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研究生：	高樹緯 Kao, Shu-Wei
論文名稱：	丙型肝炎病毒鞘蛋白(HCVcore)狹持異構核糖核蛋白H1(hnRNPH1)調節病毒複製，經由操控微小核糖核酸-16(microRNA-16)進程以及內部核糖體進入位點(IRES)活性。 The hepatitis C virus core protein hijacks cellular hnRNPH1 to modulate viral replication through regulations of microRNA-16 processing and internal ribosomal entry site activity.
指導教授：	王憲威 Wang, Shainn-Wei
學位類別：	碩士 Master
系所名稱：	醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	62
中文關鍵詞：	丙型肝炎病毒、鞘蛋白、異構核糖核蛋白H1 、微小核糖核酸進程、微小核糖核酸-16 、脂肪酸合成酶、內部核糖體進入位活性
外文關鍵詞：	HCV, HCVcore, hnRNPH1, miRNA processing, miR-16, FASN, IRES activity
相關次數：	點閱：124 下載：0
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丙型肝炎病毒（HCV）感染肝細胞和免疫細胞相當地倚靠HCV鞘蛋白（HCVcore）和細胞蛋白間的交互作用，並用此交互作用來建立慢性感染及致病機轉。我們先前的研究指出在HCV複製過程中，HCVcore會吸引異構核糖核蛋白H1（hnRNPH1）並在細胞質中形成有重要功能的顆粒或脂肪滴。從肝細胞瘤Huh7、cHuh7.5和帶有HCV亞基因組複製子（SGR）或全基因組複製子（FGR）的cHuh7.5中分離出hnRNPH1複合物，發現hnRNPH1可能參與微小RNA（miRNA）的調節，以及與病毒RNA一起調控病毒基因組的複製。相對於不帶有HCVcore的SGR細胞，FGR細胞中的hnRNPH1複合體與HCVcore之交互作用能促使聚集更多負責miRNA生合成的蛋白，並造成hnRNPH1複合體中的miRNA數量及種類有所不同。此外，減益hnRNPH1的表現會衰減FGR或SGR的複製水平，暗示著hnRNPH1是促進複製子複製的因子且不需依賴HCVcore。雖然hnRNPH1能單獨增強SGR複製子複製能力，但在SGR細胞中共同過度表達HCVcore及hnRNPH1或單獨過度表達HCVcore會降低SGR複製子水平和其轉譯產物的產量。這強烈指出hnRNPH1可以通過增強病毒基因組複製水平來協助病毒複製，然而hnRNPH1和/或HCVcore可能通過尚未釐清的轉錄後修飾機制來調控HCV的複製。在本篇研究中我們假設hnRNPH1 / HCVcore複合物可以通過調節miRNA生合成或控制蛋白質轉譯來影響HCV複製，並探討miR-16的成熟與活性分析，以及探討hnRNPH1/HCVcore是否能調控CAP和IRES介導的蛋白質轉譯。經由比較FGR和SGR細胞中hnRNPH1複合體上的miRNA，我們發現了44種miRNA能與hnRNPH1/HCVcore複合物有交互作用，並從中挑選miR-16當作候選目標。在報導細胞株中透過雙螢光素酶miRNA標靶測定實驗，我們發現mir-16-1會結合在HCV-1b基因組中核苷酸707-730位置，也會與細胞脂肪酸合成酶（fasn）mRNA的3'UTR結合。有趣的是， HCVcore能加快mir16-1的成熟進程，並在細胞質中保留更多的hnRNPH1。另外，過度表達hnRNPH1會提升CAP和IRES介導的轉譯活性，但此現象會被HCVcore調降。但單獨表達HCVcore對CAP或IRES介導的轉譯活性並不會有影響。我們還意外地發現hnRNPH1參與的一個非典型CAP介導轉譯機制：在沒有IRES的CAP介導報導系統上的能忽略首個報導基因的終止密碼子而轉譯出下一個報導基因。總歸來說，這篇研究表明hnRNPH1是個多項功能調控因子，並與HCVcore影響了miRNA的生合成以及轉譯調控，進而在HCV複製和致病機制中有關鍵的影響。

Hepatitis C virus (HCV) invades hepatocytes and immune cells, and relies heavily the interactions of HCV core protein (HCVcore) with many cellular factors to establish chronic infection and pathogenesis. We have previously shown that HCVcore attracts the heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) to form predominant cytoplasmic granules and/or lipid droplets during HCV replication. Isolation of the hnRNPH1-complexes from hepatoma 7 (Huh7)-derived cell lines, including cHuh7.5 and its derivatives that harbors HCV subgenome (cHuh7.5-SGR) or full-genome replicon (cHuh7.5-FGR), reveals their possible association with microRNA (miRNA) regulation and viral RNA (vRNA) for genome replication in the presence or absence of HCVcore in cis. The hnRNPH1 complex that is associated with HCVcore from FGR cells, in contrast to without in SGR cells, concentrates more components that are essential for microRNA (miRNA) biogenesis and shows differential miRNAs in numbers and contents. In addition, hnRNPH1-knockdown in contrast to overexpression inversely attenuates the level of replicating FGR or SGR, indicating that hnRNPH1 is required to promote replicon replication independent of HCVcore expression in cis or not. However, in SGR cells, expression of HCVcore in trans with or without ectopic hnRNPH1 demotes both the levels of SGR genome and translational products, albeit that hnRNPH1 alone can promote the level of SGR genome. This highly suggested that hnRNPH1 can assist viral replication through enhancing viral genome level, yet the levels of hnRNPH1 and/or HCVcore may have critical modulatory effect to HCV replication through unclarified posttranscriptional controls. To demonstrate that the hypothetic hnRNPH1/HCVcore complex can modulate HCV replication through miRNA regulation and/or translational control, this study validates an associating miR-16 precursor for its maturation and functional activities as well as the roles of hnRNPH1/HCVcore in CAP- and IRES-mediated translational control through reporter assays. We report that 44 miRNA candidates could be statistically validated to associate with the hnRNPH1/HCVcore complex by a pair-wise comparison of miRNAs that were identified from the hnRNPH1 complex of FGR and SGR cells through an inferential test (one-way ANOVA). A mir-16-1 from 44 hnRNPH1/HCVcore-associated miRNA candidates was found to targets HCV-1b genome at nt position 707-730 and cellular fatty acid synthase (fasn) mRNA at 3’UTR as determined in a transient reporter cell line by a dual-luciferase miRNA targeting assay. Interestingly, HCVcore was found to promote mir-16-1 processing from primary to mature form and retained more hnRNPH1 in the cytoplasmic fraction that may be crucial for miRNA processing. In addition, ectopic hnRNPH1 promoted CAP- and IRES-dependent translation and could be down-modulated by HCVcore as determined in another pool of transient reporter cell for dual-luciferase assay. However, HCVcore alone did not show substantial effect to CAP- or IRES- mediated translational activities in comparison to mock vector control. We also unexpectedly identify an hnRNPH1-mediated non-canonical CAP-translation machinery to bypass the first report’s stop codon for translation of next reporter gene without IRES. Collectively, this study supports that hnRNPH1 is a multifunctional modulator with HCVcore to modulate at least miRNA biogenesis and translational control, which in turns may have critical effect to HCV replication and pathogenesis.

Index
中文摘要	I
Abstract	II
Acknowledgements	IV
Index	V
Figure Index	IX
Abbreviations	XII
Introduction	- 1 -
HCV pathogenesis and epidemiology	- 1 -
Current therapeutics and concerns	- 1 -
HCV replication and replicon-containing cell culture system	- 1 -
HCV replication complex in lipid droplet and ER-associated membrane web	- 2 -
Novel interaction and putative role of HCVcore and hnRNPH1	- 2 -
Functional role of hnRNPH1 in mRNA transport and metabolism	- 3 -
MicroRNA biogenesis and nomenclature	- 3 -
HCVcore and hnRNPH1 has a role in miRNA processing	- 4 -
Inference and questions to be answered in this study	- 5 -

Materials and Methods	- 6 -
Reagents	- 6 -
HCV replicon cell lines	- 6 -
Cell culture	- 7 -
DNA plasmids, microRNAs, and transfection	- 7 -
Pathway enrichment analysis of the hypothetic hnRNPH1/HCVc complex-associated miRNAs by via DIANA-mirPath analysis	- 8 -
Dual-Luciferase microRNA targeting reporter plasmids construction and cell line establishment	- 8 -
The dual-luciferase HCV IRES reporter (pRF-HCV IRES377) plasmid construction and reporter cell line establishment	- 9 -
Dual-Luciferase Assay (DLA) kit	- 10 -
Quantitative Real-Time reverse transcription Polymerase Chain Reaction system (qRT-PCR)	- 10 -
Sodium Dodecyl Sulfate (SDS) Polyacrylamide Gel Electrophoresis (PAGE) and Western Blot analysis	- 12 -
Statistical analysis	- 12 -

Results	- 13 -
Subsets of 1049, 1182, and 1150 miRNAs are respectively associated with hnRNPH1 complexes deriving from cHuh7.5 cells, cHuh7.5/SGR, and cHuh7.5/FGR cells	- 13 -
89 miRNAs are significantly modulated by the hnRNPH1 complex of each cell line, and 44 of them are likely associated with the hnRNPH1/HCVcore complex	- 14 -
Nineteen of the hnRNPH1/HCVcore complex-associated 44 miRNAs may target HCV-1b con1 genome, as predicted by Virus’ miRNA Target (ViTa) database	- 15 -
DIANA-mirPath v2.0 analysis of the hnRNPH1/HCVcore complex-associated 44 miRNAs suggests their criticalness in fatty acid biosynthesis	- 15 -
Ectopic HCVcore promotes mir-16-1 processing from primary to mature form as determined by reverse-transcription real-time PCR	- 16 -
HCVcore has potential to retain more hnRNPH1 in the cytoplasmic fraction for miRNA processing	- 17 -
MiRNA-16-5p targets HCV genome at position 707-730 and fasn mRNA at 3’UTR as determined by a dual-luciferase miRNA targeting assay	
	- 18 -
Ectopic hnRNPH1 promotes CAP- and IRES-dependent translation and may be modulated by HCVcore as determined by a dual-luciferase reporter assay	- 20 -

Discussion	- 22 -
References	- 29 -
Supporting Information	- 38 -
Table	- 38 -
Figure	- 43 -
Supplementary Figure	- 57 -
Supplementary Table	- 60 -
Curriculum Vitae	- 63 -

Figure Index
Table	- 38 -
Table 1. Next Generation Sequencing (NGS) identification and comparative miRNA species analysis of the hnRNPH1 complexes deriving from cHuh7.5, cHuh7.5/SGR, and cHuh7.5/FGR cells	- 38 -
Table 2. Classification of identified miRNAs that are statistically validated to be significantly or non-significantly modulated by the hnRNPH1-containing miRNA processor from cHuh7.5/FGR cells in relevant to that from cHuh7.5/SGR and cHuh7.5 cells.	- 39 -
Table 3. The list of 19 miRNA candidates that could be processed by the hypothetic HCVcore/hnRNPH1 complex and predicted to target HCV viral genome	- 40 -
Table 4. Pathway enrichment analysis of 44 miRNA candidates that may be modulated by the hypothetic hnRNPH1/HCVc complex by DIANA-mirPath v2.0	- 41 -
Table 5. The miR-16-5p candidate, deriving from the miR-15 family that are processed from the precursor mir-16-1, may target HCV genome and cellular mRNAs in fatty acid biogenesis as predicted by several miRNA databases.	- 42 -
Figure	- 43 -
Figure 1. Cross comparison of the Vita-predicted HCV-targeting miRNAs and the 89 validated miRNAs that differentially present in the hnRNPH1-containing miRNA processor among cHuh7.5, cHuh7.5/FGR, and cHuh7.5/SGR cells.	- 43 -

Figure 2. Hypothesis of the HCVcore/hnRNAPH1 complex in modulating microRNA processing and HCV multiplication.	- 44 -
Figure 3. Ectopic HCVcore191 expression reduces the level of primary mir-16-1 but enhances that of miR-16-5p in cHuh7.5 cells.	- 45 -
Figure 4. The presence of HCVcore during HCV replication or ectopic expression is critical to concentrate hnRNPH1 to the cytoplasm.	- 46 -
Figure 5. The dual-luciferase reporter vector (pmirGLO) used for miRNA targeting assay.	- 47 -
Figure 6. The miR-16-5p targets the core sequence of the HCV-con1 genome at position 707-730	- 48 -
Figure 7. A miR-16-5p-mimic affect the activity of a reporter with a predicted miR-16-5p targeting site from HCV con1 genome at position 707-730.	- 49 -
Figure 8. A hsa-miR-16-5p inhibitor did not affect the activity of a reporter with a predicted miR-16-5p targeting site from HCV con1 genome at position 707-730	- 50 -
Figure 9. Ectopic HCVcore reprograms fasn but not oxsm expression	
	- 51 -
Figure 10. The fasn mRNA contains three functional miR-16-5p targeting sites	- 52 -
Figure 11. Construction of a dual-luciferase reporter vector (pRF) for monitoring HCV IRES activity	- 53 -

Figure 12. Effects of ectopic HCVcore/hnRNPH1 on CAP and HCV IRES regulation by dual-luciferase reporter assay.	- 54 -
Figure 13. A non-canonical translation control of hnRNPH1 may occur from Cap-dependent reporters	- 55 -
Supplementary Figure	- 56 -
Supplementary Figure 1. Workflow and algorithms of SOLiDTM sequencing of small RNAs that are associated with hnRNPH1 complexes from cHuh7.5, cHuh7.5/SGR, and cHuh7.5/FGR cells.	- 57 -
Supplementary Figure 2. The miRNAs (miR-15, -16, -195, -424, -497) in the family of miR-15 contain the same seed region, which may have similar functional compensation to each other.	- 58 -
Supplementary Table	- 59 -
Supplementary Table 1A. The list of eighty-nine miRNAs that are statistically validated to be significantly (≥ 1.5-fold) modulated by the hnRNPH1-containing microRNA processor from cHuh7.5/FGR cells in relevant to that from cHuh7.5/SGR and cHuh7.5 cells	- 59 -
Supplementary Table 1B. The list of eighty-nine miRNAs that are statistically validated to be non-significantly (< 1.5-fold) modulated by the hnRNPH1-containing microRNA processor from cHuh7.5/FGR cells in relevant to that from cHuh7.5/SGR and cHuh7.5 cells	- 60 -
Supplementary Table 2. The significant involvement of mirPath v2.0-predicted four miRNAs and their target genes in fatty acid biosynthesis	
	- 61 -
                                    

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