請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49474
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余明俊 | |
dc.contributor.author | Chieh-Wen Lo | en |
dc.contributor.author | 羅傑文 | zh_TW |
dc.date.accessioned | 2021-06-15T11:30:24Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-17 | |
dc.identifier.citation | References
1. Hajarizadeh, B., J. Grebely, and G.J. Dore, Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol, 2013. 10(9): p. 553-562. 2. Dubuisson, J. and F.L. Cosset, Virology and cell biology of the hepatitis C virus life cycle--an update. J Hepatol, 2014. 61(1 Suppl): p. S3-S13. 3. Chen, S.L.M., T. R., The natural history of hepatitis C virus (HCV) infection. International journal of medical sciences, 2006. 3(2): p. 47-52. 4. Simmonds, P., et al., Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology, 2005. 42(4): p. 962-973. 5. Gower, E., et al., Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol, 2014. 61(1 Suppl): p. S45-57. 6. Moradpour, D., F. Penin, and C.M. Rice, Replication of hepatitis C virus. Nat Rev Microbiol, 2007. 5(6): p. 453-463. 7. Paul, D., V. Madan, and R. Bartenschlager, Hepatitis C Virus RNA Replication and Assembly: Living on the Fat of the Land. Cell Host Microbe, 2014. 16(5): p. 569-579. 8. Perni, R.B., et al., Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother, 2006. 50(3): p. 899-909. 9. Clarke, D., et al., Evidence for the formation of a heptameric ion channel complex by the hepatitis C virus p7 protein in vitro. J Biol Chem, 2006. 281(48): p. 37057-37068. 10. Moradpour, D. and F. Penin, Hepatitis C virus proteins: from structure to function. Curr Top Microbiol Immunol, 2013. 369: p. 113-142. 11. Appel, N., et al., From structure to function: new insights into hepatitis C virus RNA replication. J Biol Chem, 2006. 281(15): p. 9833-9836. 12. Huang, Y., et al., Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology, 2007. 364(1): p. 1-9. 13. Ross-Thriepland, D. and M. Harris, Hepatitis C virus NS5A: enigmatic but still promiscuous 10 years on! J Gen Virol, 2015. 96(Pt 4): p. 727-738. 14. Appel, N., et al., Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog, 2008. 4(3): p. e1000035. 15. Masaki, T., et al., Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol, 2008. 82(16): p. 7964-7976. 16. Lohmann V, K.F., Herian U, Bartenschlager R., Biochemical Properties of Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase and Identification of Amino Acid Sequence Motifs Essential for Enzymatic Activity. JOURNAL OF VIROLOGY, 1997. 71(11): p. 8416–8428. 17. Coller, K.E., et al., RNA interference and single particle tracking analysis of hepatitis C virus endocytosis. PLoS Pathog, 2009. 5(12): p. e1000702. 18. Blanchard, E., et al., Hepatitis C virus entry depends on clathrin-mediated endocytosis. J Virol, 2006. 80(14): p. 6964-6972. 19. Yamamoto, H., et al., Molecular architecture of the ribosome-bound Hepatitis C Virus internal ribosomal entry site RNA. EMBO J, 2015. 34(24): p. 3042-3058. 20. Salonen, A., T. Ahola, and L. Kääriäinen, Viral RNA Replication in Association with Cellular Membranes. 2005. 285: p. 139-173. 21. Mackenzie, J., Wrapping things up about virus RNA replication. Traffic, 2005. 6(11): p. 967-977. 22. El-Hage, N. and G. Luo, Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. J Gen Virol, 2003. 84(Pt 10): p. 2761-2769. 23. Kim, J.H., et al., Interaction of stomatin with hepatitis C virus RNA polymerase stabilizes the viral RNA replicase complexes on detergent-resistant membranes. J Microbiol Biotechnol, 2014. 24(12): p. 1744-1754. 24. Miyanari, Y., et al., The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol, 2007. 9(9): p. 1089-1097. 25. Lindenbach, B.D. and C.M. Rice, The ins and outs of hepatitis C virus entry and assembly. Nat Rev Microbiol, 2013. 11(10): p. 688-700. 26. Tellinghuisen, T.L., K.L. Foss, and J. Treadaway, Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog, 2008. 4(3): p. e1000032. 27. Appel, N., T. Pietschmann, and R. Bartenschlager, Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol, 2005. 79(5): p. 3187-3194. 28. Masaki, T., et al., Involvement of Hepatitis C Virus NS5A Hyperphosphorylation Mediated by Casein Kinase I-alpha in Infectious Virus Production. J Virol, 2014. 29. Neddermann, P., et al., Reduction of hepatitis C virus NS5A hyperphosphorylation by selective inhibition of cellular kinases activates viral RNA replication in cell culture. J Virol, 2004. 78(23): p. 13306-13314. 30. Fridell, R.A., et al., Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol, 2013. 87(4): p. 2320-2329. 31. Masaki, T., et al., Involvement of Hepatitis C Virus NS5A Hyperphosphorylation Mediated by Casein Kinase I-α in Infectious Virus Production. Journal of virology, 2014. 88(13): p. 7541-7555. 32. Douglas Ross-Thriepland, M.H., Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation. J Virol, 2014. 88(3): p. 1421-1432. 33. Lemay, K.L., et al., A hepatitis C virus NS5A phosphorylation site that regulates RNA replication. J Virol, 2013. 87(2): p. 1255-1260. 34. Chong, W.M., et al., Phosphoproteomics Identified an NS5A Phosphorylation Site Involved in Hepatitis C Virus Replication. Journal of Biological Chemistry, 2016. 291(8): p. 3918-3931. 35. Eyre, N.S., et al., Phosphorylation of NS5A Serine-235 is essential to hepatitis C virus RNA replication and normal replication compartment formation. Virology, 2016. 491: p. 27-44. 36. Quintavalle, M., et al., The alpha isoform of protein kinase CKI is responsible for hepatitis C virus NS5A hyperphosphorylation. J Virol, 2006. 80(22): p. 11305-11312. 37. Knippschild, U., et al., The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal, 2005. 17(6): p. 675-689. 38. Ross-Thriepland, D. and M. Harris, Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation. Journal of virology, 2014. 88(3): p. 1421-1432. 39. Ross-Thriepland, D., J. Mankouri, and M. Harris, Serine phosphorylation of the hepatitis C virus NS5A protein controls the establishment of replication complexes. J Virol, 2015. 89(6): p. 3123-3135. 40. Aizaki, H., et al., Characterization of the hepatitis C virus RNA replication complex associated with lipid rafts. Virology, 2004. 324(2): p. 450-461. 41. T. Kaneko, Y.T., S. Satoh, M. Hijikata, S. Asabe, K. Kimura, K. Shimotohno, Production of Two Phosphoproteins from the NS5A Region of the Hepatitis C Viral Genome. Biochem Biophys Res Commun, 1994. 205(1): p. 320-326. 42. Gao, L., et al., Interactions between Viral Nonstructural Proteins and Host Protein hVAP-33 Mediate the Formation of Hepatitis C Virus RNA Replication Complex on Lipid Raft. Journal of Virology, 2004. 78(7): p. 3480-3488. 43. Quinkert, D., R. Bartenschlager, and V. Lohmann, Quantitative analysis of the hepatitis C virus replication complex. J Virol, 2005. 79(21): p. 13594-13605. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49474 | - |
dc.description.abstract | C型肝炎病毒 (hepatitis C virus , HCV) 非結性構蛋白質5A (non-structure protein 5A , NS5A) 在病毒生活史中扮演重要的角色。許多研究以將NS5A上絲氨酸 (serine, S) 突變的方式,發現了一些可能參與NS5A的高度磷酸化態且對病毒生活史重要的磷酸化位點。然而,對於NS5A高度磷酸化態是否存在著不同的種類,與高度磷酸化態中不同的磷酸化位點彼此是否有互相依存的關係是尚未被研究過的。利用可以專一辨認磷酸化位點的抗體,我們分析了高度磷酸化的NS5A中S232, S235與S238的磷酸化情形。發現NS5A存在著不同的高度磷酸化態。分別約有6%, 92%與46%的高度磷酸化態NS5A具有S232, S235與S238的磷酸化。其中S232的磷酸化不須依賴S235或S238的磷酸化即能發生,但S238的磷酸化卻依賴S235的磷酸化才能發生。此結果暗示著S232, S235與S238的磷酸化是以S232為起點按順序、由casein kinase 1 這個具有辨認-3位置胺基酸是否磷酸化而決定磷酸化進行與否的激酶所介導完成的。S238的磷酸化可能僅是此一連續磷酸化下的副產物,對病毒生活史進行並無貢獻。而S235的磷酸化是最主要且具功能的磷酸化位點,S235磷酸化發生的時間與地點和病毒複製的情形相符。且在機制上,我們發現了S235磷酸化的NS5A會促進病毒複製體 (replication complex) 聚集於內質網膜狀結構中的脂筏 (lipid raft)上,有利於HCV複製的進行。 | zh_TW |
dc.description.abstract | Phosphorylation of the hepatitis C virus (HCV) non-structure protein 5A (NS5A) plays critical roles in the viral life cycle. Based on genetic mutations followed by functional assays, numerous studies have pinpointed several serine residues that are critical for NS5A hyper-phosphorylation and for the viral life cycle. However, the hyper-phosphorylated NS5A species were not directly measured and whether phosphorylation among these sites is interdependent was unknown. Using three phosphorylation-specific antibodies, we profiled the NS5A species with single, double or triple phosphorylation at S232, S235 and/or S238. S232, S235 and S238 constitute respectively about 6, 92 and 46% of the hyper-phosphorylated NS5A. S232 phosphorylation occurs independently of S235 and S238 phosphorylation whereas S238 phosphorylation occurs only when S235 is phosphorylated. Our data suggest that S232 phosphorylation primes S235 by casein kinase 1 that requires priming phosphorylation at the -3 amino acid. S238 phosphorylation is perhaps a by-stander event dispensable for viral activity. S235 phosphorylation is the major and functional phosphorylation event that occurs at the time and intracellular location corresponding to viral replication. Mechanistically, S235-phosphoryalted NS5A probably facilitates clustering of the replication protein complexes in the ER lipid raft membranes for HCV replication. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:30:24Z (GMT). No. of bitstreams: 1 ntu-105-R03442027-1.pdf: 3573429 bytes, checksum: 112e5b4ebb7a8e3425e4a37bcc927af4 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 摘要 2
Abstract 3 Introduction 4 Results 15 Characterization of NS5A S232, S235 and S238 phosphorylation-specific antibodies 15 Profile of the NS5A hyper-phosphorylation species in the HCV-infected Huh7.5.1 cells 16 S235 and S238 phosphorylated NS5A co-localized with the replication marker dsRNA vs. the assembly marker lipid droplet 20 S235 phosphorylation affects NS5A distribution 21 NS5A S235 phosphorylation affects viral replication complex formation 23 Discussion 25 Figures 30 References 35 | |
dc.language.iso | en | |
dc.title | 絲氨酸235是C型肝炎病毒非結構性蛋白質5A的主要磷酸化位點可增進其與內質網膜的結合與病毒複製體形成 | zh_TW |
dc.title | S235 is a dominant hepatitis C virus NS5A hyper-phosphorylation site that promotes ER association and replication complex formation | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張明富,林敬哲,張淑媛,柯博元 | |
dc.subject.keyword | C型肝炎病毒,結構性蛋白質5A,病毒複製, | zh_TW |
dc.subject.keyword | HCV,NS5A,replication, | en |
dc.relation.page | 37 | |
dc.identifier.doi | 10.6342/NTU201603149 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
顯示於系所單位: | 生物化學暨分子生物學科研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-105-1.pdf 目前未授權公開取用 | 3.49 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。