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系統識別號 U0026-1307201422034900
論文名稱(中文) 載脂蛋白J為C型肝炎病毒顆粒組裝之必要宿主因子
論文名稱(英文) Apolipoprotein J is an essential host factor for hepatitis C virus particle assembly
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 林君杰
研究生(英文) Chun-Chieh Lin
學號 S58961167
學位類別 博士
語文別 英文
論文頁數 110頁
口試委員 指導教授-楊孔嘉
口試委員-張定宗
召集委員-蔡曜聲
口試委員-劉校生
口試委員-余明隆
口試委員-張淑媛
中文關鍵字 C型肝炎病毒  載脂蛋白J  伴護蛋白  內質網  高基氏體  油滴  胞膜接觸位 
英文關鍵字 HCV  apoJ  chaperone  endoplasmic reticulum  Golgi  lipid droplet  membrane contact site 
學科別分類
中文摘要 C型肝炎病毒感染除了導致肝臟疾病外,亦會使脂質與葡萄糖代謝失調。C型肝炎病毒依賴油滴胞器進行病毒顆粒組裝,以及利用極低密度脂蛋白分泌途徑釋出病毒顆粒。然而在病毒顆粒組裝及釋出過程細節仍泰半未明。載脂蛋白J為存在於高基氏體中之伴護蛋白且受到葡萄糖濃度調控,並隨著極低密度脂蛋白分泌途徑而釋出胞外。本研究主要為研究載脂蛋白J對C型肝炎病毒生活史之影響。人類肝細胞在感染C型肝炎病毒之後,發現胞內載脂蛋白J表現量有增加之情形。使用siRNA方式降低感染C型肝炎病毒之Huh7.5肝癌細胞內載脂蛋白J表現,發現胞內與胞外C型肝炎病毒顆粒與RNA量有下降情形,然而胞內病毒RNA有累積現象。藉由免疫沉澱實驗證實載脂蛋白J可與核心蛋白與非結構蛋白5A (NS5A) 進行作用並穩固核心蛋白與NS5A蛋白之間交互作用。C型肝炎病毒感染促使高基氏體與載脂蛋白J同時散佈於細胞質當中並圍繞於油滴周圍,散佈於細胞質之載脂蛋白J與病毒核心蛋白、NS5A蛋白、病毒RNA、油滴、內質網,高基氏體以及內質網-高基氏體胞膜接觸位有共位現象。此外,探討葡萄糖、載脂蛋白J以及C型肝炎病毒顆粒產生之間交互作用時,發現在慢性感染C型肝炎病毒病友之血清中,載脂蛋白J與血糖濃度以及病毒RNA量呈現正比關係;在受到慢性感染C型肝炎病毒以及給與高葡萄糖濃度細胞培養液之Huh7.5細胞中發現載脂蛋白J表現增加。本研究結論為受到葡萄糖刺激之載脂蛋白J在受感染C型肝炎病毒細胞中位於圍繞油滴之內質網-高基氏體胞膜接觸位上,並藉由穩定位於油滴上核心蛋白和NS5A蛋白交互作用而幫助病毒顆粒組裝。
英文摘要 Hepatitis C virus (HCV) infection not only induces hepatic diseases but also leads to disorder of lipid and glucose metabolism. HCV depends on lipid droplets (LDs) for viral particle assembly and very-low density lipoproteins (VLDLs) for virion egression. However, the components and locations for this process remain unidentified. Apolipoprotein J (apoJ) serves as a Golgi-resident molecular chaperone which can be upregulated by glucose, and is secreted to extracellular space along with the route of VLDLs. This study investigated the effects of apoJ on HCV life cycle. HCV infection could elevate intracellular apoJ expression in primary human hepatocytes. Silencing of apoJ expression by siRNA strategy reduced intracellular and extracellular HCV infectivity and extracellular HCV RNA in HCV-infected Huh7.5 hepatoma cells, whereas intracellular HCV RNA was accumulated in HCV-infected cells. ApoJ was shown to interact with HCV core and NS5A proteins by immunoprecipitation and could further stabilize the protein complex of HCV core and NS5A. HCV infection facilitated the dispersion of intracelluar apoJ along with Golgi to encircle LDs, and the dispersed apoJ colocalized with the core, NS5A, HCV RNA, LDs, endoplasmic reticulum (ER), Golgi, and ER-Golgi membrane contact site. Furthermore, the interplay among glucose, apoJ and HCV particle production was investigated. Serum apoJ was positively correlated with fasting blood glucose concentration and HCV RNA titer in chronic hepatitis C patients. Increase of glucose concentration in culture medium of HCV-infected Huh7.5 cells could upregulate apoJ expression. In conclusion, the glucose-stimulated apoJ protein facilitates infectious HCV particle assembly via stabilization of core-NS5A interaction which encircles LDs and locates at the ER-Golgi membrane contact site.
論文目次 摘要........................................................................................................................................I
Abstract................................................................................................................................II
Acknowledgement..............................................................................................................III
Contents..............................................................................................................................IV
Figure contents.................................................................................................................VIII
Abbreviations...................................................................................................................... X
I. Introduction......................................................................................................................1
1. Molecular biology of hepatitis C virus (HCV)..................................................................1
1.1 Background of HCV.........................................................................................................1
1.2 Genome organization of HCV..........................................................................................2
1.3 HCV viral proteins...........................................................................................................2
1.4 Life cycle of HCV.............................................................................................................6
1.5 Therapeutic methods for HCV-infected patients..............................................................7
1.6 HCV experimental systems..............................................................................................8
1.6.1 HCV replicon.................................................................................................................8
1.6.2 HCV pseudoparticle (HCVpp)......................................................................................9
1.6.3 Infectious HCV particle from cell culture (HCVcc)...................................................10
1.6.4 Permissive cell lines for HCV propagation.................................................................10
1.6.5 Animal model for HCV study......................................................................................11
2. Host factors in HCV life cycle.........................................................................................12
2.1 Cellular lipids and lipid metabolism-related genes........................................................12
2.2 Glucose metabolism-related genes.....................13
2.3 Apolipoproteins..............................14
2.4 Molecular chaperones.....................................................................................................15
3. Molecular biology of apolipoprotein J.............................................................................15
3.1 Background of apolipoprotein J.....................................................................................15
3.2 Functions of apoJ............................................................................................................16
4. Aims of this study.............................................................................................................17
II. Materials and methods..................................................................................................18
1. Cell culture.......................................................................................................................18
2. Construction of plasmids for protein expression..............................................................19
3. Transfection of plasmids and siRNAs..............................................................................20
4. Western blot......................................................................................................................21
5. RNA extraction.................................................................................................................22
6. Reverse transcription........................................................................................................23
7. Real-time quantitative PCR (Q-PCR) for detection of HCV RNA..................................23
8. Immunofluorescence assay (IFA).....................................................................................24
9. Linearization and purification of plasmids containing HCV replicon.............................24
10. In vitro transcription.......................................................................................................25
11. Electroporation of HCV replicon RNA into Huh7.5 cells..............................................26
12. Preparation of infectious HCV particles and determination of HCV infectivity............27
13. Immunoprecipitation (IP) ..............................................................................................27
14. MTS assay......................................................................................................................28
15. SEAP assay...................................28
16. Antibody neutralization assay.........................................................................................29
17. Oil Red O staining and quantification of neutral lipids..................................................29
18. Flow cytometric analysis................................................................................................30
19. Subcelular fractionation.................................................................................................30
20. Serum sample collection and detection of serum apoJ concentration by ELISA..........30
III. Results...........................................................................................................................32
1. HCV infection induces apoJ expression in primary human hepatocytes.........................32
2. ApoJ silencing reduces the expression of HCV core and NS5A proteins in HCV-infected cells. .....................................................................................................................................32
3. ApoJ facilitates infectious HCV virion production..........................................................33
4. ApoJ does not affect HCV replication, viral entry or cell survival..................................33
5. ApoJ stabilizes the core-NS5A viral protein complex which is essential for viral assembly...............................................................................................................................34
6. ApoJ interacts with HCV core and NS5A proteins..........................................................35
7. HCV infection locates apoJ-core and apoJ-NS5A complexes to surround LDs at the ER-Golgi membrane contact site.........................................................................................37
8. Elevated glucose increases apoJ expression and HCV virion production in vitro...........38
9. High glucose concentration increases serum apoJ expression and HCV titer from clinical study......................................................................................................................................40
IV. Discussion......................................................................................................................41
1. The role of apoJ in HCV particle production...................................................................41
2. Mechanism of apoJ on affecting HCV particle assembly................................................42
3. HCV infection promotes the rearrangement of organelle membranes in host cells.........43
4. The relationship among glucose concentration, apoJ expression and HCV particle production.............................................................................................................................44
5. Potential for applying inhibitory therapeutic strategy of apoJ on treatment of HCV infection................................................................................................................................45
6. Conclusion and perspective..............................................................................................46
7. Suggestions for future research........................................................................................47
V. References.......................................................................................................................49
VI. Tables.............................................................................................................................67
Table 1. Comparisons of intracellular and extracellular HCV RNA contents associated with apoE, apoJ and cognate control IgGs...................................................................................67 Table 2. Demographic and laboratory data for the two groups of naive chronic hepatitis C patients with and without T2DM..........................................................................................68
VII. Figures.........................................................................................................................69
VIII. Appendix..................................................................................................................106
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