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Is a Novel Cellular Binding Partner of the Papillomavirus E5 Proteins

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YIP1 family member 4 (YIPF4) is a novel cellular binding partner of the papillomavirus E5 proteins Marietta Müller Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Molecular and Cellular Biology January, 2014 I 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 © 2013 The University of Leeds, Marietta Müller The right of Marietta Müller to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. II Für Philip Simeon Müller III Acknowledgement I would like to thank my two supervisors Dr Andrew Macdonald and Prof Nicola Stonehouse for their support and guidance throughout this project. I would also like to thank all past and present members of the Macdonald and Stonehouse labs for their helpful discussions and advice. In particular, thank you to Dr Christopher Wasson for the primary cell work and lab entertainment and to ‘team lunch’ Özlem Cesur and Dr Emma Prescott for invaluable chats. Thank you to Hussein Abdul-Sada for interesting perspectives and challenging questions. Many thanks to Gareth Howell and Jamel Mankouri for help with microscopy and flow cytometry. Thank you to Dr Cheryl Walter for help with the vaccinia virus expression system and Rosella Doble and Dr Sophie Forrest for help with qPCR. I would also like to thank Dr Tobias Lamkemeyer for granting insights into his expertise in mass spectrometry. Thank you to my advisor Prof G. Eric ‘Excuse me, you are on fire’ Blair for his advice and support. Many thanks to Susan Matthews and Rajni Bhardwaj for keeping the lab organised – you are truly invaluable! I would also like to thank Yorkshire Cancer Research for funding my PhD. Ich danke meinen Eltern und Geschwistern für Ihre Unterstützung während der ganzen Promotion und speziell der letzten Monate. Auch meinen Taufpaten Maria und Andreas möchte ich für Ihre Unterstützung danken. Ich danke Sandra und Kerstin für eine unvergessliche Zeit in Leeds. Ich danke allen meinen Freunden für Ihr Verständnis und Ihre Motivation. Im Besonderen möchte ich Nadine danken – ohne Dich hätte ich es nicht so weit gebracht! Eugene moratuwa wa pelo yaka, ke leboha tshehetso le rotlohetso eo o mphang yona ka dinako tsohle ke kahoo ke o ratang ka lerato le ke keng ja lekangwa le bophara ba lefatshe le tswang botebong ba pelo yaka. IV Abstract Papillomaviruses (PVs) are capable of causing a broad spectrum of diseases with the human PVs (HPVs) being responsible for a great portion of cervical, anogenital and head and neck cancers worldwide. The PV oncoprotein E5 plays roles in host cell transformation, the PV life-cycle and viral immune evasion. However, the mechanisms by which E5 achieves this are unclear. A yeast two- hybrid screen identified a novel Golgi protein, YIPF4, as a potential interactor of 16E5. YIPF4 is a member of the integral membrane protein family YIP1 that is thought to mediate intracellular trafficking. Quantitative polymerase chain reaction, Western blot and immuno-histochemistry analysis confirmed that YIPF4 is expressed in host cells of HPV infection in cell culture systems and in clinical samples of HPV16 induced cervical lesions. This implies that YIPF4 could be a relevant in vivo binding partner of E5. Upon the differentiation of HPV18 positive keratinoctyes in semisolid medium, the YIPF4 expression levels were stabilised compared to control cells suggesting that YIPF4 might play a role during the productive viral life-cycle. A differential, detergent permeabilisation assay provided the first experimental evidence for a three trans-membrane domain model of YIPF4. Co-immuno-precipitation revealed a conserved interaction of YIPF4 with E5 proteins from clinically important PVs indicating a potentially invaluable role of this complex for the virus. A flow cytometry approach unexpectedly revealed that neither E5 nor YIPF4 proteins modulate the trafficking of human leukocyte antigen class I molecules to facilitate viral immune evasion. A preliminary cellular interactome of YIPF4 was determined in a label free mass spectrometry experiment to facilitate the search for the function of the highly conserved E5/YIPF4 protein complex. This knowledge might contribute to elucidating new targets for the development of therapeutic agents against the broad spectrum of PV associated diseases. V Table of contents Acknowledgement ...................................................................................... III Abstract ...................................................................................................... IV List of tables ............................................................................................... IX List of illustrative material.......................................................................... X Abbreviations ........................................................................................... XIII Chapter 1. Introduction ............................................................................... 1 1.1. Family of Papillomaviruses ............................................................. 1 1.2. Classification of PVs ....................................................................... 1 1.3. HPV induced diseases .................................................................... 2 1.3.1. Cutaneous lesions ............................................................... 2 1.3.2. Benign mucosal lesions ....................................................... 4 1.3.3. Malignant mucosal lesions ................................................... 5 1.3.4. BPV induced pathology ........................................................ 8 1.3.5. Epidemiology of malignant HPV associated lesions ............ 9 1.3.6. Transmission...................................................................... 11 1.3.7. HPV and the immune system............................................. 11 1.3.8. Prevention and treatment of HPV induced lesions ............. 13 1.4. PV virology .................................................................................... 15 1.4.1. PV genome organisation .................................................... 15 1.4.2. PV life-cycle ....................................................................... 17 1.5. PV proteins ................................................................................... 22 1.5.1. E1 regulatory protein .......................................................... 22 1.5.2. E2 regulatory protein .......................................................... 24 1.5.3. E4 protein .......................................................................... 26 1.5.4. L1 structural protein ........................................................... 28 1.5.5. L2 structural protein ........................................................... 29 1.5.6. E6 oncoprotein ................................................................... 31 1.5.7. E7 oncoprotein ................................................................... 34 1.6. E5, a multifunctional oncoprotein .................................................. 38 1.6.1. Oncogenic potential of E5 .................................................. 41 1.6.2. E5 and the viral life-cycle ................................................... 48 1.6.3. E5 and PV immune evasion ............................................... 51 1.7. Work leading to this project ........................................................... 54 1.8. YIP1 protein family ........................................................................ 56 1.8.1. Rab GTPases .................................................................... 58 1.8.2. YIP1 proteins in yeast ........................................................ 60 1.8.3. YIP1 proteins in mammals ................................................. 64 1.9. Aims and objectives ...................................................................... 72 VI Chapter 2. Materials and Methods ............................................................ 73 2.1. Bacterial cell culture ...................................................................... 73 2.1.1. Bacteria growth and storage .............................................. 73 2.1.2. Preparation of chemically competent bacteria ................... 73 2.1.3. Transformation of competent bacteria with plasmid DNA .. 73 2.1.4. Preparation of plasmid DNA .............................................. 74 2.2. Molecular Cloning ......................................................................... 75 2.2.1. Plasmid DNA vectors and oligonucleotides ....................... 75 2.2.2. Polymerase chain reaction ................................................. 75 2.2.3. Agarose gel electrophoresis .............................................. 75 2.2.4. Restriction enzyme digestion ............................................. 76 2.2.5. Antarctic Phosphatase treatment of destination vectors .... 76 2.2.6. DNA ligation reactions ....................................................... 76 2.2.7. Screening clones and sequencing ..................................... 76 2.2.8. Basic bioinformatics ........................................................... 77 2.3. Protein Biochemistry ....................................................................
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