臺灣博碩士論文加值系統

D型肝炎病毒為一含外套的病毒顆粒，外套蛋白質由B型肝炎病毒之表面抗原所組成。病毒顆粒內部則含有約1.7 kb的單股環狀RNA基因體與其所轉譯的delta抗原。delta抗原可分大型(214個胺基酸；27 kDa)與小型(195個胺基酸；24 kDa)兩者的差別僅在於大型delta抗原的羧端多了19個胺基酸。大小型抗原雖然在胺基酸組成及結構上有相當高的相似性，但兩者在病毒的生活史扮演著不同的角色。大型Delta抗原多出的19個胺基酸對於病毒顆粒的包裹是重要的。其具有促使大型delta抗原由細胞核輸送到細胞質中，與B型肝炎病毒之表面抗原共同組成病毒顆粒之功能。而小型delta抗原為病毒基因體複製所必須，大型delta抗原則抑制之。先前的研究即發現，大型delta抗原C端第198至210胺基酸為一細胞核輸出訊號(nuclear export signal; NES)而被命名為NES(HDAg-L)。本篇論文即針對病毒基因體探討細胞因子GAPDH與HDV基因體結合，對病毒複製的生物功能。另一方面則是針對與delta抗原核輸出訊號結合的細胞因子對病毒生活史的調控。
為了進一步了解GAPDH和HDV RNA間交互作用所扮演的可能功能，以能在哺乳動物細胞中，由SV40 promoter轉錄出HDV雙套體RNA並進行複製的質體pSVD2，轉染Huh7細胞。兩天後以間接免疫螢光染色，以觀察GAPDH在HDV RNA複製情況下，在細胞內分布的情形。在正常狀態下，GAPDH主要位於細胞質中。在轉染細胞中，則可以觀察到部分細胞核中觀測到GAPDH的存在。以間接免疫螢光染色及螢光原位雜交法同時觀察轉染細胞中，HDV RNA所在位置，發現其出現在細胞核質。將包含有GAPDH結合區域的HDV antigenomic RNA片段以活體外轉錄反應方式產生出來；隨著反應時間的增長，在GAPDH存在的狀況下確實使切割產物增加。結果也暗示GAPDH藉由與病毒RNA的結合，而在HDV RNA自我切割之核酸酶(ribozyme)活性扮演重要的角色。
利用酵母菌雙雜交系統我們找到一個會與輸出/包裹功能健全之delta抗原核輸出訊號〈NES(HDAg-L)〉但不與功能缺陷delta抗原核輸出訊號〈NES*(HDAg-L) 〉結合的細胞因子並將之命名為NESI (NES interacting)。NESI主要分佈于人類肝臟組織並包含467個胺基酸，含有一假設的actin結合區及bipartite核位訊息。以共同免疫沉澱及免疫螢光染色法則進一步確認大型delta抗原與NESI的特異性結合。在轉染細胞中過量表現反意(antisense) NESI RNA會抑制由大型delta抗原所媒介之HDV genomic RNA共同包裹於類病毒顆
粒。這些結果指出，藉由與大型delta抗原結合，NESI
發揮其在HDV的包裹扮演著關鍵性的角色。

Heaptitis virus (HDV) is the causative agent of acute and chronic liver diseases including fulminant hepatitis and accelerated liver cirrhosis. HDV particles contain a single-stranded circular RNA genome of 1.7 kilobases. The HDV antigenomic RNA contains an open reading frame which encodes delta antigens( HDAgs). There are two forms of HDAgs, the small HDAg (HDAg-S, 24 kDa) and the large HDAg (HDAg-L, 27 kDa). The two HDAgs are identical in the amino acid sequence, except that the HDAg-L contains an additional 19 amino acids at it C terminus. Nevertheless, functions of two forms of HDAgs are quite different. The HDAg-S is required for the HDV replication, whereas the HDAg-L has negative effects on genome replication is required for HDV assembly. The HDV genome RNA is associated with delta antigen to form ribonucleoprotein. Previous results have shown that a cellular factor, GAPDH interacted with HDV RNA. In addition, nuclear export signal that located in the C-terminus of HDAg-L from amino acid residues 198-210, designated NES(HDAg-L), has been identified. To investigate the biological role of GAPDH in HDV life cycle, cells were transfected with plasmid pSVD2 representing the dimeric HDV cDNA and proceeded to fluorescence in situ hybridization/immunofluorescence staining. In the presence of HDV replication, GAPDH relocalized from the cytoplasm to the nucleus. The biological significance of the interaction between GAPDH and HDV RNA was further elucidate by examing the possible role of GAPDH on the catalysis of HDV ribozyme. This cis-cleavage activity of the HDV anigenomic RNA increase from 34 to 62 % following a 40-min incubation with 50 ng/ l of GAPDH. The enhancing effect of GAPDH on the catalysis of HDV ribozyme was reproducible and was not observed with bovine serum albumin (BSA). These results suggest a possible role of GAPDH involved in HDV multiplication.
The process of host factor-mediated nucleocytoplasmic transport is critical for diverse cellular events in eukaryotes and the life cycle of viruses. A previously identified chromosome region maintenance 1 (CRM1)-independent nuclear export signal (NES) at the C-terminus of the large form of hepatitis delta antigen (HDAg), designated NES(HDAg-L) is required for the assembly of hepatitis delta virus (HDV) To look for interacting proteins of the NES(HDAg-L), yeast two-hybrid screening was applied using GAL4 binding domain fused to NES(HDAg-L) as bait. Among the positive clones, one encodes a protein, designated NESI (NES-interacting protein) that specifically interacted with the wild-type NES(HDAg-L), but not with the export/package-defective HDAg-L mutant, NES*(HDAg-L) in which Pro-205 has been replaced by Ala. Northern blot analysis revealed NESI as the gene product of a 1.9 kb endogenous mRNA transcript that is present predominantly in human liver tissue. NESI consists of 467 amino acid residues and bears a putative actin-binding site and a bipartite nuclear localization signal. Specific interaction between HDAg-L and NESI was further confirmed by coimmunoprecipitation and immunofluorescence staining. Overexpression of an antisense NESI RNA abolished HDAg-L-mediated assembly of HDV genomic RNA into virus-like particles. These data indicate a critical role of NESI, through the interaction of HDAg-L, involved in the assembly of HDV.

論文摘要---------------------------------------------------------------------------I
Abstract--------------------------------------------------------------------------II
圖目錄 (List of Figures)-------------------------------------------------------III
表目錄 (List of Table)---------------------------------------------------------IV
第一章、研究背景、目的與實驗構想-----------------------------------------1
第二章、甘油脂醛-3-磷酸去氫酶(GAPDH)與D型肝炎病毒RNA結
合在D型肝炎病毒增殖之生物功能研究--------------------8
緒論-----------------------------------------------------------------------8
材料與方法-------------------------------------------------------------10
實驗結果--------------------------------------------------------------------------16
討論------------------------------------------------------------------------18
第三章、細胞因子NESI與大型D型肝炎病毒抗原核輸出訊號之結合
及功能分析------------------------------------------------------------21
緒論--------------------------------------------------------------------------------21
材料與方法-------------------------------------------------------------------27
實驗結果--------------------------------------------------------------------------48
討論--------------------------------------------------------------------------------56
第四章、未來展望---------------------------------------------------------------60
參考文獻------------------------------------------------------------------------90
附錄—Publications-----------------------------------------------------100

1.Rizzetto, M., Canese, M. G., Arico, S., Crivelli, O., Bonono, F., Trepo, C. G. and Verme, G. (1977) Immunofluorescence detection of a new antigen/antibody system (delta/anti-delta) associated with hepatitis B virus in liver and serum of HBsAg carriers. Gut 18: 997-1003.
2.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 infection in chronic hepatitis B virus carrier chimpanzees. Hepatology 8: 1655-1661.
3.Ponzetto, A., Cote, P. J., Popper, H., Boyer, B. H., London, W. T., Ford, E. C., Bonino, F., Purcell, R. H., and Gerin, J. L. (1984) Transmission of hepatitis B-associated delta agent to the eastern woodchunk. Proc. Natl. Acad. Sci. USA 81: 2208-2211.
4.Makino, S., Chang, M. F., Shieh, C. K., Kamahora, T., Vannier, D. M., Govindarajan, S., and Lai, M. M. C. (1987) Molecular cloning and sequencing of the hepatitis delta virus RNA. Nature (London) 329: 343-346.
5.Wang, K. S., Choo, Q. L., Weiner, A. J., Ou, J. H., Najarian, R. C., Thayer, R. M., Mullenbach, G. T., Denniston, D. J., Gerin, J. L. and Honghton, M. (1986) Structure sequence and expression of the hepatitis delta viral genome. Nature (London) 323: 508-514.
6.Lai, M. M. C. (1995) The molecular biology of hepatitis delta virus. Annu. Rev. Biochem. 64:259-286.
7.Govindarajan, S., Chin, K. P., Redeker and Peters, R. L. (1984) Fulminant B viral hepatitis: role of delta antigen. Gastroenterology 86: 1416-1420.
8.Hoofnagle, J. H. (1989) Type D (delta) hepatitis. J. Am. Med. Assoc. 216: 1321-1325
9.Chen, D. S. and Sung, J. L. (1978) Hepatitis B virus infection and chronic liver disease in Taiwan. ACTA. Hepato-Gastroenterol. 25: 423-430.
10.Sung, J. L. (1981) Hepatitis B virus infection and its sequalae in Taiwan. Proc. Natl. Acad. Sci. ROC 5: 385-399.
11.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.
12.Rizzetto, M., Hoyer, M. B., Canese, M. G., Shih, J. W. K., 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. USA 77: 6124-6128.
13.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 antigen. J. Virol. 66: 1241-1245.
14.Monjardino J. (1996) Replication of hepatitis delta virus. J. Viral Hepatitis 3: 163-166.
15.Wang, C. J., Chen, P. J., Wu, J. C., Patal, 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.
16.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.
17.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.
18.Kos, A., Dijkema, R., Arnberg, A. C., van de Merde, P. H. and Schelekens, H. (1986) The HDV possesses a circular RNA. Nature (London) 323: 558-560.
19.Wang, K. S., Choo, Q. L., Weiner, A. J., Ou, J. H., Najarian, R. C., Thayer, R. M., Mullenbach, G. T., Denniston, D. J., Gerin, J. L. and Honghton, M. (1986) Structure sequence and expression of the hepatitis delta viral genome. Nature (London) 323: 508-514.
20.Kuo, M. Y. P., Golderg, J., Coates, L., Mason, W., Gerin, J. and Taylor, J. M. (1988) Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and application. J. Virol. 62:1855-1860.
21.Diener, T. O. (1991) Subviral pathogens of plants: viroids and viroidlike satellite RNAs. FASEB J. 5:2808-2813.
22.Kuo, M. Y. P., Sharmeen, L., Dinter-Gottlieb, G. and Taylor, J. (1988) Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J. Virol. 62: 4439-4444.
23.Perrotta, A. T. and Been, M. D. (1991) A pseudoknot-like structure required for efficient self-cleavage of hepatitis delta virus RNA. Nature (London) 350:434-436.
24.Sharmeen, L., Kuo, M. Y. P., Dinter-Gottlieb, G. and Taylor, J. M. (1988) Antigenomic RNA of human hepatitis delta virus can undergo self-cleavage. J. Virol. 62:2674-2679.
25.Wu, H. N., and Lai, M. M. C. (1990) RNA conformational requirements for self-cleavage of hepatitis delta virus RNA. Mol. Cell Biol. 10:5575-5579.
26.Wu, H. N., Lin,Y. J., Lin, F., Makino, P. S., Chang, M. F., and Lai, M. M. C. (1989) Human hepatitis delta virus RNA subfragments contain an autocleavage activity. Proc. Natl. Acad. Sci. USA 86:1831-1835.
27.Fauzi, H., Chiba, A., Nishikawa, F., Roy, M., Kawakami, J. and Nishikawa, S. (1998) Minimization of genomic human hepatitis delta virus ribozyme. Anal. Chim. Acta. 365: 309-317.
28.Ferr’e-D’Amar’e, A. R., Zhou, K. and Doudna, J. A.（1998）Crystal structure of a hepatitis delta virus ribozyme. Nature 395: 567-574.
29.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.
30.Wadkins, T. S., Perrotta, A. T., Ferré-D’amaré, 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 5: 720-727.
31.Lazinski, D. W. and Taylor, J. (1994) Expression of hepatitis delta virus RNA deletion: cis and trans requirement for self-cleavage ligation and RNA package. J. Virol. 68: 2879-2888.
32.Branch, A. D. and Robertson, H. D. (1991) Efficient trans cleavage and a common structural motif for the ribozymes of human hepatitis delta agent. Proc. Natl. Acad. Sci. USA 88: 10163-10167.
33.Perrotta, A. T. and Been, M. D. (1992) Cleavage of oligonucleotides by a ribozyme derived from the hepatitis delta virus RNA sequence. Biochemistry 31: 16-21.
34.Lazinski, D. W. and Taylor, J. (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.
35.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.
36.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
37.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 glyceraldehydes 3-phosphate dehydrogenase: an enhancement on ribozyme catalysis. Virology 271: 46-57.
38.Branch, A. D. and Robertson, H. D. (1984) A replication cycle for viroids and other small infectious RNAs. Science 223: 450-455.
39.Macnaughton, T. B., Wang, Y. J. and Lai, M. M. C. (1993) Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J. Virol. 67: 2228-2234.
40.Symons, R. H. (1989) Self-cleavage of RNA in the replication of small pathogens of plants and animals. Trends Bio. Sci. 14: 445-450.
41.Chen, P. J., Kalpana, G., Golderg, 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. USA. 83: 8774-8778.
42.Kuo, M. Y. P., 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.
43.Lin, Y. L. (1995) Studies on the functional motifs of viral RNA required for the replication of hepatits delta virus. National Taiwan University Master thesis.
44.Hoyer, B. H., Bonino, F., Ponzetto, A., Denniston, K. J., Nelson, J. Purcell, R. and Gerin, J. L. (1983) In “viral hepatitis and delta infection” Verme, G., Bonino, F. and Rizzetto, M. (eds.) A.R. Liss New York.
45.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.
46.Macnaughton, T. B., Gowan, E. J., McNamara, S. P. and Burrell, C. J. (1991) Hepatitis δvirus RNA to the cell transcriptional machinery but is not part of the transcriptional complex. Virology 184: 387-390.
47.Modahl, L. E., Macnaughton, T. B., Zhu, N., Johnson, D. L. and Lai, M. M. C. (2000) RNA-dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol. Cell. Biol. 20: 6030-6039.
48.Chao, H. C. (2002) Characterization of replication initiation complexes of hepatitis delta virus. National Taiwan University Master thesis.
49.Bergman, K. and Gerin, J. (1986) Antigens of hepatitis delta virus in the liver and serum of humans and animals. J. Infect. Dis. 154: 702-706.
50.Chang, M. F., Baker, S. C., Soe, L. H., Kamahora, J. G., Makino, K. S., Govindarajan, S. and Lai, M. M. C. (1988) Human hepatitis delta antigen is a nuclear phosphoprotein with RNA-binding activity. J. Virol. 62: 2403-2410.
51.Weiner, A. J., Choo, Q. L., Wang, K. S., Govindarajan, S., Redeker, A., Gerin, J. L. and Houghton, M. (1988) A single antigenomic open reading frame of hepatitis delta virus encode the epitope(s) of both hepatitis delta antigen polypeptides p24 and p27. J. Virol. 62: 594-599.
52.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.
53.Casey, J. L. and Gerin, J. L. (1995) Hepatitis D virus editing: specific modification of adenosine in the antigenomic RNA. J. Virol. 69: 7593-7600.
54.Wong, S. K. and Lazinski, D. W. (2002) Replicating hepatitis delta virus RNA is editited in the nucleus by the small form of ADAR1. Proc. Natl. Acad. Sci. USA 99: 15118-15123.
55.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. 67: 2529-2536.
56.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. USA 88: 8490-8494.
57.Nakano, S., Chadalavada, D. M. and Bevilacqua, P. C. (2000) General acid-base catalysis in the mechanism of a hepatitis ribozyme. Science 287:1493-1497
58.Hsieh, S. Y., and Taylor, J. M. (1991) Regulation of polyadenylation of hepatitis delta virus antigenomic RNA. J. Virol. 65:6438-6446.
59.Hsieh, S. Y., Chao, M., Coates, L. and Taylor, J. M. (1990) Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen. J. Virol. 64:3192-3198.
60.Polo, J. M., Jeng, K., Lim, S. B., Govindarajan, S., Hofman, F., Sangiorgi, F. and Lai, M. M. C. (1995) Transgenic mice support replication of hepatitis delta virus RNA in multiple tissues, particularly in skeletal muscle. J. Virol. 69:4880-4887.
61.Gowans, E. J. and Bonino, F. (1993) Hepatitis delta virus pathogenicity, p. 125-130. In Hadziyannis, S. J. Taylor, J. M. and Bonino, F. (ed.), Hepatitis delta virus: molecular biology, pathogenesis, and clinical aspects. Wiley-Liss, New York.
62.Cunha, C., Monjardino, J., Chang, D., Krause, S. and Carmo-Fonseca, M. (1998) Localization of hepatitis delta virus RNA in the nucleus of human cells. RNA 4:680-693.
63.Taylor, J. M., Mason, W., Summers, J., Goldberg, J., Aldrich, C., Coates, L., Gerin, J. and Gowans, E. (1987) Replication of human hepatitis delta virus in primary cultures of woodchuck hepatocytes. J. Virol. 61:2891-2895.
64.Makino, S., Chang, M. F., Kamahora, T., Vannier, D. M., Govindarajan, S. and Lai, M. M. C. (1987) Molecular biology of a human hepatitis delta virus RNA. In ”Hepadna viruses” (Robinson, W., Koike, K. and Will, H. eds.), pp. 549-564. Alan R. Liss, New York.
65.Landers, T. A., Blumenthal, T. and Weber, K. (1974) Function and structure in ribonucleic acid phage Qβribonucleic acid replicase. J. Biol. Chem. 249:5801-5808.
66.Hayes, R. J., and Buck, K. W. (1990) Complete replication of a eukaryotic virus RNA in vitro by a purified RNA-dependent RNA polymerase. Cell 63:363-368.
67.Barton, D. J., Black, E. P. and Flanegan, J. B. (1995) Complete replication of poliovirus in vitro: preinitiation RNA replication complexes require soluble cellular factors for the synthesis of VPg-linked RNA. J. Virol. 69:5516-5527.
68.Blackwell, J. L., and Brinton, M. A. (1997) Translation elongation factor-1 alpha interacts with the 3'' stem-loop region of West Nile virus genomic RNA. J. Virol. 71:6433-6444.
69.Blyn, L. B., Chen, R., Semler, B. L. and Ehrenfeld, E. (1995) Host cell proteins binding to domain IV of the 5'' noncoding region of poliovirus RNA. J. Virol. 69:4381-4389.
70.Furuya, T., and Lai, M. M. C. (1993) Three different cellular proteins bind to complementary sites on the 5''-end-positive and 3''-end-negative strands of mouse hepatitis virus RNA. J. Virol. 67:7215-7222.
71.Kusov, Y., Weitz, M., Dollenmeier, G., Gauss-Muller, V. and Siegl, G. (1996) RNA-protein interactions at the 3'' end of the hepatitis A virus RNA. J. Virol. 70:1890-1897.
72.Leopardi, R., Hukkanen, V., Vainionpaa, R. and Salmi, A. A. (1993) Cell proteins bind to site within the 3'' noncoding region and the positive-strand leader sequence of measles virus RNA. J. Virol. 67:785-790.
73.Pardigon, N., Lenches, E. and Strauss, J. H. (1993) Multiple binding sites for cellular proteins in the 3'' end of sindbis alphavirus minus-sense RNA. J. Virol. 67: 5003-5011.
74.Shi, P. Y., Li, W. and Brinton, M. A. (1996) Cell proteins bind specifically to west nile virus minus-strand 3'' stem-loop RNA. J. Virol. 70:6278-6287.
75.Meyer, K., Petersen, A., Niepmann, M. and Beck, E. (1995) Interaction of eukaryotic initiation factor eIF-4B with a picornavirus internal translation initiation site. J. Virol. 69:2819-2824.
76.Pardigon, N., and Strauss, J. H. (1996) Mosquito homolog of the La autoantigen binds to sindbis virus RNA. J. Virol. 70:1173-1181.
77.Yen, J. H., Chang, S. C., Hu, C. R., Chu, S. C., Lin, S. S., Hsieh, Y. S. and Chang, M. F. (1995) Cellular proteins specifically bind to the 5''-noncoding region of hepatitis C virus RNA. Virology 208:723-732.
78.Yu, W., and Leibowitz, J. L. (1995) Specific binding of host cellular proteins to multiple sites within the 3'' end of mouse hepatitis virus genomic RNA. J. Virol. 69:2016-2023.
79.Zhang, X. M., and Lai, M. M. C. (1995) Interactions between the cytoplasmic proteins and the intergenic (promoter) sequence of mouse hepatitis virus RNA: correlation with the amounts of subgenomic mRNA transcribed. J. Virol. 69:1637-1644.
80.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.
81.Brazas, R., and Ganem, D. (1996) A cellular homolog of hepatitis delta antigen: implications for viral replication and evolution. Science 274:90-94.
82.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.
83.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.
84.Huang, Z. S., and Wu, H. N. (1998) Identification and characterization of the RNA chaperone activity of hepatitis delta antigen peptides. J. Biol. Chem. 273:26455-26461.
85.Jeng, K. S., Su, P. Y. and Lai, M. M. C. (1996) Hepatitis delta antigens enhance the ribozyme activities of hepatitis delta virus RNA in vivo. J. Virol. 70:4205-4209.
86.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.
87.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.
88.Sirover, M. A. 1997. Role of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in normal cell function and in cell pathology. J. Cell. Biochem. 66:133-140.
89.Sioud, M., and Jespersen, L. (1996) Enhancement of hammerhead ribozyme catalysis by glyceraldehyde-3-phosphate dehydrogenase. J. Mol. Biol. 257:775-789.
90.Ronai, Z. (1993) Glycolytic enzymes as DNA binding proteins. Int. J. Biochem. 25:1073-1076.
91.Singh, R., and Green, M. R. (1993) Sequence-specific binding of transfer RNA by glyceraldehyde-3-phosphate dehydrogenase. Science 259:365-368.
92.Nagy, E., and Rigby, W. F. C. (1995) Glyceraldehyde-3-phosphate dehydrogenase selectively binds AU-rich RNA in the NAD+-binding region (Rossmann fold). J. Biol. Chem. 270:2755-2763.
93.Kumagi, H., and Sakai, H. (1983) A porcine brain protein (35K protein) which bundles microtubules and its identification as glyceraldehyde 3-phosphate dehydrogenase. J. Biochem. 93:1259-1269.
94.Lin, T., and Allen, R. W. (1986) Isolation and characterization of a 37,000-Dalton protein associated with the erythrocyte membrane. J. Biol. Chem. 261:4594-4599.
95.Burke, J. R., Enghild, J. J., Martin, M. E. Jou, Y. S., Myers, R. M., Roses, A. D., Vance, J. M. and Strittmatter, W. J. (1996) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2:347-350.
96.Koshy, B., Matilla, T., Burright, E. N., Merry, D. E., Fischbeck, K. H., Orr, H. T. and Zoghbi, H. Y. (1996) Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceradehyde-3-phosphate dehydrogenase. Hum. Mol. Genet. 5:1311-1318.
97.Schulze, H., Schuyler, A., Stuber, D., Dobeli, H., Langen, H. and Huber, G. (1993) Rat brain glyceradehyde-3-phosphate dehydrogenase interacts with the recombinant cytoplasmic domain of Alzheimer’s β-amyloid precursor protein. J. Neurochem. 60:1915-1922.
98.Baxi, M. D., and Vishwanatha, J. K. (1995) Uracil DNA -glycosylase/glyceraldehyde-3-phosphate dehydrogenase is an Ap4A binding protein. Biochemistry 34:9700-9707.
99.Meyer-Siegler, K., Mauro, D. J., Seal, G., Wurzer, J., DeRiel, J. K. and Sirover, M. A. (1991) A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. USA 88:8460-8464.
100.Kawamoto, R. M., and Caswell, A. H. (1986) Autophosphorylation of glyceraldehydephosphate dehydrogenase and phosphorylation of protein from skeletal muscle microsomes. Biochemistry 25:656-661.
101.Epner, D. E., Partin, A. W., Schalken, J. A., Issacs, J. T. and Coffey, D. S. (1993) Association of glyceraldehyde-3-phosphate dehydrogenase expression with cell motility and metastatic potential of rat prostatic adenocarcinoma. Cancer Res. 53:1995-1997.
102.Ishitani, R., Sunaga, K., Hirano, A., Saunders, P., Katsube, N. and Chuang, D. M. (1996) Evidence that glyceradehyde-3-phosphate dehydrogenase is involved in age-induced apoptosis of mature cerebellar neurons in culture. J. Neurochem. 66:928-935.
103.Sunaga, K., Takahashi, H., Chuang, D. M. and Ishitani, R. (1995) Glyceradehyde-3-phosphate dehydrogenase is overexpressed during apoptotic death of neuronal cultures and is recognized by a monoclonal antibody against amyloid plaques from Alzheimer’s brain. Neurosci. Lett. 200:133-136.
104.Morgenegg, G., Winkler, G. C., Hubscher, U., Heizmann, C. W., Mous, J. and Kuenzle, C. C. (1986) Glyceraldehyde-3-phosphate dehydrogenase is a nonhistone protein and a possible activator of transcription in neurons. J. Neurochem. 47:54-62.
105.Karpel, R. L., and Burchard, A. C. (1981) A basic isozyme of yeast glyceraldehyde-3-phosphate dehydrogenase with nucleic acid helix-destabilizing activity. Biochim. Biophys. Acta. 654:256-267.
106.Schultz, D. E., Hardin, C. C. and Lemon, S. M. (1996) Specific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5''-nontranslated RNA of hepatitis A virus. J. Biol. Chem. 271:14134-14142.
107.Prody, G. A., Bakos, J. T., Buzayan, J. M., Schneider, I. R. and Bruening, G. (1986) Autolytic processing of dimeric plant virus satellite RNA. Science 231:1577-1580.
108.Forster, A. C., and R. H. Symons. 1987. Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites. Cell 49:211-220.
109.Tsagris, M., Tabler, M., Muhlbach, H. and Sanger, H. L. (1987) Linear oligomeric potato spindle tuber viroid (PSTV) RNAs are accurately processed in vitro to the monomeric circular viroid proper when incubated with a nuclear extract from healthy potato cells. EMBO J. 6:2173-2183.
110.Thill, G., Vasseur, M. and Tanner, N. K. (1993) Structural and sequence elements required for the self-cleaving activity of the hepatitis delta virus ribozyme. Biochemistry 32:4254-4262.
111.Rosenstein, S. P., and Been, M. D. (1991) Evidence that genomic and antigenomic RNA self-cleaving elements from hepatitis delta virus have similar secondary structures. Nucleic Acids Res. 19:5409-5416.
112.Macnaughton, T. B., Wang, Y. J. and Lai, M. M. C. (1993) Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J. Virol. 67:2228-2234.
113.Herschlag, D., Khosla, M., Tsuchihashi, Z. and Karpel, R. L. (1994) An RNA chaperone activity of non-specific RNA binding proteins in hammerhead ribozyme catalysis. EMBO J. 13:2913-2924.
114.Tsuchihashi, Z., M. Khosla, and D. Herschlag. 1993. Protein enhancement of hammerhead ribozyme catalysis. Science 269:99-102.
115.Bertrand, E., and J. J. Rossi. 1994. Facilitation of hammerhead ribozyme catalysis by the nucleocapsid protein of HIV-1 and the heterogeneous nuclear ribonucleoprotein A1. EMBO J. 13:2904-2912
116.Perrotta, A. T., and Been, M. D. (1990) The self-cleaving domain from the genomic RNA of hepatitis delta virus: sequence requirements and the effects of denaturant. Nucleic Acids Res. 18:6821-6827.
117.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: 6019-6029.
118.Wang, J. G. and Lemon, S. M. (1993) Hepatitis delta virus antigen forms dimers and multimeric complex in vivo. J. Virol. 67: 446-454.
119.Xia, Y. P. and Lai, M. M. C. (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.
120.Lee, C. Z., Lin, J. H., Chao, M., Mcknight, K. and Lai, M. M. C. (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.
121.Chao, M., Hsieh, S. Y. and Taylor, J. (1991) The antigen of hepatitis delta virus: examination of in vitro RNA-binding specificity. J. Virol. 65: 4057-4062.
122.Lin, J. H., Chang, M. F., Baker, S. C., Govindarajan, S. and Lai, M. M. C. (1990) Characterization of hepatitis delta antigen: specific binding to hepatitis delta virus RNA. J. Virol. 64: 4051-4058.
123.Glenn, J. S., Watson, J. A., Havel, C. M. and White, J. M. (1992) Identification of a isoprenylation site in delta virus large antigen. Science 256: 1331-1333.
124.Moores, S. L., Schaber, M. D., Moores, S. D., Rands, S. D., Rands, E., O’Hara, M. B. (1991) Sequence dependence of protein isoprenylation. J. Biol. Chem. 266: 14603-14610.
125.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-destablizing properties. J. Biol. Chem. 267: 2955-2959.
126.Tuteja, N., Huang, N., W., Skopac, D., Tuteja, R., Hrvatic, S., Zhang, J., Ponger, S., Joseph, G., Faucher, C., Amalric, F. and Falachi, A. (1995) Human DNA helicase IV is nucleolin an RNA helicase modulated by phosphorylation. Gene 160: 143-148.
127.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 viral genome. Nature (London) 323: 508-513.
128.Xia, Y. P., Chang, M. F., Wei, D., Govindarajan, S. and Lai, M. M. C. (1990) Heterogeneity of hepatitis delta antigen. Virology 178: 331-336.
129.Lee, C. Z., Chen, P. J., Lai, M. M. C. 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.
130.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 acid and amino-terminal sequence. J. Virol. 69: 5332-5336.
131.Lee, C. H., Chang, S. C., Wu, C. H. 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.
132.de Bruin, W., Leenders, T. K. 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. Virus Res. 31: 27-37.
133.Hwang, S. B. and Lai, M. M. C. (1993) Isoprenylation mediated direct protein-protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J. Virol. 70: 5611-5617.
134.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.
135.Bichko, V. V., Lemon, S. M., Wang, J. G., Hwang, S., Lai, M. M. C. and Taylor, J. M. (1996) Epitopes exposed on hepatitis delta virus ribonucleoproteins. J. Virol. 70: 5807-5811.
136.Piechaczyk, M., Blanchard, J. M., Marty, L., Dani, C., Panabieres, F., El-Sabouty, S., Fort, P., and Jeanteur, P. (1984) Post-transcriptional regulation of glyceraldehyde-3-phosphate- dehydrogenase gene expression in rat tissues. Nucleic Acids Res. 12: 6951-6963.
137.Young, D., M. Riggs, J. Field, A. Vojtek, D. Broek, Wigler. P. (1989) The adenylyl cyclase gene from Schizosaccharomyces pombe. Proc. Natl. Acad. Sci. USA 86:7989-7993.
138.Lin, S. S. (2000) Purification of recombinant dekta antigen and preparation of its polyclonal and monoclonal antibodies. National Taiwan University Ph. D. thesis.
139.Gorlich, D., Pante, N., Kutay, U., Aebi, U., and Bischoff, F. R. (1996) Identification of different roles for RanGDP and RanGTP innuclear protein import.EMBO J. 15: 5584-5594.
140.Wang, J. G., Jansen, R. W., E. A. Brown, E. A. and Lemon, S. M. (1990) Immunogenic domains of hepatitis delta virus antigens: peptide mapping of epitopes recognized by human and woodchuck antibodies. J. Virol. 64:1108-1116.
141.Fischer, U., Huber, J., Boelens, W. C., Mattaj, I. W. and Luhrmann, R. (1995) The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 82:475-483.
142.Michael, W. M., Eder, P. S. and Dreyfuss. G. (1997) The K nuclear shuttling domain: a novel signal for nuclear import and nuclear export in the hnRNP K protein. EMBO J. 16:3587–3598.
143.Michael, W. M., Choi, M. and Dreyfuss. G. (1995) A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 83:415–422.
144.Rashevsky-Finkel, A., Silkov, A. and Dikstein. R. (2001) A composite nuclear export signal in the TBP-associated factor TAFII105. J. Biol. Chem. 276:44963-44969.
145.Koffa, M. D., Clements, J. B., Izaurralde, E., Wadd, S., Wilson, S. A., Mattaj, I. W., Kuersten, S. (2001) Herpes simplex virus ICP27 protein provides viral mRNA with access to the cellular mRNA export pathway. EMBO J. 20: 5769-5778.
146.Lischka, P., Rosorius, O., Trommer, E. and Stamminger. T. (2001) A novel transferable nuclear export signal mediates CRM1-independent nucleocytoplasmic shuttling of the human cytomegalovirus transactivator protein pUL69. EMBO J. 20:7271-7283.
147.Huang, W. H., Yung, B. Y. M., Syu, W. J. and Wu-Lee. Y. H. (2001) The Nucleolar Phosphoprotein B23 Interacts with Hepatitis Delta Antigens and Modulates the Hepatitis Delta Virus RNA Replication. J. Biol. Chem. 276:25166-25175.
148.Dingle, K., Bichko, V., Zuccola, H., Hogle, J. and Taylor. J. (1998) Initiation of hepatitis delta virus genome replication. J. Virol. 72:4783-4788.
149.Tavanez, J. P., Cunha, C., Silva, M. C. A., David, E., Monjardino, J. and M. Carmo-Fonseca. (2002) Hepatitis delta virus ribonucleoproteins shuttle between the nucleus and the cytoplasm. RNA 8:637-646.
150.Macnaughton, T. B., and M. M. Lai. 2002. Genomic but not antigenomic hepatitis delta virus RNA is preferentially exported from the nucleus immediately after synthesis and processing. J. Virol. 76:3928-3935.
151.Hoffmann, W., Reichart, B., Ewald, A., Muller, E., Schmitt, I., Stauber, R. H., Lottspeich, F., Jockusch, B. M., Scheer, U., Hauber, J. and Dabauvalle. M. C. (2001) Cofactor requirements for nuclear export of Rev response element (RRE)- and constitutive transport element (CTE)-containing retroviral RNAs: an unexpected role for actin. J. Cell Biol. 152:895-910.