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Proquest Dissertations MAMMALIAN UBC6 E2 CONJUGATING ENZYMES AND STRESS-RELATED PHOSPHORYLATION OF UBC6E by Ray Sangin Oh A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy, Graduate Department of Molecular Genetics University of Toronto © Copyright by Ray Sangin Oh (2008) Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-40002-9 Our file Notre reference ISBN: 978-0-494-40002-9 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada MAMMALIAN UBC6 E2 CONJUGATING ENZYMES AND STRESS-RELATED PHOSPHORYLATION OF UBC6E Doctor of Philosophy (2008) Ray Sangin Oh Graduate Department of Molecular and Medical Genetics University of Toronto ABSTRACT Endoplasmic reticulum associated degradation (ERAD) of misfolded membrane proteins is critical for maintenance of cellular homeostasis. 'ER stress', caused by overload of misfolded proteins as commonly occurs in many physiological and disease states, activates the Unfolded Protein Response (UPR) which promotes restoration of homeostasis but also triggers apoptosis and other physiological responses. Ubc6 is an ER membrane-associated E2 ubiquitin- conjugating enzyme, implicated in the ERAD of many misfolded proteins in S. cerevisiae. These studies examine two recently identified human homologs, Ubc6 and Ubc6e, and reveal stress-related modification of Ubc6e. These homologues were confirmed to be ER-localized, UPR-regulated, and possess E2 enzyme activity in vitro, which supports their role in mammalian ERAD. Intriguingly, one of these homologs, Ubc6e, is modified by phosphorylation via a PKR-like ER Kinase (PERK) pathway during pharmalogically induced ER stress. This phosphorylation involves residue Ser- 184, and is associated with inhibited E2 activity, in vitro. These findings suggest that Ubc6e activity can be regulated by UPR via phosphorylation and highlight diversity in function between the mammalian homologues. ii Emerging evidence of cross-talk between UPR and other stress pathways, and the role of ERAD in maintaining cellular homeostasis, led to investigations of a broader role of Ubc6e in stress response. It was observed that additional and diverse environmental stresses, including hyperosmotic, genotoxic, and pharmacologic stress as well as heat shock and various mitogens also rapidly induce phosphorylation of Ubc6e. A role for p38 MAPK (Mitogen-Activated Protein Kinase) signaling in Ubc6e modification, with direct involvement of MK2 (MAPK- activated Kinase) was further established. Phosphorylation is triggered via different routes as PERK involvement was limited to ER stress. Cell lines expressing Ubc6e wild-type, phospho- mutant and phospho-mimic variants revealed that phosphorylation is associated with apoptosis, and involves c-Jun kinase and caspase-12 activation during ER stress. These studies elaborate the central role of the ER in mediating stress signaling by establishing MK2 as a novel regulator of Ubc6e in a wide array of cell stimuli. They further suggest that modulation of the function of this E2 enzyme is critical to stress-related responses and cell survival. iii ACKNOWLEDGEMENTS Foremost, I cannot express enough gratitude to my supervisor, Dr. Johanna Rommens, who has been a constant source of support and encouragement over the years. Thank you for your enthusiastic mentorship, patience, and for teaching me to think like a scientist. I extend thanks to my thesis committee members, Drs. Paul Sadowski, John Glover and Gergely Lukacs, for providing guidance and the occasional whip-crack to help me get to this point. Thank you also for offering helpful comments on this thesis and various manuscripts. My numerous labmates have taught me many things and I consider myself fortunate for having worked with such great people. I want to thank them for useful discussions on a 'non- disease'-related research topic, and for making the lab an enjoyable place to work. In particular, I thank Mark van Oene for patiently showing me the ropes when I was green and Xinli Bai for providing great technical help. I would also like to express my gratitude to several grad students and post-docs who have helped me in one way or another, and made this odyssey bearable with their friendship. In particular, I wish to thank - Arvin Dar, Kengo Asai, Daniel Suh, Pam Cheung, Mike Szego, Pleasantine Mill, Janet Atkinson, Darlene Ellenor, Nicole Richards, Siyi Zhang, Lingling Chen, Isabel Aznarez, Adam Smith, John Cleary, Paul Bradshaw, Rachel Szilard. I am especially grateful to Joy Nishikawa for being an excellent thesis writing partner, and for making the last few years more enjoyable and meaningful. Lastly, I would like to thank my friends and family for their encouragement and love. IV TABLE OF CONTENTS ABSTRACT ii ACKNOWLEDGEMENTS iv LIST OF FIGURES viii LIST OF TABLES x LIST OF ABBREVIATIONS xi INTERNET RESOURCES xiv CHAPTER I: UBIQUITIN-MEDIATED PROTEOLYSIS, ENDOPLASMIC RETICULUM-ASSOCIATED DEGRADATION AND STRESS RESPONSE 1.1 Ubiquitin-mediated proteolysis 2 1.1.1 Introduction 2 1.1.2 Ubiquitin-conjugating machinery: E1, E2 and E3 enzymes 3 1.1.2.1 El ubiquitin-activating enzyme 3 1.1.2.2 E2 ubiquitin-conjugating enzyme 6 1.1.2.3 E3 ubiquitin ligase 8 1.1.3 Substrate selection and regulation 9 1.1.4 Poly-ubiquitination, de-ubiquitination and proteasomal degradation 11 1.2 ER-quality control and ER-associated degradation 13 1.2.1 Introduction 13 1.2.2 ER protein folding factory 15 1.2.3 ER-quality control 19 1.2.4 ER-associated degradation 21 1.2.4.1 Degradation of ERAD substrates by cytosolic proteasomes 21 1.2.4.2 Selection of ERAD substrates by chaperones 21 1.2.4.3 Retro-translocation 23 1.2.4.4 Ubiquitination of ERAD substrates 23 1.2.4.5 Membrane extraction and delivery to the proteasome 26 1.2.5 ERAD substrates of medical relevance 27 1.3 ER stress and the Unfolded Protein Response 29 1.3.1 Introduction 29 1.3.2 IRE1, PERK and ATF6-sensors of ER stress 30 1.3.3 Reducing ER folding stress: adaptive UPR pathways 34 1.3.3.1 IRE1 34 1.3.3.2 ATF6 35 1.3.3.3 PERK 35 1.3.4 Coordination and regulation of UPR pathways 37 1.3.5 Other strategies to reduce ER folding stress 38 1.3.6 Integration of UPR with other physiological responses and apoptosis 39 pathways 1.3.6.1 Inflammation and immune responses 40 1.3.6.2 Stress-activated MAPK pathways 42 1.3.6.3 Pro-apoptotic transcription factor CHOP/GADD153 42 1.3.6.4 Caspases 43 1.3.6.5 BCL-2 family proteins 44 1.3.7 Balance between survival and death pathways 45 1.3.8 ER stress and disease 45 1.4 Thesis Outline 47 CHAPTER II: HUMAN HOMOLOGS OF UBC6P UBIQUITIN- CONJUGATING ENZYME AND PHOSPHORYLATION OF HSUBC6E IN RESPONSE TO ER STRESS Summary 50 2.1 Introduction 51 2.2 Experimental procedures 52 2.2.1 Construction of hsUbc6 and hsUbc6e mammalian expression plasmids 52 2.2.2 Cell culture and transfections 54 2.2.3 Protein extract preparation, electrophoresis, immunoblotting 54 2.2.4 Phosphatase assay 55 2.2.5 UPR induction, RNA and protein analysis 55 2.2.6 PERK in vitro kinase assay 56 2.2.7 Metabolic labeling and immunoprecipitation 57 2.2.8 Membrane isolation 58 2.2.9 Immunofluorescence 58 2.2.10 Cloning of Parkin and Pael-R cDNA 59 2.2.11 Co-immunoprecipitation of Parkin and Ubc6e 60 2.2.12 Pulse-chase analysis of Pael-R 60 2.2.13 Recombinant expression and purification of hsUbc6e, hsUbc6esl84D and 61 hsUbc6esl84E 2.2.14 Yeast-two hybrid screening 62 2.2.15 Thiol-ester assay 62 2.3 Results 63 2.3.1 HsUbc6 and hsUbc6e sequence analysis and confirmation of E2 activity 63 by thiol-ester assay 2.3.2 HsUbc6 and hsUbc6e are upregulated with distinct responses during UPR 65 2.3.3 HsUbc6e is phosphorylated in response to ER stress 65 2.3.4 ER stress induced phosphorylation of mmUbc6e requires PERK 70 signaling 2.3.5 HsUbc6e is phosphorylated at Ser-184 73 2.3.6 Phosphorylated hsUbc6e is
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