DOI QR코드

DOI QR Code

Gene Expression Profiles of HeLa Cells Impacted by Hepatitis C Virus Non-structural Protein NS4B

  • Zheng, Yi (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Ye, Lin-Bai (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Liu, Jing (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Jing, Wei (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Timani, Khalid A. (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Yang, Xiao-Jun (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Yang, Fan (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Wang, Wei (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Gao, Bo (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University) ;
  • Wu, Zhen-Hui (Key Laboratory of Virology, Ministry of Education, College of Life Sciences, Wuhan University)
  • Published : 2005.03.31

Abstract

By a cDNA array representing 2308 signal transduction related genes, we studied the expression profiles of HeLa cells stably transfected by Hepatitis C virus nonstructural protein 4B (HCV-NS4B). The alterations of the expression of four genes were confirmed by real-time quantitative RT-PCR; and the aldo-keto reductase family 1, member C1 (AKR1C1) enzyme activity was detected in HCV-NS4B transiently transfected HeLa cells and Huh-7, a human hepatoma cell line. Of the 2,308 genes we examined, 34 were up-regulated and 56 were down-regulated. These 90 genes involved oncogenes, tumor suppressors, cell receptors, complements, adhesions, transcription and translation, cytoskeletion and cellular stress. The expression profiling suggested that multiple regulatory pathways were affected by HCV-NS4B directly or indirectly. And since these genes are related to carcinogenesis, host defense system and cell homeostatic mechanism, we can conclude that HCV-NS4B could play some important roles in the pathogenesis mechanism of HCV.

Keywords

References

  1. Bartenschlager, R. and Lohmann, V. (2000) Replication of hepatitis C virus. J. Gen. Virol. 81, 1631-1648
  2. Bigger, C. B., Brasky, K. M. and Lanford, R. E. (2001) DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection . J. Virol. 75, 7059-7066 https://doi.org/10.1128/JVI.75.15.7059-7066.2001
  3. Chisari, F. V. (1997) Cytotoxic T cells and viral hepatitis . J. Clin. Investig. 99, 1472-1477 https://doi.org/10.1172/JCI119308
  4. Dekisi, J. L., Lyer, V. R. and Brown, P. O. (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 273, 680-686
  5. Dekisi, J. L., Penland, L., Brown, P. O., Bittner, M. L., Meltzer, P. S., Ray, M. C. Y., Su, Y. A. and Trent, J. M. (1996) Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat. genet. 14, 457-460 https://doi.org/10.1038/ng1296-457
  6. Egger, D., Walk, B., Gosert, R., Bianchi, L., Blum, H. E., Moradpour, D. and Bienz, K. (2002) Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J. Virol. 76, 5974-5984 https://doi.org/10.1128/JVI.76.12.5974-5984.2002
  7. Farci, P., Shimoda, A., Coiana, A., Diaz, G., Peddis, G., Melpolder, J. C., Strazzera, A., Chien D. Y., Munoz, S. J., Balestrieri, A., Purcell, R. H. and Alter, H. J. (2000) The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 288, 399-342 https://doi.org/10.1126/science.288.5464.339
  8. Ferrari, E., Wright-Minogue, J., Fang, J. W. S., Baroudy, B. M., Lau, J. Y. N. and Hong, Z. (1999) Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expression in Escherichia coli. J. Virol. 73, 1649-1654
  9. Florese, R. H., Motoko, N. F., Iwanaga, Y., Hidajat, R. and Hotta, H. (2002) Inhibition of protein synthesis by nonstructural proteins NS3, NS4A and NS4B. Virus Res. 90, 119-131 https://doi.org/10.1016/S0168-1702(02)00146-6
  10. Gass J. N., Gifford, N. M. and Brewer J. W. (2002) Activation of an unfold protein response during differentiation of antibodysecreting B cells. J. Biol. Chem. 277, 49047-49054 https://doi.org/10.1074/jbc.M205011200
  11. Gordon, S. C., Bayati, N. and Silverman, A. L. (1998) Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology 28, 562-567 https://doi.org/10.1002/hep.510280238
  12. Grakoui, A., Wychowshi, 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
  13. Guiditti, L. G., Rochford, R. Chung, J., Shapri, M., Purcell, R. and Chisari, F. V. (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science. 284, 825- 829 https://doi.org/10.1126/science.284.5415.825
  14. Hahm, B., Han, D. S., Back, S. H., Song, O. K, Cho, M. J., Shimotone, K. and Jang, S. K. (1995) NS3-4A of hepatitis C virus is a chymotrypsin-like protease. J. Virol. 69, 2534-2539
  15. Hsu, E. C., Hsi, B., Masami, T. H., Jurgen, R., Cathy, I., Farida, S., Diao, J. Y., Giovanni, M., Lorne, T. D., Norman, K. and Richardson, C. D. (2003) Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers. Nature Biotechnol. 21, 19-525 https://doi.org/10.1038/nbt0103-19
  16. Hwang, S. B., Park, K. J., Kim, Y. S., Sung, Y. S. and Lai, M. M. C. (1997) Hepatitis C virus NS5B protein is a membraneassociated phosphoprotein with a predominantly perinuclear localization. Virology 227, 439-446 https://doi.org/10.1006/viro.1996.8357
  17. Imasato, A., Desbois-Mouthon, C. Han, J., Kai, H., Cato, A. C., Akira, S. and Li, J. D. (2002) Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor2. J. Biol. Chem. 277, 47444- 47450 https://doi.org/10.1074/jbc.M208140200
  18. Iversen, N., Lindahl, A. K. and Abildgaard, U. (1998) Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation. British J. Haematol. 102, 889-895 https://doi.org/10.1046/j.1365-2141.1998.00875.x
  19. Jordan R., Nikolaeva, O., Wang L., Conyers B., Mehta A., Dwek R. A. and Block T. M. (2002) Inhibition of host ER glucosidase activity prevents Golgi processing of virionassociated bovine viral diarrhea virus E2 glycoprotein and reduces infectivity of secreted virions. Virology 295, 10-19 https://doi.org/10.1006/viro.2002.1370
  20. Kato, J., Kato, N. Y., Yoshida, H., Nita, S. K. O., Shiratori, Y. and Omata, M. (2002) Hepatitis C virus NS4A and NS4B proteins suppress translation in vivo. J. Med. Virol. 66, 187-199 https://doi.org/10.1002/jmv.2129
  21. Kaufman, R. J. (1999) Stress signaling from lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211-1233 https://doi.org/10.1101/gad.13.10.1211
  22. Keskinen, P., Melen, K. and Julkunan I. (2002) Expression of HCV structural protein impairs IFN-mediated antiviral response. Virology 299, 164-171 https://doi.org/10.1006/viro.2002.1527
  23. Kittlesen D. J. F., Chianese-Bullock, K. A. F., Yao, Z. Q. F., Braciale, T. J. F. and Hahn, Y. S. (2000) Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation. J. Clin. Invest. 106, 1239- 1249 https://doi.org/10.1172/JCI10323
  24. Koch, J. O. and Bartenschlager, R. (1999) Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A and NS4B. J. Virol. 73, 7138-7146
  25. Laar, T. V., Van der, E. A. J. and Terleth, C. (2002) A role for Rad 23 proteins in 26S proteasome-dependent protein degradation. Mutat. Res. 499, 53-61 https://doi.org/10.1016/S0027-5107(01)00291-3
  26. Li, M., Zhou, J. Y., Ge, Y., Matherly, L. H. and Wu, G. S. (2003) The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. J. Biol. Chem. 278, 41059- 41068 https://doi.org/10.1074/jbc.M307149200
  27. Liu, C. and Rice, C. M. (1995) Hepatitis C virus NS3 serine proteinase and NS4A cofactor: establishment of a cell-free trans-processing assay. Proc. Natl. Acad. Sci. USA 92, 7622-7626 https://doi.org/10.1073/pnas.92.17.7622
  28. Lohmann, V., Korner, F., Herian, V. and Bartenschlager, R. (1997) Biochemical properties of hepatitis C virus NS5B RNAdependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. J. Virol. 71, 8416-8428
  29. Ma, Y. and Hendershot, L. M. (2001) The unfolding tale of the unfolded protein response. Cell 107, 827-830 https://doi.org/10.1016/S0092-8674(01)00623-7
  30. Maio M., Coral, S., Fratta, E., Altomonte, M. and Sigalotti, L. (2003) Epigenetic targets for immune intervention in human malignancies. Oncogene 22, 6484-6488 https://doi.org/10.1038/sj.onc.1206956
  31. National Institutes of Health Consensus Development Conference Panel Statement: Management of Hepatitis C. (1997) Hepatology 26, 2S-10S https://doi.org/10.1002/hep.510260701
  32. OConnor, T., Ireland, L. S., Harrison, D. J. and Hayes, J. D. (1999) Major differences in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase (AFAR) and the principal human aldo-keto reductase AKR1 family members. Biochem. J. 343, 487-504 https://doi.org/10.1042/0264-6021:3430487
  33. Okabe, H., Satoh, S., Kato, T., Kitahara, O., Yanagawa, R., Yamaoka, Y., Tsunoda, T., Furakawa, Y. and Nakamura, Y. (2001) Genome-wide analysis of gene expression in human hepatocellular carcinoma using cDNA microarray: Identificationof genes involved in viral carcinogenesis and tumor progression. Cancer Res. 61, 2129-2137
  34. Park, J. S., Yang, J. M. and Min, M. K. (2000) Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. Biochem. Biophys. Res. Commun. 267, 581-587 https://doi.org/10.1006/bbrc.1999.1999
  35. Piccininni, S., Varaklioti, A., Nardelli, M., Dave, B., Raney, K. D. and McCarthy, J. E. (2002) Modulation of the hepatitis C virus RNA-dependant RNA polymerase activity by the non-structural (NS3) helicase and the NS4B membrane protein. J. Biol. Chem. 227, 45670-45679 https://doi.org/10.1074/jbc.M204124200
  36. Pietu, G., Alibert, O., Guichard, V., Lamy, B., Bois, F., Leroy, E., Mariage-Sampson, R., Soularue, P. and Auffray, C. (1996) Novel gene transcripts preferentially expressed in human mucles revealed by quantitative hybridization of a high density cDNA array. Genome Res. 6, 492-503 https://doi.org/10.1101/gr.6.6.492
  37. Ray, R. B., Meyer, K., Steele, R. 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
  38. Ray, R. B., Lagging, L. M., Meger, K., Steele, R. and Ray, R. (1995) Transcriptional regulation of cellular and viral promoters by the hepatitis C virus core protein. Virol. Res. 37, 209-220
  39. 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 tumorigenetic phenotype. J. Virol. 70, 4438-4443
  40. Rosenberg, S. (2001) Recent advances in the molecular biology of hepatitis C virus. J. Mol. Biol. 313, 451-464 https://doi.org/10.1006/jmbi.2001.5055
  41. Sakamuro, D., Furukawa T. and Takegami T. (1995) Hepatitis C virus non-structural protein NS3 transform NIH3T3 cells. J. Virol. 69, 3893-3896
  42. Steel, L. F., Mattu, T. S., Mehta, A., Hebestreit, H., Dwek, R., Evans, A. A., London, W. T. and Block, T. (2001) A proteomic approach for the discovery of early detection markers of hepatocellular carcinoma. Dis. Marker. 17, 179-189 https://doi.org/10.1155/2001/963023
  43. Suzich, J. A., Taura, J., Palmer-Hill, F., Warrenger, P., Grakoui, A., Rice, C. M., Feinstone, S. M. and Collett, M. S. (1993) Hepatitis C virus NS3 protein plynucleotide-stimulated nucleoside triphosphatase and comparison with the telated Pestivirus and Flavivirus enzymes. J. Virol. 67, 6152-6158
  44. Tai, D., Tsai, S., Chen, Y., Chuang, Y., Peng, C., Yeh, C., Chang, K. S. S., Huang, S., Kuo, G. C. and Liaw, Y. F. (2000) Activation of nuclear factor kB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology 31, 656-664 https://doi.org/10.1002/hep.510310316
  45. Tan, S. L., Nakao, H., He, Y., Vijaysri, S., Neddermann, P., Jacobs, B. L., Mayer, B. J. and Kaze, M. G. (1999) NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptor-bound protein 2 adaptor protein in Src homology 3 domain/ligand-dependent manner and perturbs mitogenic signaling. Proc. Natl. Acad. Sci. USA 96, 5533-5538 https://doi.org/10.1073/pnas.96.10.5533
  46. Tardif, K. D., Mori, K., Kaufman, R. and Siddiqui, A. (2004) Hepatitis C virus suppresses the IRE1-XBP1 pathway of the unfolded protein response. J. Biol. Chem. 279, 17158-17164 https://doi.org/10.1074/jbc.M312144200
  47. World Health Organization. (1999) Global surveillance and control of hepatitis C. J. Viral. Hepat. 6, 35-47 https://doi.org/10.1046/j.1365-2893.1999.6120139.x

Cited by

  1. Immunochemical identification and partial characterization of a native hepatitis C viral non-structural 4 antigen in sera of HCV infected patients vol.388, pp.1-2, 2008, https://doi.org/10.1016/j.cca.2007.10.019
  2. Hepatitis C virus—biology, host evasion strategies, and promising new therapies on the horizon vol.27, pp.3, 2007, https://doi.org/10.1002/med.20063
  3. Clinical evaluation of a colorimetric oligonucleotide chip for genotyping hepatitis C virus vol.43, pp.1-2, 2010, https://doi.org/10.1016/j.clinbiochem.2009.09.013
  4. Interaction networks of hepatitis C virus NS4B: implications for antiviral therapy vol.14, pp.7, 2012, https://doi.org/10.1111/j.1462-5822.2012.01773.x