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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 張明富 | |
dc.contributor.author | Cheng Huang | en |
dc.contributor.author | 黃琤 | zh_TW |
dc.date.accessioned | 2021-06-13T02:03:12Z | - |
dc.date.available | 2009-07-20 | |
dc.date.copyright | 2007-07-20 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-06 | |
dc.identifier.citation | Bergmann, K.F. and Gerin, J.L. (1986) Antigens of hepatitis delta virus in the liver and serum of humans and animals. J Infect Dis, 154, 702-706.
Bichko, V.V., Lemon, S.M., Wang, J.G., Hwang, S., Lai, M.M. and Taylor, J.M. (1996) Epitopes exposed on hepatitis delta virus ribonucleoproteins. J Virol, 70, 5807-5811. Bonino, F., Heermann, K.H., Rizzetto, M. and Gerlich, W.H. (1986) Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J Virol, 58, 945-950. Branch, A.D. and Robertson, H.D. (1984) A replication cycle for viroids and other small infectious RNA's. Science, 223, 450-455. Branch, A.D. and Robertson, H.D. (1991) Efficient trans cleavage and a common structural motif for the ribozymes of the human hepatitis delta agent. Proc Natl Acad Sci U S A, 88, 10163-10167. Bruss, V. (1997) A short linear sequence in the pre-S domain of the large hepatitis B virus envelope protein required for virion formation. J Virol, 71, 9350-9357. Bruss, V. and Ganem, D. (1991) The role of envelope proteins in hepatitis B virus assembly. Proc Natl Acad Sci U S A, 88, 1059-1063. Casey, J.L. and Gerin, J.L. (1995) Hepatitis D virus RNA editing: specific modification of adenosine in the antigenomic RNA. J Virol, 69, 7593-7600. Chang, F.L., Chen, P.J., Tu, S.J., Wang, C.J. and Chen, D.S. (1991) The large form of hepatitis delta antigen is crucial for assembly of hepatitis delta virus. Proc Natl Acad Sci U S A, 88, 8490-8494. Chang, M.F., Baker, S.C., Soe, L.H., Kamahora, T., Keck, J.G., Makino, S., Govindarajan, S. and Lai, M.M. (1988) Human hepatitis delta antigen is a nuclear phosphoprotein with RNA-binding activity. J Virol, 62, 2403-2410. Chang, M.F., Chang, S.C., Chang, C.I., Wu, K. and Kang, H.Y. (1992) Nuclear localization signals, but not putative leucine zipper motifs, are essential for nuclear transport of hepatitis delta antigen. J Virol, 66, 6019-6027. Chang, M.F., Chen, C.H., Lin, S.L., Chen, C.J. and Chang, S.C. (1995) Functional domains of delta antigens and viral RNA required for RNA packaging of hepatitis delta virus. J Virol, 69, 2508-2514. Chang, M.F., Chen, C.J. and Chang, S.C. (1994) Mutational analysis of delta antigen: effect on assembly and replication of hepatitis delta virus. J Virol, 68, 646-653. Chang, M.F., Sun, C.Y., Chen, C.J. and Chang, S.C. (1993) Functional motifs of delta antigen essential for RNA binding and replication of hepatitis delta virus. J Virol, 67, 2529-2536. Chao, H.C. (2002) Characterization of replication initiation complexes of hepatitis delta virus. Master thesis, National Taiwan University, Taipei, Taiwan Chao, M., Hsieh, S.Y., Luo, G.X. and Taylor, J. (1991) The antigen of human hepatitis delta virus: the significance of the two major electrophoretic forms. Prog Clinic & Biol Res, 364, 275-281. Chao, M., Hsieh, S.Y. and Taylor, J. (1990) Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J Virol, 64, 5066-5069. Chen, C.W., Tsay, Y.G., Wu, H.L., Lee, C.H., Chen, D.S. and Chen, P.J. (2002) The double-stranded RNA-activated kinase, PKR, can phosphorylate hepatitis D virus small delta antigen at functional serine and threonine residues. J Biol Chem, 277, 33058-33067. Chen, D.S. and Sung, J.L. (1978) Hepatitis B virus infection and chronic liver disease in Taiwan. Acta Hepato-Gastroenterol, 25, 423-430. Chen, P.J., Kalpana, G., Goldberg, J., Mason, W., Werner, B., Gerin, J. and Taylor, J. (1986) Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci U S A, 83, 8774-8778. de Bruin, W., Leenders, W., Kos, T. and Yap, S.H. (1994) In vitro binding properties of the hepatitis delta antigens to the hepatitis B virus envelope proteins: potential significance for the formation of delta particles. Vir Res, 31, 27-37. Diener, T.O. (1991) Subviral pathogens of plants: viroids and viroidlike satellite RNAs. FASEB, 5, 2808-2813. Fauzi, H., Kawakami, J., Nishikawa, F. and Nishikawa, S. (1997) Analysis of the cleavage reaction of a trans-acting human hepatitis delta virus ribozyme. Nucl. Acids Res, 25, 3124-3130. Ferre-D'Amare, A.R., Zhou, K. and Doudna, J.A. (1998) Crystal structure of a hepatitis delta virus ribozyme.[see comment]. Nature, 395, 567-574. Fu, T.B. and Taylor, J. (1993) The RNAs of hepatitis delta virus are copied by RNA polymerase II in nuclear homogenates. J Virol, 67, 6965-6972. Ghisolfi, L., Joseph, G., Amalric, F. and Erard, M. (1992) The glycine-rich domain of nucleolin has an unusual supersecondary structure responsible for its RNA-helix-destabilizing properties. J Biol Chem, 267, 2955-2959. Glenn, J.S., Watson, J.A., Havel, C.M. and White, J.M. (1992) Identification of a prenylation site in delta virus large antigen. Science, 256, 1331-1333. Goodman, O.B., Jr., Krupnick, J.G., Gurevich, V.V., Benovic, J.L. and Keen, J.H. (1997) Arrestin/clathrin interaction. Localization of the arrestin binding locus to the clathrin terminal domain. J Biol Chem, 272, 15017-15022. Govindarajan, S., Chin, K.P., Redeker, A.G. and Peters, R.L. (1984) Fulminant B viral hepatitis: role of delta agent. Gastroenterology, 86, 1417-1420. Hartmann-Stuhler, C. and Prange, R. (2001) Hepatitis B virus large envelope protein interacts with gamma2-adaptin, a clathrin adaptor-related protein. J Virol, 75, 5343-5351. Hirst, J. and Robinson, M.S. (1998) Clathrin and adaptors. Biochim Biophy Acta, 1404, 173-193. Hoofnagle, J.H. (1989) Type D (delta) hepatitis.[see comment][erratum appears in JAMA 1989 Jun 23-30;261(24):3552]. JAMA, 261, 1321-1325. Hsu, S.C., Wu, J.C., Sheen, I.J. and Syu, W.J. (2004) Interaction and replication activation of genotype I and II hepatitis delta antigens. J Virol, 78, 2693-2700. Huang, C. (2002) The C terminus of the large hepatitis delta antigen interferes the clathrin-mediated protein export pathway. Master thesis, National Taiwan University, Taipei, Taiwan Huovila, A.P., Eder, A.M. and Fuller, S.D. (1992a) Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment. J Cell Biol, 118, 1305-1320. Huovila, A.P., Eder, A.M. and Fuller, S.D. (1992b) Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment. J Cell Biol, 118, 1305-1320. Hwang, S.B. and Lai, M.M. (1993) Isoprenylation mediates direct protein-protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J Virol, 67, 7659-7662. Kirchhausen, T. (2000) Clathrin. Annu Rev Biochem, 69, 699-727. Kos, A., Dijkema, R., Arnberg, A.C., van der Meide, P.H. and Schellekens, H. (1986) The hepatitis delta (delta) virus possesses a circular RNA. Nature, 323, 558-560. Kuo, M.Y., Chao, M. and Taylor, J. (1989) Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J Virol, 63, 1945-1950. Kuo, M.Y., Goldberg, J., Coates, L., Mason, W., Gerin, J. and Taylor, J. (1988a) Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J Virol, 62, 1855-1861. Kuo, M.Y., Sharmeen, L., Dinter-Gottlieb, G. and Taylor, J. (1988b) Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J Virol, 62, 4439-4444. Lai, M.M. (1995) The molecular biology of hepatitis delta virus. Annu Rev Biochem, 64, 259-286. Lazinski, D.W. and Taylor, J.M. (1994) Expression of hepatitis delta virus RNA deletions: cis and trans requirements for self-cleavage, ligation, and RNA packaging. J Virol, 68, 2879-2888. Lazinski, D.W. and Taylor, J.M. (1995) Intracellular cleavage and ligation of hepatitis delta virus genomic RNA: regulation of ribozyme activity by cis-acting sequences and host factors. J Virol, 69, 1190-1200. Lee, C.H., Chang, S.C., Chen, C.J. and Chang, M.F. (1998) The nucleolin binding activity of hepatitis delta antigen is associated with nucleolus targeting. J Biol Chem, 273, 7650-7656. Lee, C.H., Chang, S.C., Wu, C.H. and Chang, M.F. (2001) A novel chromosome region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly. J Biol Chem, 276, 8142-8148. Lee, C.Z., Chen, P.J. and Chen, D.S. (1995) Large hepatitis delta antigen in packaging and replication inhibition: role of the carboxyl-terminal 19 amino acids and amino-terminal sequences. J Virol, 69, 5332-5336. Lee, C.Z., Chen, P.J., Lai, M.M. and Chen, D.S. (1994) Isoprenylation of large hepatitis delta antigen is necessary but not sufficient for hepatitis delta virus assembly. Virology, 199, 169-175. Lee, C.Z., Lin, J.H., Chao, M., McKnight, K. and Lai, M.M. (1993) RNA-binding activity of hepatitis delta antigen involves two arginine-rich motifs and is required for hepatitis delta virus RNA replication. J Virol, 67, 2221-2227. Li, Y.J., Macnaughton, T., Gao, L. and Lai, M.M. (2006) RNA-templated replication of hepatitis delta virus: genomic and antigenomic RNAs associate with different nuclear bodies. J Virol, 80, 6478-6486. Lin, J.H., Chang, M.F., Baker, S.C., Govindarajan, S. and Lai, M.M. (1990) Characterization of hepatitis delta antigen: specific binding to hepatitis delta virus RNA. J Virol, 64, 4051-4058. Lin, S.S., Chang, S.C., Wang, Y.H., Sun, C.Y. and Chang, M.F. (2000) Specific interaction between the hepatitis delta virus RNA and glyceraldehyde 3-phosphate dehydrogenase: an enhancement on ribozyme catalysis. Virology, 271, 46-57. MacNaughton, T.B., Gowans, E.J., McNamara, S.P. and Burrell, C.J. (1991) Hepatitis delta antigen is necessary for access of hepatitis delta virus RNA to the cell transcriptional machinery but is not part of the transcriptional complex. Virology, 184, 387-390. Macnaughton, T.B., Shi, S.T., Modahl, L.E. and Lai, M.M. (2002) Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J Virol, 76, 3920-3927. Macnaughton, T.B., Wang, Y.J. and Lai, M.M. (1993) Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J Virol, 67, 2228-2234. Makino, S., Chang, M.F., Shieh, C.K., Kamahora, T., Vannier, D.M., Govindarajan, S. and Lai, M.M. (1987) Molecular cloning and sequencing of a human hepatitis delta (delta) virus RNA. Nature, 329, 343-346. Marsh, M. and Helenius, A. (2006) Virus entry: open sesame. Cell, 124, 729-740. Mellman, I. (1996) Endocytosis and molecular sorting. Annu Rev Cell Dev Biol, 12, 575-625. Modahl, L.E., Macnaughton, T.B., Zhu, N., Johnson, D.L. and Lai, M.M. (2000) RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol Cell Biol, 20, 6030-6039. Monjardino, J. (1996) Replication of hepatitis delta virus. J Viral Hepat, 3, 163-166. Moores, S.L., Schaber, M.D., Mosser, S.D., Rands, E., O'Hara, M.B., Garsky, V.M., Marshall, M.S., Pompliano, D.L. and Gibbs, J.B. (1991) Sequence dependence of protein isoprenylation. J Biol Chem, 266, 14603-14610. Motley, A., Bright, N.A., Seaman, M.N. and Robinson, M.S. (2003) Clathrin-mediated endocytosis in AP-2-depleted cells. J Cell Biol, 162, 909-918. Mullins, C. and Bonifacino, J.S. (2001) The molecular machinery for lysosome biogenesis. Bioessays, 23, 333-343. Nishikawa, F. and Nishikawa, S. (2000) Requirement for canonical base pairing in the short pseudoknot structure of genomic hepatitis delta virus ribozyme. Nucl. Acids Res, 28, 925-931. Niswonger, M.L. and O'Halloran, T.J. (1997) A novel role for clathrin in cytokinesis. Proc Natl Acad Sci U S A, 94, 8575-8578. Owen, D.J. and Luzio, J.P. (2000) Structural insights into clathrin-mediated endocytosis. Curr Opin Cell Biol, 12, 467-474. Payne, G.S., Hasson, T.B., Hasson, M.S. and Schekman, R. (1987) Genetic and biochemical characterization of clathrin-deficient Saccharomyces cerevisiae. Mol Cell Biol, 7, 3888-3898. Payne, G.S. and Schekman, R. (1985) A test of clathrin function in protein secretion and cell growth. Science, 230, 1009-1014. Pearse, B.M., Smith, C.J. and Owen, D.J. (2000) Clathrin coat construction in endocytosis. Curr Opin Struct Biol, 10, 220-228. Perrotta, A.T. and Been, M.D. (1991) A pseudoknot-like structure required for efficient self-cleavage of hepatitis delta virus RNA. Nature, 350, 434-436. Perrotta, A.T. and Been, M.D. (1992) Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis delta virus RNA sequence. Biochemistry, 31, 16-21. Polson, A.G., Bass, B.L. and Casey, J.L. (1996) RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature, 380, 454-456. Ponzetto, A., Cote, P.J., Popper, H., Hoyer, B.H., London, W.T., Ford, E.C., Bonino, F., Purcell, R.H. and Gerin, J.L. (1984) Transmission of the hepatitis B virus-associated delta agent to the eastern woodchuck. Proc Natl Acad Sci U S A, 81, 2208-2212. Ponzetto, A., Negro, F., Popper, H., Bonino, F., Engle, R., Rizzetto, M., Purcell, R.H. and Gerin, J.L. (1988) Serial passage of hepatitis delta virus in chronic hepatitis B virus carrier chimpanzees. Hepatology, 8, 1655-1661. Puertollano, R. (2004) Clathrin-mediated transport: assembly required. Workshop on Molecular Mechanisms of Vesicle Selectivity. EMBO Rep, 5, 942-946. Raiborg, C., Bache, K.G., Mehlum, A., Stang, E. and Stenmark, H. (2001) Hrs recruits clathrin to early endosomes. EMBO J, 20, 5008-5021. Richardson, D.R. and Ponka, P. (1997) The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim Biophy Acta, 1331, 1-40. Rizzetto, M., Canese, M.G., Arico, S., Crivelli, O., Trepo, C., Bonino, F. and Verme, G. (1977) Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut, 18, 997-1003. Rizzetto, M., Hoyer, B., Canese, M.G., Shih, J.W., Purcell, R.H. and Gerin, J.L. (1980) delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. Proc Natl Acad Sci U S A, 77, 6124-6128. Rizzetto, M., Verme, G., Recchia, S., Bonino, F., Farci, P., Arico, S., Calzia, R., Picciotto, A., Colombo, M. and Popper, H. (1983) Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med, 98, 437-441. Robertson, H.D., Manche, L. and Mathews, M.B. (1996) Paradoxical interactions between human delta hepatitis agent RNA and the cellular protein kinase PKR. J Virol, 70, 5611-5617. Roingeard, P., Lu, S.L., Sureau, C., Freschlin, M., Arbeille, B., Essex, M. and Romet-Lemonne, J.L. (1990) Immunocytochemical and electron microscopic study of hepatitis B virus antigen and complete particle production in hepatitis B virus DNA transfected HepG2 cells. Hepatology, 11, 277-285. Ryu, W.S., Netter, H.J., Bayer, M. and Taylor, J. (1993) Ribonucleoprotein complexes of hepatitis delta virus. J Virol, 67, 3281-3287. Sachse, M., Urbe, S., Oorschot, V., Strous, G.J. and Klumperman, J. (2002) Bilayered clathrin coats on endosomal vacuoles are involved in protein sorting toward lysosomes. Mol Biol Cell, 13, 1313-1328. Schmid, S.L. (1997) Clathrin-coated vesicle formation and protein sorting: an integrated process. Annu Rev Biochem, 66, 511-548. Sharmeen, L., Kuo, M.Y., Dinter-Gottlieb, G. and Taylor, J. (1988) Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage. J Virol, 62, 2674-2679. Smith, C.J. and Pearse, B.M. (1999) Clathrin: anatomy of a coat protein. Trends Cell Biol, 9, 335-338. Sung, J.L. (1984) Hepatitis B virus infection and its sequelae in Taiwan. Gastroenterol Japon, 19, 363-366. Sureau, C., Guerra, B. and Lanford, R.E. (1993) Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J Virol, 67, 366-372. Sureau, C., Guerra, B. and Lee, H. (1994) The middle hepatitis B virus envelope protein is not necessary for infectivity of hepatitis delta virus. J Virol, 68, 4063-4066. Sureau, C., Moriarty, A.M., Thornton, G.B. and Lanford, R.E. (1992) Production of infectious hepatitis delta virus in vitro and neutralization with antibodies directed against hepatitis B virus pre-S antigens. J Virol, 66, 1241-1245. Symons, R.H. (1989) Self-cleavage of RNA in the replication of small pathogens of plants and animals. Trends Bio Sci, 14, 445-450. Turner, M.D. and Arvan, P. (2000) Protein traffic from the secretory pathway to the endosomal system in pancreatic beta-cells. J Biol Chem, 275, 14025-14030. Tuteja, N., Huang, N.W., Skopac, D., Tuteja, R., Hrvatic, S., Zhang, J., Pongor, S., Joseph, G., Faucher, C. and Amalric, F. (1995) Human DNA helicase IV is nucleolin, an RNA helicase modulated by phosphorylation. Gene, 160, 143-148. Wadkins, T.S., Perrotta, A.T., Ferre-D'Amare, A.R., Doudna, J.A. and Been, M.D. (1999) A nested double pseudoknot is required for self-cleavage activity of both the genomic and antigenomic hepatitis delta virus ribozymes. Rna-A Publication of the RNA Society, 5, 720-727. Wang, C.J., Chen, P.J., Wu, J.C., Patel, D. and Chen, D.S. (1991) Small-form hepatitis B surface antigen is sufficient to help in the assembly of hepatitis delta virus-like particles. J Virol, 65, 6630-6636. Wang, D., Pearlberg, J., Liu, Y.T. and Ganem, D. (2001) Deleterious effects of hepatitis delta virus replication on host cell proliferation. J Virol, 75, 3600-3604. Wang, J.G. and Lemon, S.M. (1993) Hepatitis delta virus antigen forms dimers and multimeric complexes in vivo. J Virol, 67, 446-454. Wang, K.S., Choo, Q.L., Weiner, A.J., Ou, J.H., Najarian, R.C., Thayer, R.M., Mullenbach, G.T., Denniston, K.J., Gerin, J.L. and Houghton, M. (1986) Structure, sequence and expression of the hepatitis delta (delta) viral genome.[erratum appears in Nature 1987 Jul 30-Aug 5;328(6129):456]. Nature, 323, 508-514. Wang, L.H., Rothberg, K.G. and Anderson, R.G. (1993) Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol, 123, 1107-1117. Wang, Y.H., Chang, S.C., Huang, C., Li, Y.P., Lee, C.H. and Chang, M.F. (2005) Novel nuclear export signal-interacting protein, NESI, critical for the assembly of hepatitis delta virus. J Virol, 79, 8113-8120. Weiner, A.J., Choo, Q.L., Wang, K.S., Govindarajan, S., Redeker, A.G., Gerin, J.L. and Houghton, M. (1988) A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta. J Virol, 62, 594-599. Wong, S.K. and Lazinski, D.W. (2002) Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc Natl Acad Sci U S A, 99, 15118-15123. Wu, H.N. and Lai, M.M. (1990) RNA conformational requirements of self-cleavage of hepatitis delta virus RNA. Mol Cell Biol, 10, 5575-5579. Wu, H.N., Lin, Y.J., Lin, F.P., Makino, S., Chang, M.F. and Lai, M.M. (1989) Human hepatitis delta virus RNA subfragments contain an autocleavage activity. Proc Natl Acad Sci U S A, 86, 1831-1835. Wu, J.C., Choo, K.B., Chen, C.M., Chen, T.Z., Huo, T.I. and Lee, S.D. (1995) Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet, 346, 939-941. Xia, Y.P., Chang, M.F., Wei, D., Govindarajan, S. and Lai, M.M. (1990) Heterogeneity of hepatitis delta antigen. Virology, 178, 331-336. Xia, Y.P. and Lai, M.M. (1992) Oligomerization of hepatitis delta antigen is required for both the trans-activating and trans-dominant inhibitory activities of the delta antigen. J Virol, 66, 6641-6648. Xu, Z., Bruss, V. and Yen, T.S. (1997) Formation of intracellular particles by hepatitis B virus large surface protein. J Virol, 71, 5487-5494. Yamaguchi, Y., Filipovska, J., Yano, K., Furuya, A., Inukai, N., Narita, T., Wada, T., Sugimoto, S., Konarska, M.M. and Handa, H. (2001) Stimulation of RNA polymerase II elongation by hepatitis delta antigen. Science, 293, 124-127. Yu, I.C. (2001) Identification of a cellular factor specifically interacted with the nuclear export signal of the large hepatitis delta antigen. Master thesis, National Taiwan University, Taipei, Taiwan | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30412 | - |
dc.description.abstract | D型肝炎病毒(HDV)為一具有外套之球狀RNA病毒,其外套蛋白質由B型肝炎病毒之表面抗原所組成,並藉此感染肝細胞。病毒顆粒內部則含有約1.7 kb的單股環狀RNA基因體,其所轉譯產生之delta抗原有兩種:大型delta抗原(214個胺基酸,約為27 kDa)和小型delta抗原(195個胺基酸,約為24 kDa)。比較大小型delta抗原的胺基酸序列可以發現,兩者的差別僅在於大型delta抗原的羧端多了19個胺基酸;而在功能上的比較則可以發現,小型delta抗原為病毒RNA基因體複製所必需,而大型delta抗原具有與小型B型肝炎表面抗原組成類D型肝炎病毒顆粒之能力,且C端所多出的19個胺基酸對於病毒顆粒之包裹是重要的,具有促使大型delta抗原由細胞核輸送到細胞質中,與B型肝炎表面抗原共同組成病毒顆粒之功能。並且之前的研究也證明,大型delta抗原C端之第198至第210胺基酸具有細胞核輸出訊號(nuclear export signal;NES)之功能。
為了進一步了解HDV感染所造成的致病原因,首先,分析大型delta抗原C端與宿主細胞因子之間的交互作用,利用GST pull-down assay研究發現,一細胞因子clathrin heavy chain蛋白質(CHC)可能直接或間接對於大型delta抗原的細胞核輸出訊號有專一性的辨認。仔細比較大型delta抗原C端的胺基酸序列,我們發現大型delta抗原第199至203的胺基酸序列(199-LFPAD-203),與clathrin box的序列具有高度相似性。並且進一步利用點突變(L199A及D203A)的實驗,證明大型delta抗原的確利用其C端clathrin box的序列,與CHC結合。以in vitro蛋白質親和力之結合試驗及in vivo共同免疫沉澱的方式,更證實CHC與大型delta抗原C端具有專一性結合的現象。以共軛焦顯微鏡觀察,在小型B型肝炎病毒表面抗原存在下,CHC與大型delta抗原在細胞中的共同座落的位置為trans-Golgi network (TGN)中。在蔗糖梯度離心實驗中,也證實大型delta抗原與CHC存在於同一個複合體中。 Clathrin是細胞中主要進行vesicles形成和運送之重要蛋白質,利用clathirn所調控之胞外分泌(exocytosis)及內涵體運輸(endosomal trafficking)的抑制劑,brefeldin A及wortmannin,可以有效抑制HDV類病毒顆粒之組裝及釋出,但對小型B型肝炎病毒表面抗原之釋出並無明顯影響。將大型delta抗原之clathrin box進行點突變,也發現HDV類病毒顆粒之組裝及釋出有明顯降低的結果;另外,利用shRNA降低細胞內生性CHC之表現,對於HDV類病毒顆粒包裹也有抑制的結果,因此可以推論CHC對HDV病毒包裹的重要性。在哺乳類細胞的系統中,已知運鐵蛋白(transferrin)的內吞作用(endocytosis)及上皮生長因子(EGF) 之降解作用(degradation)也是依靠clathrin所調控的,因此,我們也證明大型delta抗原C端與CHC的結合,會影響運鐵蛋白的內吞或運輸作用;另外,也證明了細胞內上皮生長因子之降解作用,可能因細胞質內大型delta抗原的存在而有減緩的現象,推測CHC與大型delta抗原C端的專一性結合,會影響到細胞內正常依賴clathrin進行的蛋白質之運輸作用。 本論文顯示大型delta抗原為一clathrin adaptor-like的蛋白質,並進一步瞭解大型delta抗原與clathrin的交互作用可能參與在D型肝炎病毒之病毒分泌及其致病機制。 | zh_TW |
dc.description.abstract | Hepatitis delta virus (HDV) is a human pathogen associated with fulminant hepatitis and progressive chronic liver cirrhosis upon superinfection and coinfection with hepatitis B virus (HBV). HDV particles contain a single-stranded circular RNA genome of 1.7 kilobases. The HDV antigenomic RNA contains an open reading frame which encodes two forms of hepatitis delta antigen (HDAg), HDAg-S (24 kDa) and HDAg-L (27 kDa). The two HDAgs are identical in the amino acid sequence, except that the HDAg-L possesses an extra 19-amino-acid extension at the C terminus. Nevertheless, functions of two forms of HDAgs are quite different. The HDAg-S facilitates the replication of HDV RNA, whereas the HDAg-L is required for HDV assembly. Previous studies have also indicated that the HDAg-L contains a nuclear export signal located in its C terminus from amino acid residues 198-210.
To study the molecular mechanisms by which HDV infection causes hepatitis, possible interactions between HDAg-L and host proteins were analyzed. GST pull-down assay was performed with a GST-HDAg-L(198-210) fusion protein and HepG2 cell lysate to identify host proteins that interact with the C terminus of HDAg-L. By performing GST pull-down assay and mass spectrometry analysis, clathrin heavy chain (CHC) that represents the major structural component of the coated pit lattice, was identified to be an HDAg-L(198-210)-interacting protein. In vitro binding assay demonstrated that the N-terminal 107 amino acid residues of the CHC and the putative clathrin box (199-LFPAD-203) in the HDAg-L are critical for the interaction. The specific interaction between HDAg-L and CHC was further demonstrated by confocal microscopy and co-immunoprecipitation. Sucrose gradient centrifugation followed by co-immunoprecipitation analysis indicated that HDAg-L constitutes part of the clathrin complex. To investigate the biological role of CHC in HDV life cycle, inhibitors of clathrin-mediated transport were used to investigate the association of CHC and HDV assembly. Here, we demonstrated that brefeldin A (BFA) and wortmannin, inhibitors of clathrin-mediated exocytosis and endosomal trafficking, respectively, specifically blocked HDV assembly, but had no effect on the assembly of the small surface antigen of HBV. HDAg-L with mutations at the conserved amino acid residues of clathrin box failed to interact with CHC and to assemble into virus-like particles. In addition, small hairpin RNA (shRNA)-mediated CHC down-regulation effectively reduced the assembly of HDV. These data suggest that the formation of HDV VLPs is mainly mediated by the association of HDAg-L with CHC in the trans-Golgi network (TGN), indicating that CHC is a key component to the process of HDV assembly. In addition, possible effects of HDAg-L in regulating the functions of CHC were also examined. In the presence of the surface antigen of HBV, cytoplasm-localized HDAg-L inhibited the clathrin-mediated endocytosis of transferrin and the ligand-induced degradation of epidermal growth factor receptor in transfected mammalian cells. These data suggest that HDAg-L interferes with the function of clathrin. The cell growth defects observed in HDV-infected hepatocytes may be partially due to a lost of control in clathrin-mediated protein trafficking. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T02:03:12Z (GMT). No. of bitstreams: 1 ntu-96-D92442004-1.pdf: 1153822 bytes, checksum: 313be44c931dcfa4d53c989dde2be3f1 (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 中文摘要……………………………………………….………………i-ii
英文摘要……………………………….…………………………….iii-iv 前言…………………………………………………………………...1-11 實驗材料與方法…………………………………………………….12-18 實驗結果…………………………………………………………….19-28 討論………………………………………………………………….29-32 圖表………………………………………………………………….33-56 參考文獻…………………………………………………………….57-67 | |
dc.language.iso | zh-TW | |
dc.title | Clathrin依賴性之蛋白質運輸路徑參與D型肝炎病毒之組合及致病機轉 | zh_TW |
dc.title | Clathrin-mediated protein transport pathway is involved in the assembly and pathogenesis of hepatitis delta virus | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林榮耀,張智芬,林淑華,張玉生,廖經倫,譚婉玉 | |
dc.subject.keyword | 蛋白質運輸,D型肝炎病毒, | zh_TW |
dc.subject.keyword | Clathrin,hepatitis delta virus, | en |
dc.relation.page | 68 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-06 | |
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 |
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