BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Suppression of Ceramide-induced Cell Death by Hepatitis C Virus Core Protein

  • Kim, Jung-Su (Department of Genetic Engineering, Division of Life Sciences, Hallym University) ;
  • Ryu, Ji-Yoon (Department of Genetic Engineering, Division of Life Sciences, Hallym University) ;
  • Hwang, Soon-Bong (Ilsong Institute of Life Science, Hallym University) ;
  • Lee, Soo-Young (Division of Molecular Life Science and Center for Cell Signaling, Ewha Womans University) ;
  • Choi, Soo-Young (Department of Genetic Engineering, Division of Life Sciences, Hallym University) ;
  • Park, Jin-Seu (Department of Genetic Engineering, Division of Life Sciences, Hallym University)
  • Published : 2004.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

The hepatitis C virus (HCV) core protein is believed to be one of viral proteins that are capable of preventing virus-infected cell death upon various stimuli. But, the effect of the HCV core protein on apoptosis that is induced by various stimuli is contradictory. We examined the possibility that the HCV core protein affects the ceramide-induced cell death in cells expressing the HCV core protein through the sphingomyelin pathway. Cell death that is induced by $C^2$-ceramide and bacterial sphingomyelinase was analyzed in 293 cells that constitutively expressed the HCV core protein and compared with 293 cells that were stably transfected only with the expression vector. The HCV core protein inhibited the cell death that was induced by these reagents. The protective effects of the HCV core protein on ceramide-induced cell death were reflected by the reduced expression of $p21^{WAF1/Cip1/Sid1}$ and the sustained expression of the Bcl-2 protein in the HCV core-expressing cells with respect to the vector-transfected cells. These results suggest that the HCV core protein in 293 cells plays a role in the modulation of the apoptotic response that is induced by ceramide. Also, the ability of the HCV core protein to suppress apoptosis might have important implications in understanding the pathogenesis of the HCV infection.

Keywords

References

  1. Aach, R. D., Stevens, C. E., Hollinger, F. B., Mosley, J. W., Peterson, D. A., Taylor, P. E., Johnson, R. G., Barbosa, L. H. and Nemo, G. J. (1991) Hepatitis C virus infection in posttransfusion hepatitis. An analysis with first- and secondgeneration assays. New Engl. J. Med. 325, 1325-1329. https://doi.org/10.1056/NEJM199111073251901
  2. Bradford, M. A. (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254. https://doi.org/10.1016/0003-2697(76)90527-3
  3. Chang, J., Yang, S. H., Cho, Y. G., Hwang, S. B., Hahn, Y. S. and Sung, Y. C. (1998) Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in cooperation with the H-ras oncogene. J. Virol. 72, 3060-3065.
  4. Cho, Y. -G., Yoon, J. -W., Jang, K. -L., Kim, C. -M. and Sung, Y.-C. (1993) Full genome cloning and nucleotide sequence analysis of hepatitis C virus from sera of chronic hepatitis patients in Korea. Mol. Cells 3, 195-202.
  5. Choo, Q. -L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W. and Houghton, M. (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244, 359-362. https://doi.org/10.1126/science.2523562
  6. Chung, Y. M., Park, K. J., Choi, S. Y., Hwang, S. B. and Lee, S. Y. (2001) Hepatitis C virus core protein potentiates TNF-alphainduced NF-kappaB activation through TRAF2-IKKbetadependent pathway. Biochem. Biophys. Res. Commun. 284, 15-19. https://doi.org/10.1006/bbrc.2001.4936
  7. Di-Bisceglie, A. M., Simpson, L. H., Lotze, M. T. and Hoofnagle, J. H. (1994) Development of hepatocellular carcinoma among patients with chronic liver disease due to hepatitis C viral infection. J. Clin. Gastroenterol. 19, 222-226. https://doi.org/10.1097/00004836-199410000-00011
  8. Grakoui, A., Wychowski, C., Lin, C., Feinstone, S. M. and Rice, C. M. (1993) Expression and identification of hepatitis C virus polyprotein cleavage products. J. Virol. 67, 1385-1395.
  9. Hannun, Y. A. (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274, 1855-1859. https://doi.org/10.1126/science.274.5294.1855
  10. Hijikata, M., Kato, N., Ootsuyama, Y., Nakagawa, M. and Shimotohno, K. (1991) Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc. Natl. Acad. Sci. USA 88, 5547-5551. https://doi.org/10.1073/pnas.88.13.5547
  11. Honda, M., Kaneko, S., Shimazaki, T., Matsushita, E., Kobayashi, K., Ping, L. -H., Zhang, H. -C. and Lemon, S. M. (2000) Hepatitis C virus core protein induces apoptosis and impairs cell-cycle regulation in stably transformed Chinese hamster ovary cells. Hepatology 31, 1351-1359. https://doi.org/10.1053/jhep.2000.7985
  12. Inchauspe, G., Zebedee, S., Lee, D. -H., Sugitani, M., Nasoff, M. and Prince, A. M. (1991) Genomic structure of the human prototype strain H of hepatitis C virus: Comparison with American and Japanese isolates. Proc. Natl. Acad. Sci. USA 88, 10292-10296. https://doi.org/10.1073/pnas.88.22.10292
  13. Kato, N., Hijikata, M., Ootsuyama, Y., Nakagawa, M., Ohkoshi, S., Sugimura, T. and Shimotohno, K. (1990) Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc. Natl. Acad. Sci. USA 87, 9524-9528. https://doi.org/10.1073/pnas.87.24.9524
  14. Kolesnick, R. N. and Kronke, M. (1998) Regulation of ceramide production and apoptosis. Annu. Rev. Physiol. 60, 643-665. https://doi.org/10.1146/annurev.physiol.60.1.643
  15. Kim, C. -H., Park, Y. -S., Chung, K. -N. and Elwood, P. C. (2002) Sorting and function of the human foliate receptor is independent of the caveolin expression in fisher rat thyroid epithelial cells. J. Biochem. Mol. Biol. 35, 395-402. https://doi.org/10.5483/BMBRep.2002.35.4.395
  16. Kim, S. Y., Kim, R. H., Huh, T. -L. and Park, J. -W. (2001) $\alpha$- Phenyl-N-t-butylnitrone protects oxidative damage to HepG2 cells. J. Biochem. Mol. Biol. 34, 43-46.
  17. Kim, W. H., Kang, K. H., Kim, M. Y. and Choi K. H. (2000) Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. Biochem. Cell. Biol. 78, 127-135. https://doi.org/10.1139/bcb-78-2-127
  18. Lee, S. W., Han, S. I., Kim, H. H. and Lee, Z. H. (2002) TAK1- dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-$\kappa$B. J. Biochem. Mol. Biol. 35, 371-376. https://doi.org/10.5483/BMBRep.2002.35.4.371
  19. Lin, C., Lindenbach, B. D., Pragai, B. M., McCourt, D. W. and Rice, C. M. (1994) Processing in the hepatitis C virus E2-NS2 region: identification of p7 and two distinct E2-specific products with different C termini. J. Virol. 68, 5063-5073.
  20. Lo, S. -Y., Masiarz, F., Hwang, S. B., Lai, M. M. C. and Ou, J.-H. (1995) Differential subcellular localization of hepatitis C virus core gene products. Virology 213, 455-461. https://doi.org/10.1006/viro.1995.0018
  21. Manabe, S., Fuke, I., Tanishita, O., Kaji, C., Gomi, Y., Yoshida, S., Mori, C., Takamizawa, A., Yoshida, I. and Okayama, H. (1994) Production of nonstructural proteins of hepatitis C virus requires a putative viral protease encoded by NS3. Virology 198, 636-644. https://doi.org/10.1006/viro.1994.1075
  22. Marusawa, H., Hijikata, M., Chiba, T. and Shimotohno, K. (1999) Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF-kappaB activation. J. Virol. 73, 4713-4720.
  23. Matsumoto, M., Hsieh, T. -Y., Zhu, N., VanArsdale, T., Hwang, S. B., Jeng, K. -S., Gorbalenya, A. E., Lo, S. -Y., Ou, J. -H., Ware, C. F. and Lai, M. M. C. (1997) Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-beta receptor. J. Virol. 71, 1301-1309.
  24. Oh, W. J., Kim, W. H., Kang, K. H., Kim, T. Y., Kim, M. Y. and Choi, K. H. (1998) Induction of p21 during ceramide-mediated apoptosis in human hepatocarcinoma cells. Cancer Lett. 129, 215-222. https://doi.org/10.1016/S0304-3835(98)00105-0
  25. Park, K. J., Choi, S. H., Koh, M. S. Kim, S. W. and Hwang, S. B. (2000) Identification of a cellular protein interacting with RNA polymerase of hepatitis C virus. J. Biochem. Mol. Biol. 30, 59-62.
  26. Park, K. J., Choi, S. H., Koh, M. S., Kim, D. J., Yie, S. W., Lee, S. Y. and Hwang, S. B. (2001) Hepatitis C virus core protein potentiates c-Jun N-terminal kinase activation through a signaling complex involving TRADD and TRAF2. Virus Res. 74, 89-98. https://doi.org/10.1016/S0168-1702(00)00251-3
  27. Ray, R. B., Lagging, L. M., Meyer, K. and Ray, R. (1996) Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J. Virol .70, 4438-4443.
  28. Ray, R. B., Lagging, L. M., Meyer, K., Steele, R. and Ray, R. (1995) Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein. Virus Res. 37, 209-220. https://doi.org/10.1016/0168-1702(95)00034-N
  29. Ray, R. B., Meyer, K. and Ray, R. (1996) Suppression of apoptotic cell death by hepatitis C virus core protein. Virology 226, 176-182. https://doi.org/10.1006/viro.1996.0644
  30. Ray, R. B., Meyer, K., Steele, R., Shrivastava, A., Aggarwal, B. B. and Ray, R. (1998) Inhibition of tumor necrosis factor (TNFalpha)-mediated apoptosis by hepatitis C virus core protein. J. Biol. Chem. 273, 2256-2259. https://doi.org/10.1074/jbc.273.4.2256
  31. Ray, R. B., Steele, R., Meyer, K. and Ray, R. (1997) Transcriptional repression of p53 promoter by hepatitis C virus core protein. J. Biol. Chem. 272, 10983-10986. https://doi.org/10.1074/jbc.272.17.10983
  32. Ray, R. B., Steele, R., Meyer, K. and Ray, R. (1998) Hepatitis C virus core protein represses p21WAF1/Cip1/Sid1 promoter activity. Gene 208, 331-336. https://doi.org/10.1016/S0378-1119(98)00030-4
  33. Ray, R. B. and Ray, R. (2001) Hepatitis C virus core protein: intriguing properties and functional relevance. FEMS Microbiol. Lett. 202, 149-156. https://doi.org/10.1111/j.1574-6968.2001.tb10796.x
  34. Saito, I., Miyamura, T., Ohbayashi, A., Harada, H., Katayama, T., Kikuchi, S., Watanabe, Y., Koi, S., Orji, M., Ohta, Y., Choo, Q. -L., Houghton, M. and Kuo, G. (1990) Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 87, 6547-6549. https://doi.org/10.1073/pnas.87.17.6547
  35. Shim, M. J., Kim, H. J., Yang, S. J., Lee, I. S., Choi, H. I. and Kim, T. U. (2002) Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. J. Biochem. Mol. Biol. 35, 377-383. https://doi.org/10.5483/BMBRep.2002.35.4.377
  36. Shimotohno, K. (1995) Hepatitis C virus as a causative agent of hepatocellular carcinoma. Intervirology 38, 162-169.
  37. Teodoro, J. G. and Branton, P. E. (1997) Regulation of apoptosis by viral gene products. J. Virol. 71, 1739-1746.
  38. Zhu, N., Khoshnan, A., Schneider, R., Matsumoto, M., Dennert, G., Ware, C. and Lai, M. M. C. (1998) Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J. Virol. 72, 3691-3697.

Cited by

  1. Subversion of innate host antiviral strategies by the hepatitis C virus vol.462, pp.2, 2007, https://doi.org/10.1016/j.abb.2007.03.033
  2. Hepatitis C Virus and Hepatocellular Carcinoma vol.2, pp.1, 2013, https://doi.org/10.3390/biology2010304
  3. Expression of Ki-67, transforming growth factor beta1, and B-cell lymphoma-leukemia-2 in liver tissue of patients with chronic liver diseases vol.21, pp.4, 2006, https://doi.org/10.1111/j.1440-1746.2006.04149.x