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The Mechanistic Function of the NOD-Like Receptor NLRX1 in Apoptosis and Cell Death in the Nervous System

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The Mechanistic Function of the NOD-Like Receptor NLRX1 in Apoptosis and Cell Death in the Nervous System The Mechanistic Function of the NOD-like Receptor NLRX1 in Apoptosis and Cell Death in the Nervous System by Muhammed Aashiq Rahman A thesis submitted in conformity with the requirements for the degree of Masters of Science Immunology University of Toronto © Copyright by Muhammed Aashiq Rahman 2015 ii The Mechanistic Function of the NOD-like Receptor NLRX1 in Apoptosis and Cell Death in the Nervous System Muhammed Aashiq Rahman Masters of Science Immunology University of Toronto 2015 Abstract The mitochondrial protein NLRX1 belongs to the family of cytosolic nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs). NLRs respond to invasive pathogens, and danger signals released from dead or dying cells. The function of NLRX1 was previously reported to be in anti-viral immunity, however we propose a non-immune role for this protein in apoptosis. We show here the function of NLRX1 to be inhibitory to extrinsic apoptosis and permissive to intrinsic apoptosis. Furthermore, we validate the previously reported interaction between NLRX1 and sterile-α and TIR motif containing protein 1 (SARM1). SARM1 is expressed in the nervous system, and has a pro-apoptotic function in addition to its role in promoting Wallerian degeneration. We found NLRX1 to have both SARM1-dependent and -independent functions during apoptosis. Furthermore, we test NLRX1 function during Wallerian degeneration following axotomy, and a central nervous system injury model involving ischemic stroke. iii Acknowledgments I am grateful for this opportunity to receive a Master’s of Science degree from the University of Toronto. I am honored to have worked with, and mentored by, some of the most brilliant minds in science. I take this opportunity to acknowledge some key individuals who have played essential roles during my time completing this degree. First and foremost, both Drs. Dana Philpott and Stephen Girardin have been fantastic supervisors that have kept both my passion for science, and motivation to determine the unknown fueled throughout my degree. Their continued guidance as well as scholarly insight have directed me in a highly productive and rewarding degree. Furthermore, their exemplary work ethic in balance with their personal family lives has helped me learn the lesson of prioritizing work and personal responsibilities which will be important throughout my life. My committee members Drs. Alberto Martin, and Tania Watts have helped me throughout these years, offering direction and insightful commentary at multiple checkpoints during my ongoing work. Their directional commentary has helped me focus my work and pursue angles that were previously overlooked. I also thank them for their guidance during the production of this manuscript. My lab members (from both Philpott & Girardin labs) have been nothing but extraordinary. The unity between the two laboratories, as well as mutual understandings between every member to help the daily workings of the lab created a family-like environment that facilitates scientific inquiry. Specifically, my colleagues Jessica Tsalikis and Mena Abdel-Nour have been exemplary role models that set the standards high for being ideal graduate students. Raphael Molinaro and Ivan Tattoli have been indispensable in their mentorship and technical expertise, and without them I would have been greatly overwhelmed. Furthermore, I am grateful to Dr. Konstantin Feinberg for teaching me how to compartmentalize neurons, which has helped push my project forward. Finally, Dr. Fraser Soares taught me every biochemical technique I know, and whose patience held even when asked the most basic of questions. Direct contributions: Dr. Tattoli generated the primary MEFs used extensively in this study. Dr. Soares transformed the MEFs, and cloned many of the NLRX1 and SARM1 constructs used. Ashley Zhang and I co- currently performed many of the immunoprecipitation experiments. Finally, I would also like to thank Parvati Dadwal for optimizing all tissue immunostaining experiments and her help and support during rodent surgeries. iv Table of Contents Acknowledgments ....................................................................................................................................... iii 1. Introduction .............................................................................................................................................. 1 1.1 Overview of Pattern recognition receptors ......................................................................................... 1 1.1.1 TLRs, RLRs, CLRs ALRs ........................................................................................................... 1 1.1.2 Nod-like receptors ....................................................................................................................... 4 1.2 NLRX1 ............................................................................................................................................... 7 1.2.1 The physiological conformation of NLRX1 and its localization to the mitochondrial matrix .... 7 1.2.2 NLRX1 function in ROS production, antiviral immunity, autophagy and TLR signalling. ....... 9 1.2.3 The apoptotic function of NLRX1 is observed in several physiological settings .....................13 1.3 SARM1 ............................................................................................................................................17 1.3.1 Proposed functions of SARM1 in TLR signalling and immunity. ............................................18 1.3.2 SARM1 function in Wallerian degeneration and Ca2+ dependent cell death ............................19 1.4 Cellular death – focus on apoptosis and Wallerian degeneration.....................................................22 1.4.1 Apoptotic cell death ..................................................................................................................23 1.4.2 Neuronal cell death and Wallerian degeneration ......................................................................27 2. Methodology ..........................................................................................................................................31 3. Results ....................................................................................................................................................35 3.1 NLRX1 blocks the sensitivity to extrinsic apoptosis signalled through TNF receptor following cancerous SV40 transformation. ........................................................................................................35 3.2 NLRX1 promotes the sensitivity to intrinsic apoptosis inducers following SV40 transformation ............................................................................................................................................................36 3.3 SARM1 interacts with NLRX1 and does not require it to localize to the mitochondria. ............37 3.4 NLRX1 forms homotypic interactions that affect SARM1 interaction. ......................................39 v 3.5 SARM1 functions upstream of NLRX1 during intrinsic and extrinsic apoptosis, but does not affect NLRX1 block on extrinsic apoptosis. ......................................................................................40 3.6 NLRX1 does not affect type I apoptosis via differential Smac release. .......................................42 3.7 NLRX1-KO does not delay Wallerian degeneration via axotomy as seen in SARM1 KO. ........43 3.8 NLRX1 functions during ischemic injury by limiting caspase dependent cell death and subsequent microglial activation. .......................................................................................................44 3.8 Figures .........................................................................................................................................46 3.9 Tables ...........................................................................................................................................63 4. Discussion and future directions: ...........................................................................................................64 5. References ..............................................................................................................................................69 1 1. Introduction 1.1 Overview of Pattern recognition receptors Pattern recognition receptors (PRRs) are an indispensable group of receptors that belong to the innate arm of the immune response. There are five families of innate pattern recognition receptors that are responsible for the detection and response to conserved extracellular or intracellular danger or infectious signals. These signals collectively termed MAMPs (microbe associated molecular patterns; also known as pathogen-associated molecular patterns or PAMPs) and DAMPs (danger associated molecular patterns) are expressed by microbes or released by dead or dying cells, respectively. The five PRR families consist of TLRs (Toll-like receptors), ALRs (AIM-like receptors), CLRs (C-type lectin receptors) , RLRs (RIG-I like receptors), and NLRs (Nod-like receptors), the latter of which will be the focus here. These receptors cooperatively play a role as first responders to host pathogenic invasion, and have an essential role in the development of an effective adaptive immune response. While these receptors have been classically associated with the innate and adaptive immune response, their function is not limited to these roles. Indeed, as outlined
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