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Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis

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Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis Identification of HTLV-1 Tax-1 and HBZ Binding Partners, and Their Role in HTLV-1 Biology and Pathogenesis DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jacob Jamal Al-Saleem Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2016 Dissertation Committee: Dr. Patrick L. Green, Ph.D, Advisor Dr. Jesse Kwiek, Ph.D Dr. Li Wu, Ph.D Dr. Stefan Niewiesk, DVM, Ph.D Copyrighted by Jacob Jamal Al-Saleem 2016 Abstract Human T cell Leukemia Virus type 1 (HTLV-1) is estimated to have infected 15-20 million individuals world-wide. A subgroup of infected individuals develop diseases associated with viral infection, which include adult T cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. A closely related virus, HTLV-2, shares 70% nucleotide similarity with HTLV-1, but is not associated with any disease. Previous research has demonstrated that Tax-1 serves as the primary oncoprotein of HTLV-1, and its deletion or functional disruption completely ablates the transforming capacity of HTLV-1. Tax-2 (HTLV-2) has been demonstrated to have lower transforming capabilities than Tax-1. These differences are attributed to two domains present in Tax-1 yet absent in Tax-2; the four-amino acid PDZ binding motif (PBM) and an eight-amino acid leucine zipper-like region (LZ). These domains have been demonstrated to be required for the ability of Tax-1 to activate the alternative NF-κB pathway. Chapter Two of this dissertation analyzes the role that the alternative NF-κB pathway plays in HTLV-1 mediated T cell transformation. Analysis of the Tax-1 PBM or LZ mutants revealed that deletion of the PBM does not inhibit activation of the alternative NF-κB pathway. We then show that the PBM domain is required for Tax-1 activation of Akt signaling, and the mechanism behind this activation involves interactions between Tax-1, DLG-1, and PTEN. The Tax-1 LZ domain is required for activation of alternative NF-κB and HTLV-1 featuring the mutated Tax-1 LZ transformed ii T cells with an efficiency similar to wild type virus. This is the first evidence suggesting that alternative NF-κB activity is not required for in vitro cellular transformation of primary T-lymphocytes in culture. Studies in Chapter Three focus on dissecting the mechanism for Tax-1 activation of the alternative NF-κB pathway. Binding partners of four different Tax constructs were identified, including a mutant incapable of activating alternative NF-κB. While six proteins were identified as potentially important for alternative NF-κB activation, none passed initial screening to confirm their interaction profile. Other novel interactions of Tax-1 were analyzed, and an interaction between Tax-1 and SNX27 was discovered. We demonstrated that, through SNX27, Tax-1 regulates the localization of the HTLV-1 receptor molecule GLUT1. This is the first report describing a mechanism by which HTLV-1 regulates its receptor molecule. HTLV-1 expresses HBZ from the antisense strand of the viral genome. Both HBZ protein and mRNA have been implicated to promote proliferation of T cells. Studies in Chapter Four focused on investigating the mechanism behind these proliferative effects. Binding partners of both HBZ protein and mRNA were identified and analyzed to uncover interactions that regulate proliferation. Our preliminary experiments have identified cellular candidates that bind the HBZ protein and mRNA, but to date we have yet to identify a functional interacting partner. Further analysis is on-going. Collectively the data in this dissertation demonstrates that activation of the alternative NF-κB pathway is dispensable for in vitro transformation of T cells, and identifies binding partners of both Tax-1 and HBZ. Tax-1 activation of Akt was found to be dependent on the PBM, and this activation may serve as a therapeutic target. The iii interaction between Tax-1 and SNX27 could have profound implications on HTLV-1 biology as it is the first identified method of HTLV-1 regulation of receptor molecules post-entry. Several binding partners of both HBZ protein and mRNA were discovered, and follow up studies will be required to identify the role these interactions may play in HTLV-1 biology and pathogenesis. iv Dedicated to Becky and Carmen v Acknowledgments I want to first thank my advisor, Dr. Patrick Green. I have been extremely lucky to have worked for a trusting, understanding, and patient advisor. His guidance and motivation were crucial to my development as a scientist. Thank you for allowing me to develop into an independent scientist under your tutelage. I would like to thank my committee members, Drs. Li Wu, Jesse Kwiek, and Stefan Niewiesk for their advice and encouragement during my graduate studies. I would like to thank all members of Dr. Green’s Lab, both past and present: Dr. Han Yin, Dr. Rami Doueiri, Dr. Priya Kannian, Dr. Raj Anupam, Dr. Amanda Panfil, Dr. Nathan Dissigner, Krissy Landes, Corey Howard, and Dr. Michael Martinez. For all the aid you have given me in experiments and for all the distractions from stress, I am forever grateful. Much of the work done in my dissertation would not have been possible without the assistance and technical expertise of Drs. Mamuka Kvaratskhelia and Nikolozi Shkriabai. I would like to thank Dr. Corine St. Gelais for her time spent editing my writing. I promise to ‘perform,’ not ‘preform’ my experiments in the future. I also want to thank Dr. Kate Hayes-Ozello for her editorial assistance. A special thanks to all other members of the basement and CRR labs for making my time here memorable. vi I would like to also thank my undergraduate research advisor, Dr. Maki Asano. Without her I would have never gone to graduate school. She was an amazing advisor, brilliant teacher, caring mother, and inspiring scientist. I miss her dearly. She may be gone, but she will never be forgotten. To my family, thank you for all your support during my extended stay at OSU. Your love and encouragement has propelled me throughout graduate career. And yes, I am done with school now. Last, but definitely not least, I would like to thank my loving wife, Becky. The road has been long, but you stood by my side through it all. Whenever the challenges would seem too large you were there to center me. Whenever I had a long day in the lab, you were there when I got home to lift me up. You are my rock, and with you I am a better man. SFD4L. I love you forever and always. vii Vita 2005................................................................Lakota High School Kansas, Ohio 2010................................................................B.S. Molecular Genetics The Ohio State University Columbus, Ohio 2010 to present ...............................................Graduate Research Associate, Department of Veterinary Biosciences The Ohio State University Columbus, Ohio Publications 1. Al-Saleem, J., Kvaratskhelia, M., Green, P.L. Methods for identifying and examining HTLV-1 HBZ post-translational modifications. In Human T- lymphotropic Viruses-Methods and Protocols, C Casoli (ed), Springer Science, New York In Press 2. Panfil, A. R., Al-Saleem, J., Howard, C. M., Mates, J. M., Kwiek, J. J., Baiocchi, R. A., Green, P. L. PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival. Viruses 8, 7 (2016). 3. Cherian, M., Baydoun, H., Al-Saleem, J., Shkriabai, N., Kvaratskhelia, M., Green, P., & Ratner, L. Akt Activation by Human T-Cell Leukemia Virus Tax Oncoprotein. J. Biol. Chem. jbc.M115.684746 (2015). doi:10.1074/jbc.M115.684746 4. Dissinger N., Shkriabai N., Hess S., Al-Saleem J., Kvaratskhelia M., Green PL.Identification and Characterization of HTLV-1 HBZ Post-Translational Modifications. PLoS ONE 9, e112762 (2014). 5. Panfil, A. R., Al-Saleem, J. J., & Green, P. L. Animal Models Utilized in HTLV- 1 Research. Virology Research and Treatment 2013, 49–59 (2013). viii Fields of Study Major Field: Molecular, Cellular and Developmental Biology ix Table of Contents Abstract ............................................................................................................................... ii Acknowledgments.............................................................................................................. vi Vita ................................................................................................................................... viii Publications ...................................................................................................................... viii Fields of Study ................................................................................................................... ix Table of Contents ................................................................................................................ x List of Tables .................................................................................................................. xvii List of Figures ................................................................................................................ xviii Chapter 1: Literature Review .............................................................................................. 1 1.1 Introduction to Retroviruses ...................................................................................... 1 1.2 HTLV Discovery and Epidemiology .......................................................................
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