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Characterisation of the Interactions Between the KSHV ORF57 Protein and the Human TREX Complex

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Characterisation of the Interactions Between the KSHV ORF57 Protein and the Human TREX Complex Characterisation of the interactions between the KSHV ORF57 protein and the human TREX complex Sophie Schumann Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Faculty of Biological Sciences School of Molecular and Cellular Biology September 2014 The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. © 2014 The University of Leeds and Sophie Schumann i Acknowledgements I would like to express my gratitude to my supervisor Professor Adrian Whitehouse, for his continuing trust, guidance and support throughout my thesis. He always had an open door for me. Many thanks also to my co-supervisor Dr Richard Foster, who played an invaluable part in the rational-based drug design of my project. My deepest appreciation to my colleagues and friends from the Whitehouse and Hewitt groups, past and present, for creating such a great work environment. You have often provided me with scientific advice and support, as well as a good laugh. Many thanks go to Dr Ian Yule, for his help with compound selection and in silico modelling. Acknowledgments also to Dr Brian Jackson for performing the thermophoresis experiment presented within this thesis and to Dr Belinda Baquero-Perez for proof reading sections of my work. I am grateful to the Wellcome Trust for funding my studies and for putting me in a position where I could design and shape my own project. A huge thank you to my family, for believing in me and making me believe in myself. Last, but definitely not least, I would like to thank John, who gave me his unlimited support at every step of my PhD and to whom I can say; without you, this would have been so much harder. ii Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncovirus associated with multiple malignancies, including Kaposi’s sarcoma (KS). Like all herpesviruses, KSHV can establish either a latent or a lytic infection in host cells. During latency the virus remains in a dormant state, with limited gene expression. After reactivation, KSHV enters the lytic life cycle, characterised by production of infectious virions and subsequent dissemination of the virus from its latent reservoir. Importantly, lytic replication is critical for KS tumourigenesis. KSHV replicates in the nucleus of the host cell and requires cellular mRNA export factors to efficiently export viral mRNAs from the nucleus, allowing their translation in the cytoplasm. But while mammalian mRNA export is linked to splicing, the majority of the KSHV genome encodes intronless mRNAs, prompting the virus to circumvent this step. KSHV therefore expresses ORF57, a multifunctional protein essential for lytic replication. ORF57 recruits members of the cellular human transcription/export (hTREX) complex to form an export competent viral ribonucleoprotein particle (vRNP), facilitating efficient nuclear export of intronless KSHV mRNAs. This study presents a novel mechanism for the specific disruption of the vRNP and subsequent inhibition of virus lytic replication. Results suggest an ATP-cycle dependent remodelling of hTREX, which affects the ability of ORF57 to interact and form an export competent vRNP. Specifically, inhibiting ATP hydrolysis by the hTREX component and ATPase UAP56 prevents ORF57 from recruiting the hTREX complex, while key components of the endogenous complex remain able to interact. Following this finding, UAP56 was targeted by small molecule inhibitors, using a structure- based drug design approach, to prevent ATP hydrolysis and thereby inhibiting vRNP formation. Strikingly, a hit compound identified was shown to disrupt formation of the vRNP, lytic protein expression and infectious virion production, while allowing endogenous hTREX formation within a therapeutic window, where no cytotoxicity was observed. Bearing in mind the conserved mechanism for herpesvirus intronless mRNA export, this study finally presents a series of compounds that are able to prevent both KSHV and HSV-1 lytic replication. iii Contents Acknowledgements ....................................................................................................... ii Abstract ....................................................................................................................... iii Contents ...................................................................................................................... iv List of figures ................................................................................................................ ix List of tables ................................................................................................................ xiii Abbreviations .............................................................................................................. xiv 1 Introduction ........................................................................................................... 2 1.1 Herpesviridae ........................................................................................................... 2 1.1.1 Classification of Herpesviruses ............................................................................. 2 1.1.1.1 Alphaherpesvirinae ........................................................................................... 2 1.1.1.2 Betaherpesvirinae ............................................................................................. 3 1.1.1.3 Gammaherpesvirinae ........................................................................................ 4 1.1.2 Virion architecture ................................................................................................ 4 1.1.3 Genomic structure ................................................................................................ 5 1.1.4 Life cycle ................................................................................................................ 6 1.1.4.1 Latency .............................................................................................................. 8 1.1.4.2 Lytic replication ................................................................................................. 8 1.2 The Gammaherpesvirinae ....................................................................................... 9 1.2.1 Epstein Barr virus (EBV) ...................................................................................... 10 1.2.1.1 EBV life cycle ................................................................................................... 12 1.2.2 Kaposi’s sarcoma-associated herpesvirus (KSHV) ............................................... 13 1.2.2.1 KSHV associated diseases ............................................................................... 15 1.2.2.1.1 Kaposi’s sarcoma (KS) ............................................................................... 15 1.2.2.1.2 Primary effusion lymphoma (PEL) ............................................................ 19 1.2.2.1.3 Multicentric Castleman disease (MCD)..................................................... 19 1.2.2.2 KSHV life cycles ............................................................................................... 19 1.2.2.2.1 Latency ...................................................................................................... 20 1.2.2.2.2 Lytic replication ......................................................................................... 22 1.3 Cellular mRNA export ............................................................................................ 25 1.3.1 Cellular mRNA processing ................................................................................... 25 1.3.2 The human transcription/export (hTREX) complex ............................................ 26 1.3.2.1 Assembly and function of the hTREX complex ............................................... 27 iv 1.3.2.2 The hTREX complex and the export receptor Nxf1 ......................................... 31 1.3.2.3 The hTREX complex and the exon junction complex (EJC) ............................. 33 1.3.3 Alternative mRNA export pathways ................................................................... 33 1.3.3.1 CRM1-dependent mRNA export ..................................................................... 33 1.3.3.2 Nuclear budding of mRNPs ............................................................................. 34 1.3.3.3 Export of intronless mRNA .............................................................................. 35 1.4 Viral mRNA export ................................................................................................. 36 1.4.1 Herpesvirus mRNA export ................................................................................... 36 1.4.2 mRNA export by other viruses ............................................................................ 36 1.5 KSHV ORF57 protein .............................................................................................. 39 1.5.1 ORF57-mediated mRNA export .......................................................................... 41 1.5.2 Other roles of ORF57 .......................................................................................... 44 1.5.2.1 Transcriptional enhancement by ORF57........................................................
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