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AKAP7 DEGRADES 2-5A MEDIATORS OF THE INTERFERON ANTIVIRAL RESPONSE ELONA GUSHO Bachelor of Science in Biology Fatih University, Istanbul, Turkey June 2009 Submitted in partial fulfillment of the requirements for the degree DOCTOR OF PHILOSOPHY IN REGULATORY BIOLOGY CELLULAR AND MOLECULAR MEDICINE SPECIALIZATION at the CLEVELAND STATE UNIVERSITY December 2015 We hereby approve this dissertation for Elona Gusho Candidate for the Doctor of Philosophy in Regulatory Biology degree for the Department of Biological, Geological and Environmental Sciences and the CLEVELAND STATE UNIVERSITY College of Graduate Studies ________________________________________________________________ Dissertation Chairperson, Robert H. Silverman, Ph.D. _____________________________________________ Department & Date ________________________________________________________________ Dissertation Committee Member, Sailen Barik, Ph.D. _____________________________________________ Department & Date ________________________________________________________________ Dissertation Committee Member, Donna M. Driscoll, Ph.D. ___________________________________________ Department & Date ________________________________________________________________ Dissertation Committee Member, Anton A. Komar, Ph.D. _____________________________________________ Department & Date Student’s Date of Defense: September 17, 2015 DEDICATION To my parents, Vjollca and Vangjo Gusho for their unconditional love and support in every step of my life. Thank you! Per prinderit e mi, Vjollca dhe Vangjo Gusho. FALEMINDERIT per dashurine, sakrificat besimin, dhe mbeshtetjen tuaj ne cdo hap te jetes time! ACKNOWLEDGMENT Today as I am writing my PhD thesis; I look back at the path of this unique, beautiful and challenging journey and am very grateful to many people who have supported and motivated me to get here. First I would like to express my infinite gratitude to my mentor, Dr. Robert Silverman for being such a great educator and leader in the beautiful and challenging road of scientific research. Thank you for all you have taught me, your advices, your patience, and your trust in me. Thank you very much for giving me the opportunity to be a member of your laboratory. I hope that one day my contribution to science will be as significant as yours! I would also like to extend my gratitude to my dissertation committee members: Dr. Anton Komar, Dr. Donna Driscoll, and Dr. Sailen Barik for their time and helpful feedback throughout my PhD education. Your questions, suggestions and comments have made a significant impact in my research project and my progress as a PhD candidate. Thank you! I am very thankful to Dr. George Stark and Dr. Aimin Zhou for accepting to be part of my committee. It is my pleasure to have the opportunity to have their feedback. My training as a PhD student was remarkably supported by present and past members of Silverman laboratory, an environment from which I have learned a lot. I would like to thank Dr. Jaydip Das Gupta and Dr. Arindam Chakrabarti for teaching me many techniques in the early days of my PhD training; Dr. Babal Jha for his help with the HPLC in this project and for the interesting scientific discussions in the lab; Christina Gaughan for being very friendly and helpful with many techniques; and for always taking great care of the lab; Dr. Shuvojit Banerjee for sharing his scientific ideas and technical expertise whenever I needed it; and Dr. Beihua Dong for always being so kind and knowledgeable. A significant part of this training has also been our collaboration with Dr. Susan Weiss and her laboratory members at the University of Pennsylvania. Our joined meetings have been a wonderful experience of sharing exiting data and scientific ideas. I am very thankful to Dr. Susan Weiss, Dr. Rong Zhang and Dr. Joshua Thronbourgh for the collaboration in this project. I would also like to thank the faculty members of the Regulatory Biology program at Cleveland State University, and in particular Dr. Girish Shukla for his generous advices and support. In addition, I would also like to thank all the members of the Cancer Biology department at the Lerner Research Institute, Cleveland Clinic for being very helpful and friendly. I am also very thankful to the faculty of Biology Department in Fatih University, Istanbul; an environment and city from which I carry beautiful memories. I wish to acknowledge Preca College, in my home country Albania, for the high quality education they provide to the new generations. During my studies I have met a lot of wonderful people and made lots of new friends. I would like to thank: Arishya Sharma, Bakytzhan Bakhautdin, Esen Goksoy Bakhautdin, Gaelle Muller, Gaurav Choudhary, Maria Barton, Payel Chatterjee and Turkeyah Alswillah. In particular I would like to thank my best friend and soul sister Amina Abbadi, with whom we have shared our successes and failures, the best and the worst events of our lives in the past few years. My heartfelt thanks go also to: Aiola Ambo, Ardita Gusho, Denitsa Pirinova Sokolova, Elona Murataj, Kriselda Collaku, Nina Shkurti, Uzma Jamil and Vangjola Gjika. I wish you all best of luck in making your own dreams come true! And finally, I dedicate this work to my family: to my parents, who have always emphasized to me the importance of education for a better future, even if this meant 10 years of being apart. To my dear brother Ondi and sister-in-law Rezarta for the support and courage they have given me throughout the PhD training years. It is also because of you that I am here today! And to my dear nephew, Noel, who has brought so much joy in our hearts from the day he was born. I would also like to thank two very special people: my aunt Mirjana and uncle Thomas Bicolli for their love and care. Thank you for making me feel at home, even though thousands of miles away from home. My thanks are extended to my dear cousins: Kleida, Aisha, Rajli and Peter for being both family and friends to me; and to two lovely girls: Emma and Olivia. I am blessed to have you all in my life. Thank you so much! “Wherever the art of medicine is loved, there is also a love of humanity.” Hippocrates AKAP7 DEGRADES 2-5A MEDIATORS OF THE INTERFERON ANTIVIRAL RESPONSE ELONA GUSHO ABSTRACT Higher vertebrates have evolved innate immunity genes, many of which function in the interferon (IFN) induced antiviral response. Type I IFNs are produced in response to viral infections and induce expression of several hundred IFN stimulated genes, including genes for the 2’,5’-oligoadenylate (2-5A) synthetase (OAS). The OAS/RNase L pathway is one of the principal mediators of IFN antiviral response. RNase L cleaves viral and cellular ssRNAs inhibiting viral replication. Viral-encoded 2’,5’-phosphodiesterases (2’,5’-PDEs) allow these viruses to evade the OAS/RNase L by degrading 2-5A, activators of RNase L. Moreover, mammalian 2’,5’-PDEs exist that are believed to limit RNase L activity. Sustained RNase L activity after viral clearance may lead to cell death and hence tissue damage. Thus, we hypothesized that eukaryotic members of the 2- histidine (2H)-phosphoesterase family might have a similar function to related viral 2’,5’-PDEs (murine coronavirus ns2 and rotavirus VP3). This study identified a homologous mammalian 2’,5’-PDE, a member of the A-kinase anchoring protein (AKAP) family, that cleaves 2-5A. Recombinant, purified mouse AKAP7 degraded 2-5A with kinetics similar to viral PDEs, while a mutant of two conserved histidine residues was catalytically inactive. Similiarly, in intact cells vii the expression of wild type but not mutant AKAP7 significantly reduced 2-5A levels after stimulation of OAS by transfection of synthetic dsRNA, polyI:polyC. The PDE activity was confirmed by generation of cell lines in which AKAP7 was stably depleted. To determine if AKAP7 could substitute for a viral 2′,5′-PDE, AKAP7 cDNA was inserted into an MHV genome with an inactivated mutant ns2 gene. The AKAP7 PDE domain restored the infectivity of the ns2 mutant MHV in bone marrow macrophages and in livers of infected mice. Interestingly, the PDE domain of truncated AKAP7 localized to the cytoplasm whereas full-length AKAP7 was observed only in the nuclei. We hypothesized that there might be additional related cellular 2’,5’-PDEs that degrade 2-5A, also based on structure homology. However, the cellular 2H-phosphoesterases, CGI-18, Leng9 and USB1 failed to degrade 2-5A, and apparently have different functions. We suggest that viral acquisition of AKAP7 PDE domain might have occurred during evolution, allowing diverse RNA viruses to antagonize the OAS/RNase L pathway. viii TABLE OF CONTENTS ABSTRACT ......................................................................................................... vii LIST OF FIGURES .............................................................................................. xii LIST OF ABBREVIATIONS ............................................................................... xiv CHAPTERS CHAPTER I: INTRODUCTION ............................................................................ 1 1.1 Interferons, an overview ................................................................................... 1 1.1.1 IFN classification ................................................................................. 2 1.1.2. IFN signaling ...................................................................................... 3 1.1.3. The IFN-I antiviral response .............................................................. 6 1.2
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