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A Role of Ubiquitin Regulatory X-Domain Containing Proteins (UBXN6) in Antiviral Immunity

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A Role of Ubiquitin Regulatory X-Domain Containing Proteins (UBXN6) in Antiviral Immunity Touro Scholar NYMC Student Theses and Dissertations Students 8-31-2019 A Role of Ubiquitin Regulatory X-Domain Containing Proteins (UBXN6) in Antiviral Immunity Harshada Ketkar Harshada Ketkar New York Medical College Follow this and additional works at: https://touroscholar.touro.edu/nymc_students_theses Part of the Immunology of Infectious Disease Commons, Medicine and Health Sciences Commons, and the Virology Commons Recommended Citation Ketkar, Harshada and Ketkar, Harshada, "A Role of Ubiquitin Regulatory X-Domain Containing Proteins (UBXN6) in Antiviral Immunity" (2019). NYMC Student Theses and Dissertations. 24. https://touroscholar.touro.edu/nymc_students_theses/24 This Doctoral Dissertation - Open Access is brought to you for free and open access by the Students at Touro Scholar. It has been accepted for inclusion in NYMC Student Theses and Dissertations by an authorized administrator of Touro Scholar. For more information, please contact [email protected]. A Role of Ubiquitin Regulatory X-Domain Containing Proteins (UBXN6) in Antiviral Immunity Harshada Ketkar A Thesis in the Program in Basic Medical Sciences Submitted to the Faculty of the Graduate School of Basic Medical Sciences in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at New York Medical College 2019 ii Acknowledgments I want to thank my mentor Dr. Penghua Wang for all his help, encouragement and guidance. I thank him for his thoughtful suggestions in science and life. The completion of my Ph.D. would not have been possible without his support. Most importantly I thank him for having trust in me and building my confidence. Thanks to my committee! I thank, Dr. Bakshi for his invaluable guidance and feedback that helped shape this thesis into its final form. I thank him for the encouragement and kindness. I thank Dr. Bucher for providing her expertise in Virology field. Thanks, Dr. Xu for providing insights into the mechanistic study. Thanks, Dr. Colpitas for providing valuable advice of completion of one figure at a time. I sincerely thank Dr. Tiwari, Program Director for his guidance and support throughout the course. I also sincerely appreciate Dr. Belloni, former Dean of Graduate School for his involvement in my academic progress. I am thankful to Dr. Holz, Dean of graduate school for encouragement during the completion of my thesis. I want to thank my parents, brothers, and friends for supporting me in my desire to pursue my dreams. Most deeply thank my husband, daughter, and son for sharing their time unconditional and for all the years of bestowing encouragement, patience, and love. iii Table of Contents Acknowledgments ............................................................................................................................. iii List of Tables ...................................................................................................................................... vi List of Figures and illustrations ......................................................................................................... vii Abbreviations................................................................................................................................... viii Abstract ............................................................................................................................................ xiv 1 Introduction and Background: .................................................................................................... 1 1.1 Pathogen pattern recognition receptors ............................................................................ 2 1.1.1 The RLR pathway ........................................................................................................ 4 1.2 Interferon response .......................................................................................................... 13 1.2.1 Interferon types and receptors ................................................................................ 13 1.2.2 Interferon response- JAK-STAT pathway .................................................................. 17 1.3 UBXNs ............................................................................................................................... 26 1.3.1 UBXN1 ....................................................................................................................... 28 1.3.2 UBXN2A .................................................................................................................... 30 1.3.3 UBXN2B..................................................................................................................... 31 1.3.4 UBXN3A .................................................................................................................... 32 1.3.5 UBXN3B..................................................................................................................... 34 1.3.6 UBXN4 ....................................................................................................................... 35 1.3.7 UBXN6 ....................................................................................................................... 36 1.3.8 UBXN7 ....................................................................................................................... 40 1.3.9 UBXN8 ....................................................................................................................... 41 1.3.10 UBXN9 ....................................................................................................................... 41 1.3.11 UBXN10 ..................................................................................................................... 42 1.3.12 UBXN11 ..................................................................................................................... 43 1.3.13 p47 ............................................................................................................................ 43 2 Materials and methods ............................................................................................................ 49 2.1 Materials ........................................................................................................................... 49 2.1.1 Cell lines .................................................................................................................... 49 2.1.2 Viruses ...................................................................................................................... 49 2.1.3 Plasmid construction ................................................................................................ 50 iv 2.1.4 Ligand treatment conditions .................................................................................... 50 2.1.5 Lipofectamine transfection protocol ........................................................................ 50 2.1.6 Virus infection conditions ......................................................................................... 51 2.2 Methods ........................................................................................................................... 52 2.2.1 Dual-Luciferase reporter assay ................................................................................. 52 2.2.2 Biochemical Assay for IFN-I bioavailability ............................................................... 55 2.2.3 Generation of gene knockout cell lines with CRISPR-Cas9 technology .................... 56 2.2.4 Reverse transcription and quantitative PCR (qPCR) ................................................. 65 2.2.5 PCR array of human IFN-I Response ......................................................................... 67 2.2.6 ELISA (enzyme-linked immunosorbent assay) .......................................................... 72 2.2.7 Immunoblotting ........................................................................................................ 73 2.2.8 Co-immunoprecipitation. ......................................................................................... 75 2.2.9 Quantification of infectious viral particles by Plaque-forming assay ....................... 78 2.2.10 RNA Interference by siRNA ....................................................................................... 78 2.3 Graphing and statistics ..................................................................................................... 79 3 Aims .......................................................................................................................................... 80 4 Results ...................................................................................................................................... 83 4.1 Aim 1: To identify a member of UBXN proteins as a positive regulator of RNA virus- induced innate immune responses. ............................................................................................. 84 4.2 Aim 2: To characterize the function of UBXN6 in viral pathogenesis and host innate immune responses. ...................................................................................................................... 91 4.2.1 Sub-aim 2.1: To determine the role of UBXN6 in host immune responses by siRNA knockdown of UBXN6. .............................................................................................................. 91 4.2.2 Sub-aim 2.2: To generate UBXN6 knockout in HEK293 and trophoblast cells by CRISPR-Cas9 technology and to examine
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