my lovely siblings (Hadeel, Bader, Faisal, Shahad, Mohammed and Gadah), my sisters-in-law (Abrar and Jawaher) and my lovely nieces (Almaha, Shaima, Seba, Nourah and Latein). Thanks for taking care of my parents, listening to me complain, and keeping me motivated. Special thanks to my brother Faisal, who faced challenges with me and helped me to overcome them throughout my PhD studies. Norah A. Alturki, 2019 v TABLE OF CONTENTS PREFACE ........................................................................................................................................................................................................ II ABSTRACT ................................................................................................................................................................................................... III ACKNOWLEDGMENTS .................................................................................................................................................................... IV TABLE OF CONTENTS ....................................................................................................................................................................... VI LIST OF ABBREVIATIONS ............................................................................................................................................................ VIII LIST OF FIGURES ....................................................................................................................................................................................
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