THE FUNCTIONAL ROLE OF BIG3 IN THE REGULATED SECRETORY PATHWAY LI HONGYU INSTITUTE OF MOLECULAR AND CELL BIOLOGY DEPARTMENT OF BIOCHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 THE FUNCTIONAL ROLE OF BIG3 IN THE REGULATED SECRETORY PATHWAY LI HONGYU B.Sc FUDAN UNIVERSITY A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY INSTITUTE OF MOLECULAR AND CELL BIOLOGY DEPARTMENT OF BIOCHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements I would like to express my gratitude to my supervisor, Professor Hong Wan Jin for his supervision, guidance and support to my work; and to my supervisory committee members: Dr Cai Ming Jie and Dr Walter Hunziker, for their invaluable comments and advices on my work I am grateful to Dr Jill Mae Lan Tham for her constant guidance and advices I would like to thank Dr Vadim Atlachkine and Miss Huang Cai Xia for their great contributions on generating the BIG3 knockout mice I would also like to thank Dr Wang Cheng Chun for the help on mouse work, to Ng Chee Peng for the help on electron microscopy work, to Dr Wei Shun Hui for the help on capacitance measurement assay, and to Dr Guo Ke for the help on histological work My appreciation also goes to Dr Tran Thi Ton Hoai and Dr Ong Yan Shan for their criticisms and advices on my work I would like to thank my present and past colleagues for their help and advices, Dr Chan Siew Wee, Dr Loo Li Shen, Dr Liu Ning Sheng, Dr Zhang Xiao Qian, Dr Paramjeet Singh, Dr Wang Tuan Lao, Dr Cai Lei, Dr Lu Lei, Dr Lim Koh Pang, Dr Tai Gui Hua, Miss Tan Yik Loo, Mr Lim Chun Jye and Miss Chong Yaan fun My appreciation also goes to the DNA sequencing unit and histology facility of IMCB, the animal facility of Biological Resource Centre, and the Flow Cytometry Facility of Biopolis Shared Facilities, for their excellent services I specially thank my family for their constant care and support, patience and understanding Hongyu 2010 i Table of Contents Summary List of Tables List of Figures Abbreviations Chapter Introduction 1.1 General Secretory Pathway 1.1.1 ER, the entry station of secretory pathway 1.1.2 Golgi, the sorting station of secretory pathway 1.1.2.1 Golgi structure and function 1.1.2.2 Golgi biogenesis and intra-Golgi transport 1.1.2.3 TGN, the sorting station 1.1.2.4 Post-TGN carrier formation 1.1.3 Exocytosis 1.2 Regulated Secretory Pathway 1.2.1 Identity of secretory granules 1.2.2 Biogenesis Models of secretory granules from the TGN 1.2.3 ISG Maturation 1.2.4 Secretory Cargo Sorting Mechanisms 1.2.5 Prohormone processing enzymes 1.2.6 Balance of production and demand 1.3 Sec7 proteins 1.3.1 Arf proteins: properties and functions 1.3.2 Activating Arf proteins by Sec7-family GEFs ii 1.3.2.1 The Sec7 domain of Arf-GEF 1.3.2.2 BFA inhibition 1.3.2.3 Arf-GEF family 1.3.2.4 BIG3, a putative member of Sec7 protein family Aim of the Study Figures of Chapter Chapter Materials and methods 2.1 Cloning 2.2 Expression and purification of recombinant fusion proteins 2.3 SDS-PAGE 2.4 Coomassie blue staining 2.5 Immunization of rabbits and affinity purification of antibodies 2.6 Antibodies used in the study 2.7 Cell lines used in the study 2.8 Preparation of tissue and cell lysates 2.9 Western blot 2.10 Indirect immunoflurescence microscopy 2.11 Histological analysis and immuno-staining 2.12 Pancreatic islet isolation and primary culture 2.13 K+/Ca++, glucose and cycloheximide treatment 2.14 Construct expression in mammalian cells 2.15 Electron microscopy 2.16 GST-GAT pulldown assay 2.17 Short hairpin RNA-mediated gene silencing iii 2.18 Lenti-viral infection 2.19 Cell sorting 2.20 Quantitative Real-Time PCR 2.21 Pulse-Chase assay using 35S labeling 2.22 Membrane capacitance measurement 2.23 Animal Welfare and housing 2.24 Generation of the BIG3-/- mice 2.25 DNA extraction and genotyping 2.26 Body fat composition measurement 2.27 Glucose, triglyceride, cholesterol, insulin and testosterone measurement 2.28 Glucose and insulin tolerance tests 2.29 Metabolic Cage Studies 2.30 Statistical Analysis Chapter Identification, expression and localization of BIG3 3.1 Identification of BIG3 3.2 Generation of rabbit polyclonal antibody against BIG3 3.3 Selective expression of BIG3 protein 3.3.1 Expression of BIG3 in mouse tissues 3.3.2 Expression of BIG3 in cultured cell lines 3.3.3 BIG3 is presented in the endocrine pancreatic islets 3.4 BIG3 is localized to secretory granules in MIN6 cells 3.4.1 BIG3 is partially localized to the insulin and CGA containing vesicles 3.4.2 BIG3 partially co-localized with gamma-adaptin 3.4.3 Minimal co-localization of BIG3 with Golgi or endosomal resident markers iv 3.4.4 Co-localization of BIG3 and CGA limited to the perinuclear region, and sensitive to cycloheximide inhibition 3.5 Presence of BIG3 on dense core granules revealed by EM 3.6 Null catalytic function of BIG3 Sec7 on ARF activation 3.7 Discussion Figures of Chapter Chapter Functional role of BIG3 in the regulated secretory pathway 4.1 Generation of stable BIG3 knockdown MIN6 cells 4.2 Increased secretory protein storage in BIG3-deficient cells 4.3 Elevated secretion in BIG3-deficient cells 4.3.1 Elevated betagranin secretion upon K+/Ca++ stimulation 4.3.2 Elevated total secretion upon K+/Ca++ stimulation 4.3.3 Increased exocytosis events in BIG3-deficient cells 4.4 Elevated betagranin production in BIG3-deficient cells 4.5 Generating BIG3 Knockout mice 4.6 Increased dense core granule number in BIG3-/- beta cells 4.7 Increased insulin secretion in BIG3-/- islets 4.8 Discussion Figures of Chapter Chapter Metabolic abnormalities in BIG3 knockout mice 5.1 BIG3 knockout mice developed normally 5.2 Histological examination exhibited fatty liver disease in BIG3 knockout mice 5.3 Altered glucose homeostasis and insulin sensitivity in BIG3 knockout mice 5.4 Altered metabolic parameters in BIG3-/- mice on 129/Sv background v 5.5 Reduced testosterone level in BIG3-/- male mice 5.6 Discussions Figures of Chapter Chapter General discussion and future perspectives References vi Summary The beta cell dysfunction in insulin secretion is one of the key factors in the pathophysiology of diabetes (Bell and Polonsky, 2001) However the mechanisms that underline the development of the beta cell dysfunction in humans still remain elusive Arf-GEFs are a family of Sec7 domain proteins that regulate intracellular vesicle trafficking BIG3 is identified as a putative member of the Sec7 protein family and distantly related to BIG/Sec7p subfamily BIG3 mRNA expression profile shows it is selectively expressed with high levels in the brain and islet This study therefore investigates the function of endogenous BIG3 in islet cells BIG3 protein was found highly expressed in beta cells, and predominantly localized to the secretory granules Investigations on BIG3 knockdown and knockout beta cells demonstrated that the deficiency of BIG3 caused increased amount of secretory granules and secretory proteins in the cells, and elevated secretion upon 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The interaction of TGN subdomain and motor is selective It can be a direct binding of a cargo protein with a motor protein dynein (Tai et al., 1999); or mediated via adaptor proteins (Nakagawa... coenzyme A oxidase AP-1 adaptor protein- 1 ARF ADP ribosylation factor Arg arginine ARNO ARF nucleotide binding site opener BAR Bin/amphiphysin/Rvs (domain) BFA Brefeldin A BIG1/2 BFA inhibited