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Characterization of the Nodamura Virus RNA Dependent RNA

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Characterization of the Nodamura Virus RNA Dependent RNA University of Texas at El Paso DigitalCommons@UTEP Open Access Theses & Dissertations 2015-01-01 Characterization of the Nodamura virus RNA dependent RNA polymerase and Formation of RNA Replication Complexes in Mammalian Cells Vincent Ulysses Gant University of Texas at El Paso, [email protected] Follow this and additional works at: https://digitalcommons.utep.edu/open_etd Part of the Biochemistry Commons, Molecular Biology Commons, and the Virology Commons Recommended Citation Gant, Vincent Ulysses, "Characterization of the Nodamura virus RNA dependent RNA polymerase and Formation of RNA Replication Complexes in Mammalian Cells" (2015). Open Access Theses & Dissertations. 1047. https://digitalcommons.utep.edu/open_etd/1047 This is brought to you for free and open access by DigitalCommons@UTEP. It has been accepted for inclusion in Open Access Theses & Dissertations by an authorized administrator of DigitalCommons@UTEP. For more information, please contact [email protected]. CHARACTERIZATION OF THE NODAMURA VIRUS RNA DEPENDENT RNA POLYMERASE AND FORMATION OF RNA REPLICATION COMPLEXES IN MAMMALIAN CELLS VINCENT ULYSSES GANT JR. Department of Biological Sciences APPROVED: Kyle L. Johnson, Ph.D., Chair Ricardo A. Bernal, Ph.D. Kristine M. Garza, Ph.D. Kristin Gosselink, Ph.D. German Rosas-Acosta, Ph. D. Jianjun Sun, Ph.D. Charles Ambler, Ph.D. Dean of the Graduate School Copyright © By Vincent Ulysses Gant Jr. 2015 Dedication I want to dedicate my dissertation to my beautiful mother, Maria Del Carmen Gant. My mother lived her life to make sure all of her children were taken care of and stayed on track. She always pushed me to stay on top of my education and taught me to grapple with life. My mother was incredibly strong and her strength has helped me weather many storms so that I may enjoy the warm sun. I also dedicate this work to my grandfather, James Powell Broome. Much of what I loved about my mother came from him and together they shaped me. He was my first mentor in life and his wisdom could fill the world’s oceans many times over. He taught me everything from tying a perfect Windsor knot to treating people with respect and kindness. The essence of my mother and her father is engrained into these pages and their memories will live on in them. CHARACTERIZATION OF THE NODAMURA VIRUS RNA-DEPENDENT RNA POLYMERASE AND FORMATION OF RNA REPLICATION COMPLEXES IN MAMMALIAN CELLS By VINCENT ULYSSES GANT, JR., B.S. DISSERTATION Presented to the Faculty of the Graduate School of The University of Texas at El Paso in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Department of Biological Sciences THE UNIVERSITY OF TEXAS AT EL PASO May 2015 Acknowledgements I want to thank Dr. Kyle L. Johnson for giving me all the tools and opportunity I needed to succeed. She is a very generous and understanding mentor and her guidance was invaluable. Her mentorship has pushed me to strive for the best and to keep charging forward until I’ve succeeded – and then keep going. I give many thanks to my dissertation committee for providing amazing ideas, critical feedback and a true challenge. All of our meetings were very much looked forward to and were such pleasures. I would like to thank everyone who has come through the KLJ lab at UTEP. Your company and friendship has certainly made all of this an extraordinary chapter in my life. I want to give the biggest thanks to my best friend and future wife, Stephanie Moreno. Her unending support and love have carried me through a lot of the seemingly unending hours. v Abstract Positive-strand RNA viruses amplify their genomes in membrane-bound structures associated with intracellular membranes and organelles called replication complexes (RCs). Here, we begin to elucidate mechanisms of Nodamura virus (NoV; family Nodaviridae) RC assembly. The literature reports that NoV-infected muscle tissue exhibits mitochondrial aggregation and rearrangement of mitochondrial structure, leading to disorganization of the muscle fibrils. However, the molecular basis for this pathogenesis and the role of mitochondria in NoV infection remained unclear until now. We tested the hypothesis that NoV establishes RCs in association with mitochondria in cultured mammalian cells at physiological temperature. We used immunofluorescence confocal microscopy and biochemical methods to determine that the aggregated mitochondria represent the sites of NoV RCs. We determined that the NoV RdRp (protein A; NA) uses two membrane-associated regions to localize to mitochondria as an integral membrane protein. Cells expressing NA exhibit mitochondrial morphologies similar to that described for diabetes, neurodegenerative disease and cardiovascular disease. Mitochondrial morphology is controlled by a cyclical mechanism referred to as mitochondrial dynamics, which involves fission and fusion pathways by which mitochondria cycle between two distinct forms: organelle and tubular. The tubular form resembles the clustered phenotype we observe in the presence of NA. This led us to hypothesize that NA disrupts mitochondrial fission, leading to accumulation of clustered mitochondria. In this dissertation we present evidence that NA interacts with the cellular machinery controlling mitochondrial morphology, which we interpret as the viral polymerase subverting mitochondrial dynamics to establish its RCs. vi Table of Contents Acknowledgements ........................................................................................................ v Abstract .......................................................................................................................... vi Table of Contents ......................................................................................................... vii List of Tables ................................................................................................................. ix List of Figures ................................................................................................................. x Chapter 1: Background and Significance .................................................................... 1 1.1 Family Nodaviridae .............................................................................................. 2 1.2 Ecology and Natural Host Range ....................................................................... 3 1.3 Nodavirus Virion Structure and Genome Packaging ..................................... 10 1.4 Nodavirus Genome Organization ..................................................................... 16 1.5 Nodavirus RNA Replication .............................................................................. 19 1.6 RNA Replication Systems ................................................................................. 26 1.7 Replication Complex (RC) Formation .............................................................. 36 Chapter 2: Subcellular Localization of the NoV RdRp in Mammalian Cells ........... 44 2.1 Introduction ........................................................................................................ 44 2.2 Materials and Methods ...................................................................................... 45 2.3 Results ................................................................................................................ 54 2.4 Conclusions ....................................................................................................... 85 Chapter 3: NoV RC Formation Induces Imbalance in Mitochondrial Dynamics .... 89 3.1 Introduction ........................................................................................................ 89 3.2 Materials and Methods ...................................................................................... 98 3.3 Results .............................................................................................................. 103 vii 3.4 Future Experiments ......................................................................................... 136 3.4.1 Immunofluorescence confocal microscopic analysis of Drp1 translocation inhibition in multi-labeled cells ..................................... 136 3.4.2 Kinetics of Drp1 translocation inhibition by the NoV RdRp .............. 137 3.4.3 Effect of NoV RdRp on Drp1 SUMOylation in transfected cells ........ 139 3.5 Conclusions ..................................................................................................... 142 Chapter 4: Discussion ................................................................................................ 147 4.1 NoV RC localization and NA membrane association .................................... 147 4.2 The NoV RdRp may perturb mitochondrial apoptosis during infection .... 148 4.3 The NoV RdRp interferes with mitochondrial dynamics possibly by disrupting Drp1 and mitochondrial fission ........................................... 153 4.4 The NoV RdRp may antagonize Drp1 activity by binding SUMO1 and preventing mitochondrial fission ........................................................... 157 4.5 Concluding remarks ......................................................................................... 162 References .................................................................................................................. 164 Glossary ...................................................................................................................... 193 Appendix I: .................................................................................................................
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