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研究生:陳柏樟
研究生(外文):Po-Chang Chen
論文名稱:探討N-鏈結醣化在C型肝炎病毒外套膜蛋白與受體結合作用之角色
論文名稱(外文):Role of N-Linked Glycans in the interactions of the HCV envelope glycoproteins with cellular receptors
指導教授:翁啟惠翁啟惠引用關係
口試委員:林俊宏柯博元鄭婷仁陶秘華馬徹
口試日期:2013-07-19
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:141
中文關鍵詞:外套膜蛋白凝集素受體表面薄膜共振生物感應器醣化形式高甘露糖型Man5形式Man8/9形式
外文關鍵詞:envelope proteinslectin receptorsSPRglycoformsMan5 N-glycansMan8/9 N-glycans
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一直以來,感染C型肝炎病毒是造成慢性肝炎和肝癌的主要兇手。過去研究顯示,它可以藉由和許多細胞表面受體的結合作用來感染人類的肝臟細胞,其中包括了CD81,SR-BI,claudin-1和occludin。也有不少報告指出,凝集素受體可以辨識C型肝炎病毒並間接地幫助它進入細胞中,而它的外套膜蛋白E1和E2是具有高度醣化的醣蛋白,這個特點更加指明了凝集素受體和病毒之間的結合作用在C型肝炎病毒感染細胞時的重要性。然而,其外套膜蛋白上醣化作用的多樣性是否可改變與這些細胞表面受體和凝集素受體的親和力,這方面的研究卻是極為有限。在目前的研究中,我們利用表面薄膜共振生物感應器來分析帶有不同醣化形式外套膜蛋白與各個受體的親和力,並試著生產帶有不同醣化形式的偽病毒(pseudovirus)來檢測它對病毒的組裝和感染力的影響。我們的研究結果顯示,在鈣離子存在的環境中,凝集素類的受體(DC-SIGN, L-SIGN和Langerin)相較於非凝集素類受體,與病毒的外套膜蛋白具有相當高的親和力,差距最大可達至萬倍。而其中高甘露糖型(high-mannose type)的外套膜蛋白,甘露糖的組成越高親和力就越好,Man8/9形式的外套膜蛋白與凝集素類受體的親和力可以高過Man5型和complex type約十倍。令人感興趣的是,帶有Man5形式的外套膜蛋白和非凝集素類的受體其親和力在這三種醣化形式中是最好的。而在進一步的實驗中,我們發現不同醣化形式的偽病毒,組裝病毒的能力和感染力的確都有受到影響。帶有Man5形式外套膜蛋白的偽病毒其感染Huh7細胞株的能力是最強的,而帶有Man8/9形式外套膜蛋白的偽病毒其在細胞中的蛋白質表現量和組裝蛋白質至病毒體上的量都是最高的。總結我們的研究結果,可以發現C型肝炎病毒外套膜蛋白上的醣類組成能影響病毒的組裝能力,也能藉由和各種細胞上能辨識此蛋白質的受體來調節其感染力。這些具有與病毒外套膜蛋白高度親和力的受體,也許可以為C型肝炎病毒的治療策略提供一個新的方向。

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. It infects human liver cells through interacting with several cellular protein receptors including CD81, SR-BI, Claudin-1 and occludin. There are accumulating reports indicating that lectin receptors can mediate HCV recognition and entry in the body. The envelope proteins of HCV (E1 and E2) are heavily glycosylated, further address the role of lectin receptor-viral particle interaction in HCV infection. However, there is limited report investigating the relation of glycoforms of HCV envelope proteins with the affinity toward lectin and non-lectin receptors. Here we used surface plasmon resonance (SPR) to examine the binding affinity of different glycoforms of HCV envelope protein to receptors, and inspected the infectivity and assembly of HCV pseudoparticles composed with different glycoforms of envelope proteins. Our results indicated that DC-SIGN, L-SIGN and Langerin had higher affinity to bind HCV envelope proteins in the presence of calcium ions than non-lectin receptors (SR-BI, CD81, claudin-1, and occludin), and envelope proteins with Man8/9 N-glycans showed approximate 10-folds better in binding to lectin receptors than envelopes proteins with Man5 and complex type N-glycans. Interestingly, comparing among glycoforms, envelope proteins with Man5 N-glycans showed the highest binding affinity when interacting with non-lectin receptors. It was also revealed that HCV pseudoparticles with Man5 N-glycans, among the glycoforms we tested, carried the best infectivity toward hepatoma cell lines. In summary, glycans on HCV envelope protein play a modulatory role in HCV assembly and infection, and direct HCV-receptor interaction, which mediates viral entry in different cells. Receptors with high affinity in binding to HCV envelope proteins may help establish therapeutic strategy toward HCV.

摘要 ii
Abstract iii
Table of Contents v
Table of Contents/Figures ix
Table of Contents/Tables xi
1. INTRODUCTIONS 1
1.1 An overview of Hepatitis C virus (HCV) 2
1.1.1 Discovery of HCV 2
1.1.2 HCV Transmission and Epidemiology 2
1.1.3 HCV Pathogenesis 3
1.1.4 Current Treatment 4
1.2 HCV Structure, Genome Organization and Protein Function 5
1.2.1 HCV particle 5
1.2.2 Genome Organization 6
1.2.3 Structural proteins of HCV 7
1.2.4 Non-structural proteins of HCV 8
1.3 HCV Lifecycle 10
1.4 Cellular entry factors for HCV 11
1.4.1 Attachment factors 11
1.4.2 Receptors 14
1.5 General Principles of Glycosylation 17
1.5.1. N-glycan biosynthesis 18
1.5.2. Glycoenzymes involved in N-glycan biosynthesis 19
1.6 Glycosylation on HCV 20
1.7 Significance and Purpose 22
2. MATERIALS AND METHODS 29
2.1 Materials 30
2.2 Methods 34
2.2.1 Cell culture 34
2.2.2 Plasmid construction 34
2.2.3 Cell transfection 37
2.2.4 Purification of FLAG-tagged full-length E2 proteins, Fc-tagged lectins, Fc-tagged HCV protein receptors, and His-tagged soluble E1E2 proteins 38
2.2.5 Western blotting 40
2.2.6 Enzyme-linked immunosorbent assay (ELISA) 41
2.2.7 In Solution Tryptic-Chymotryptic Digestion, N-Glycosite Determination and Assigning Glycopeptides 42
2.2.8 Surface plasmon resonance (SPR) analysis 43
2.2.9 Pseudovirus generation and infection assays 45
2.2.10 Glycosidase treatment 47
2.2.11 Lectins blocking assay for HCVpp infection 48
3. RESULTS 49
3.1 Interaction between HCV E2 protein and Fc-Innate Immune receptors 50
3.2 Characterization of the N-linked glycosylation of full-length hepatitis C virus E2 envelope glycoprotein 51
3.3 Characterization of N-linked glycosylation of truncated hepatitis C virus E1 and E2 envelope glycoprotein 52
3.4 Binding affinities of different HCV E1/E2 glycoforms toward receptors 54
3.5 Langerin and L-SIGN in blocking HCVpp infection 58
3.6 Assembly and infectivity of different glycoforms of HCVpp 59
3.7 Glycoforms of E2 proteins from HCVpp 61
4. DISCUSSION 63
4.1 Protein structure, glycosylation and cellular localization 64
4.2 Glycoforms of HCV envelope proteins 66
4.3 Receptors for HCV 69
4.3.1 Lectin-like receptors for HCV 69
4.3.2 Non-lectin receptors for HCV 73
4.3.3 Roles of lectin-like receptors for HCV binding, infection, and propagation 74
4.4 Glycoforms of envelope proteins influence HCVpp assembly and infectivity 76
4.5 Targeting HCV envelope protein 77
4.6 Prospects 77
5. FIGURES 79
6. TABLES 109
7. REFERENCES 113


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