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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 施嘉和(Chia-Ho Shih) | |
| dc.contributor.author | Shu-Fan Chou | en |
| dc.contributor.author | 周書帆 | zh_TW |
| dc.date.accessioned | 2021-06-08T02:14:58Z | - |
| dc.date.copyright | 2016-02-26 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-12-02 | |
| dc.identifier.citation | 1. Ganem D, Prince AM (2004) Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med 350: 1118-1129.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19714 | - |
| dc.description.abstract | Endosomal sorting complexes required for transport (ESCRT) 路徑負責細胞內受泛素化修飾 (ubiquitinated) 之蛋白的辨識及運送。已知多種病毒皆利用ESCRT路徑以有效釋放病毒顆粒。為了進一步探討ESCRT路徑對於B型肝炎病毒生活史的影響，我們利用小片段核醣核酸siRNA抑制ESCRT 因子表現，並偵測B型肝炎病毒DNA複製與病毒顆粒生成能力的變化。此篩選找出許多可影響B型肝炎病毒複製的ESCRT分子，其中我們也特別針對ESCRT-0中的蛋白HGS (HRS, hepatocyte growth factor-regulated tyrosine kinase substrate) 進行深入探討。表現量異常的HGS可抑制B型肝炎病毒的轉錄與DNA複製能力，進而影響病毒體的生成；此外，利用高壓流體力學 (hydrodynamic) 注射方式將HGS表現質體送入老鼠體內，亦能顯著抑制肝細胞與血清中的B型肝炎病毒表現量。有趣的是，大量表現的HGS可同時促進B型肝炎核心蛋白顆粒 (naked capsids) 的釋放，無論是空心蛋白顆粒或是包裹未成熟HBV基因體 ss-DNA、RNA之核心蛋白顆粒。利用HBV突變株進行實驗，亦發現核心蛋白上富含精氨酸之C端區域，對於空心病毒體 (empty virion)的生成十分重要。不管HGS是否大量表現，C端缺失之B肝病毒核心蛋白 (HBc 1-147) 皆僅可形成空心蛋白顆粒，而無法被表面抗原(HBsAg)包裹成可釋放的病毒體。由實驗結果推測，HGS大量促進細胞中尚未成熟的核心蛋白顆粒釋放，阻斷它們在細胞中進行DNA複製、進而形成成熟基因體的機會，因此阻礙完整病毒體的生成。同時，HGS和核心蛋白之結合與其泛素化修飾無關，兩者亦傾向共處於細胞膜周圍而非零星聚集於核內體。以上研究顯示適當表現量的HGS對於B型肝炎病毒而言十分重要；除了影響病毒轉錄能力外， HGS亦可藉由促進核心蛋白顆粒釋放以干擾完整病毒體的生成。根據HGS之多功能角色，B型肝炎病毒體與核心蛋白顆粒顯然使用不同的釋放途徑。 | zh_TW |
| dc.description.abstract | The endosomal sorting complexes required for transport (ESCRT) is an important cellular machinery for the sorting and trafficking of ubiquitinated cargos. It is also known that a number of viruses may utilize the ESCRT modules for egress. To investigate the relationship between ESCRT and hepatitis B virus (HBV), we conducted an siRNA screening of ESCRT components for their potential effect on HBV replication and virion release. We identified a number of ESCRT factors required for HBV replication, and focused our study here on HGS (HRS, hepatocyte growth factor-regulated tyrosine kinase substrate) in the ESCRT-0 complex. Aberrant levels of HGS suppressed HBV transcription, replication and virion secretion. Hydrodynamic delivery of HGS in a mouse model significantly suppressed viral replication in the liver and virion secretion in the serum. Surprisingly, overexpression of HGS stimulated the release of HBV naked capsids, irrespective of their viral RNA, DNA, or empty contents. Mutant core protein (HBc 1-147) containing no arginine-rich domain (ARD) failed to secrete empty virions with or without HGS. In contrast, empty naked capsids of HBc 1-147 could still be promoted for secretion by HGS. HGS exerted a strong positive effect on the secretion of naked capsids, at the expense of a reduced level of virions. The association between HGS and HBc appears to be ubiquitin-independent. Furthermore, HBc is preferentially co-localized with HGS near the cell periphery, instead of near the punctate endosomes in the cytoplasm. In summary, our work demonstrated the importance of an optimum level of HGS in HBV propagation. In addition to an effect on HBV transcription, HGS can diminish the pool size of intracellular nucleocapsids with ongoing genome maturation, probably in part by promoting the secretion of naked capsids. The secretion routes of HBV virions and naked capsids can be clearly distinguished based on the pleiotropic effect of HGS involved in the ESCRT-0 complex. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T02:14:58Z (GMT). No. of bitstreams: 1 ntu-104-D97445001-1.pdf: 3039203 bytes, checksum: 7dfbae5a70209637c23f13249614beeb (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 中文摘要 1
Abstract 2 Keywords 3 Abbreviations 4 Table of Contents 6 Chapter I － Introduction 10 1.1 Life cycle of Hepatitis B virus 10 1.2 Endosomal Sorting Complexes Required for Transport (ESCRT) 13 1.3 ESCRT and virus egress 14 1.4 Morphogenesis of HBV viral and subviral particles 16 1.5 ESCRT and HBV 18 1.6 Aim of the study 20 Chapter II － Materials and Methods 21 2.1 Ethics Statement 21 2.2 Cell lines and reagents 21 2.3 Plasmids 22 2.4 RNA extraction and Real-time qPCR 23 2.5 Southern and Northern blot anlysis 23 2.6 Antibodies 24 2.7 HBV particle preparation and native agarose gel analysis 24 2.8 Reporter assay 25 2.9 Hydrodynamic-based animal model study 26 2.10 Immunohistochemistry (IHC) staining 26 2.11 Co-immunoprecipitation (co-IP) assay 27 2.12 Immunofluorescence assay (IFA) 27 Chapter III － Results 28 3.1 Screening and identification of ESCRT factors required for HBV replication 28 3.2 ESCRT-0 complex is required for HBV replication 29 3.3 Aberrant stoichiometry of HGS suppressed HBV transcription and replication 32 3.4 Hydrodynamic delivery of HGS significantly suppressed HBV replication in vivo .... .............................................................................................................................33 3.5 Overexpressed ESCRT-0 protein HGS stimulated the release of HBV naked capsid particles 34 3.6 HGS promoted the secretion of naked capsids irrespective of their genome content or maturation status 37 3.7 The association between HGS and HBV core protein is ubiquitin –independent 39 3.8 Cytoplasmic HBc co-localized with HGS predominantly near the cell periphery, but not the enlarged endosomes with a punctate structure 42 Chapter IV － Discussions 44 4.1 ESCRT cascades in HBV transcription and replication 44 4.2 Roles of the ESCRT complexes on the secretion of naked capsids 46 4.3 An ubiquitin-independent recognition between HGS and HBc 47 4.4 HGS-mediated secretion route of naked capsids 48 4.5 Distinct secretion routes of HBV virions and naked capsids 49 4.6 HGS and HIV-1 51 Chapter V － References 53 Chapter VI － Figures and Tables 63 Fig. 1 siRNA-knockdown screening for ESCRT factors required for HBV replication in HepG2 cells 64 Fig. 2 Cell viability and the siRNA knockdown efficacies of various ESCRT siRNAs in HepG2 cells were determined by MTT assay and real-time PCR 66 Fig. 3 Depletion of ESCRT-0 factors HGS and STAM2 suppressed the level of intracellular HBV replication as well as the amounts of extracellular virions 67 Fig. 4 Knockdown of HGS destabilized ESCRT-0 complex and inhibited core protein expression 68 Fig. 5 Knockdown of ESCRT-0 factors inhibited HBV enhancer II and core promoter activity 69 Fig. 6 No effects of si-HGS on the reporter activity driven by a TK promoter and viral replication driven by a CMV promoter 70 Fig. 7 Overexpressed HGS suppressed HBV transcription, protein expression and DNA replication 71 Fig. 8 Overexpressed HGS inhibited HBV enhancer II and core promoter activity in a dose-dependent manner 72 Fig. 9 Overexpression of HGS significantly suppressed viral transcription and replication driven by the HBV native promoter 73 Fig. 10 Overexpressed HGS suppressed HBV protein expression in vivo 74 Fig. 11 Highly efficient co-expression of HBc and Flag-HGS proteins was detected by IHC in hepatocytes of serially sectioned liver in hydrodynamically injected mice 75 Fig. 12 Overexpressed HGS suppressed the amounts of secreted HBsAg and HBeAg in vivo 76 Fig. 13 Overexpressed HGS suppressed HBV replication in vivo 77 Fig. 14 Overexpressed HGS stimulated the release of HBV naked capsid particles 78 Fig. 15 Neither apoptosis nor cytotoxicity was detected in HGS-overexpressing cells 79 Fig. 16 The promotion effect on naked capsid secretion is HGS-dependent rather than ESCRT-0 dependent 80 Fig. 17 ALIX facilitates the process of HGS-mediated secretion of naked capsids 82 Fig. 18 HGS stimulated the secretion of empty naked capsids 83 Fig. 19 HGS stimulated the secretion of DNA-containing naked capsids 84 Fig. 20 HGS stimulated the secretion of RNA-containing naked capsids 85 Fig. 21 HGS stimulated the secretion of empty naked capsids irrespective of the ARD domain of HBc 86 Fig. 22 Quantitative comparisons of the effect of overexpressed HGS on various viral and subviral particles in HGS-transfected HuH-7 cells 87 Fig. 23 UIM domain-truncated HGS (HGS dUIM) exhibited a reduced potency in suppressing HBV transcription and viral replication 88 Fig. 24 HGS associated with HBV core protein through an ubiquitin-independent recognition 89 Fig. 25 HGS recognized the assembly domain of HBV core protein in an ubiquitin-independent recognition 91 Fig. 26 The localization patterns of endogenous and exogenous HGS were examined in HepG2 cells 92 Fig. 27 Exogenous HGS protein exhibited two distinct localization patterns both in vitro and in vivo 93 Fig. 28 HBc co-localized with HGS mostly near the cell periphery, but not within the punctate structure of HGS 94 Table. 1 A list of tested ESCRT factors that affected HBV replication in HepG2 cells 95 | |
| dc.language.iso | en | |
| dc.title | 探討具雙重功能之ESCRT-0因子HGS影響B型肝炎病毒轉錄與核心蛋白顆粒釋放之能力 | zh_TW |
| dc.title | The dual role of an ESCRT-0 component HGS in HBV transcription and naked capsid secretion | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王萬波(Won-Bo Wang),張雯(Wen Chang),廖楓(Fang Liao),張典顯(Tien-Hsien Chang) | |
| dc.subject.keyword | B型肝炎病毒,ESCRT,HGS,病毒複製,病毒體釋放,核心蛋白顆粒,空心病毒體, | zh_TW |
| dc.subject.keyword | Hepatitis B virus (HBV),endosomal sorting complexes required for transport (ESCRT),hepatocyte growth factor-regulated tyrosine kinase substrate (HGS),viral replication,virion secretion,naked capsids,empty virions, | en |
| dc.relation.page | 95 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2015-12-03 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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