An Interferon Resistance Induced by the Interaction between HCV NS5B and Host p48

C형 간염 바이러스 NS5B 단백질과 숙주의 p48 단백질의 상호작용에 의한 인터페론 저항성의 유도

  • Park, So-Yeon (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies) ;
  • Lee, Jong-Ho (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies) ;
  • Myung, Hee-Joon (Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies)
  • 박소연 (한국외국어대학교 생명공학과) ;
  • 이종호 (한국외국어대학교 생명공학과) ;
  • 명희준 (한국외국어대학교 생명공학과)
  • Published : 2008.12.28

Abstract

Hepatitis C virus (HCV) is known as the causative agent of blood transmitted hepatitis. Two viral proteins, E2 and NS5A, are known to exert interferon resistance of HCV via PKR pathway. Here, we report a third protein, the RNA-dependent RNA polymerase (NS5B) of HCV, induced interferon resistance inhibiting p56 pathway. p56 was shown to interact with p48 subunit of eukaryotic initiation factor 3 (eIF3). This interaction inhibited formation of ternary complex in translation initiation. Using dual reporter assay system, we observed that the translation decreased when interferon alpha was added to the culture. But, in the presence of HCV NS5B, the translation partly recovered. NS5B and p48 subunit of eIF3 were shown to interact. This interaction seems to inhibit the interaction between p48 and p56. This is the first report that a virus exerts interferon resistance via p56 pathway.

Keywords

References

  1. Al, R. H., Y. Xie, Y. Wang, and C. Hagedon. 1998. Expression of recombinant hepatitis C virus non-structural protein 5B in Escherichia coli. Virus Res. 53, 141-149 https://doi.org/10.1016/S0168-1702(97)00147-0
  2. Ali, N. and A. Siddiqui. 1997. Interaction of polypyrimidine tract binding protein with the 5' noncoding region of the hepatitis C virus RNA genome and its functional requirement in internal initiation. J. Virol. 69, 6367-6375
  3. Ali, N. and A. Siddiqui. 1995. Interaction of polypyrimidine binding protein with the 5' noncoding region of the HCV RNA genome and its functional requirement in internal initiation of translation. J. Virol. 69, 6367-6375
  4. Bartenschlager, R., L. Ahlborn-Laake, J. Mous, and H. Jacobsen. 1994. Kinetic and structural analyses of hepatitis C virus polyprotein processing. J. Virol. 68, 5045-5055
  5. Bartenschlager, R. and P. Friebe. 2002. Genetic analysis of sequences in the 3' nontranslated region of hepatitis C virus that are important for RNA replication. J. Virol. 76, 5326-2338 https://doi.org/10.1128/JVI.76.11.5326-5338.2002
  6. Bartenschlager, R., V. Lohmann, F. Korner, J. Koch, U. Herian, and L. Theilmann. 1999. Replication of subgenomic Hepatitis C virus RNAs in a Hepatoma cell line. Science 285, 110-113 https://doi.org/10.1126/science.285.5424.110
  7. Bartenschlager, R. and V. Lohmann. 2000. Replication of hepatitis C virus. J. Gen. Virol. 81, 1631-1648 https://doi.org/10.1099/0022-1317-81-7-1631
  8. Behrens, S. E., L. Tomei, and R. De Francesco. 1996. Identification and properties of the RNA dependent RNA polymerase of hepatitis C virus. EMBO J. 15, 12-22
  9. Cheng, J. U., M. Chang, and S. Chang. 1999. Specific interaction between the hepatitis C virus NS5B RNA polymerase and the 3' end of the viral RNA. J. Virol. 73, 7044-7049
  10. Collier, A. J., J. Gallego, R. Klinck, P. Cole, S. Harris, G. Harrison, F. Aboul-ela, G. Varani,, and S. Walke. 2002. A conserved RNA structure within the HCV IRES eIF3 binding site. Nature Struct. Biol. 9, 375-380
  11. Cohen, J. 1999. The scientific challenge of hepatitis C. Science 285, 26-30 https://doi.org/10.1126/science.285.5424.26
  12. Davis, G. L. 1999. Combination treatment with interferon and ribivirin for chronic hepatitis C. Clin. Liver Dis. 3, 811-826 https://doi.org/10.1016/S1089-3261(05)70240-3
  13. Ferrari, E., M. Wright, J. Fang, B. Baroundy, J. Lau, and Z. Hong. 1999. Characterization of soluble hepatitis C virus RNA dependent RNA polymerase expressed in Escherichia coli. J. Virol. 73, 1649-1654
  14. Gale, M., Jr and R. Blakely. 1998. Control of PKR protein kinase by hepatitis C virus nonstructural 5A protien : molecular mechanisms of kinase regulation. Mol. Cell. Biol. 18, 5208-5218 https://doi.org/10.1128/MCB.18.9.5208
  15. Guo, J., D. Hui, W. Merick, and G. Sen. 2000 . A new pathway of translational regulation mediated by eukaryotic initiation factor 3. The EMBO J. 19, 6891-6899 https://doi.org/10.1093/emboj/19.24.6891
  16. Hellen, C. U. T., T. Pestova, V. Kolupaeva, I. Lomakin, E. Pilipenko, I. Shatsky, and V. Agol. 2001. Molecular mechanisms of translation initiation in eukaryotes. Proc. Natl. Acad. Sci. USA 98, 7029-7036
  17. Hong, Z., J. Shim, G. Larson, and J. Wo. 2002. Selection of 3' template bases and initiating nucleotides by hepatitis C virus NS5B RNA dependent RNA polymerase. J. Virol. 76, 7030-7039 https://doi.org/10.1128/JVI.76.14.7030-7039.2002
  18. Hui, D., C. Bhasker, W. Merrick, and G. Sen. 2003. Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2. GTP.Met-tRNA. J. Biol. Chem. 278, 39477-39482 https://doi.org/10.1074/jbc.M305038200
  19. Lohmann, V. and F. Korner. (1999). Replication of subgenomic hepatitis c virus RNAs in a hepatoma cell line. Science. 285, 110-113 https://doi.org/10.1126/science.285.5424.110
  20. Poynard, T, J. McHutchison, M. Manns, C. Trepo, K. Lindsay, Z. Goodman, and M. Ling. 2002. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 122, 1303-1313 https://doi.org/10.1053/gast.2002.33023
  21. Purcell, R. 1994. Hepatitis viruses: Changing patterns of human disease. Proc. Natl. Acad. Sci. USA. 91, 2401-2406
  22. Taylor, D., S. Shi, and M. Lai. 2000. Hepatitis C virus and interferon resistance. Microbes Infect. 1743-1756 https://doi.org/10.1016/S1286-4579(00)01329-0
  23. Witherell, G. W., A. Knap, and C. Gluchowski. 1999. Hepatitis c virus non-structural 5A protein as a therapeutic target. Curr. Opin. Anti-infect. Invesig. Drugs. 1, 565-573
  24. Zhu, H., H. Zhao, C. Collins, S. Eckenrode, and C. Liu. 2003. Gene expression associated with interferon alfa antiviral activity in an HCV replicon cell line. Hepatology 37, 1180-2003 https://doi.org/10.1053/jhep.2003.50184