1887

Abstract

Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-/ribavirin). This study assessed the effect of ISG15 on HCV production . The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN--induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.015388-0
2010-02-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/2/382.html?itemId=/content/journal/jgv/10.1099/vir.0.015388-0&mimeType=html&fmt=ahah

References

  1. Asahina, Y., Izumi, N., Hirayama, I., Tanaka, T., Sato, M., Yasui, Y., Komatsu, N., Umeda, N., Hosokawa, T. & other authors(2008). Potential relevance of cytoplasmic viral sensors and related regulators involving innate immunity in antiviral response. Gastroenterology 134, 1396–1405.[CrossRef] [Google Scholar]
  2. Asselah, T., Bieche, I., Narguet, S., Sabbagh, A., Laurendeau, I., Ripault, M. P., Boyer, N., Martinot-Peignoux, M., Valla, D. & other authors(2008). Liver gene expression signature to predict response to pegylated interferon plus ribavirin combination therapy in patients with chronic hepatitis C. Gut 57, 516–524. [Google Scholar]
  3. Broering, R., Trippler, M., Gerken, G. & Schlaak, J. F.(2008). The interferon stimulated gene 15 is an important proviral factor for the hepatitis C virus. Hepatology 48, 758A [Google Scholar]
  4. Chen, L., Borozan, I., Feld, J., Sun, J., Tannis, L. L., Coltescu, C., Heathcote, J., Edwards, A. M. & McGilvray, I. D.(2005). Hepatic gene expression profiling discriminates responders and non-responders in treatment of chronic hepatitis C viral infection. Gastroenterology 128, 1437–1444.[CrossRef] [Google Scholar]
  5. Chen, L., Sun, J., Meng, X., Edwards, A. M., Heathcote, J. & McGilvray, I. D.(2008). USP18 promotes HCV replication and blunts the antiviral effect of IFNα in a protease-independent fashion. Hepatology 48, 399A[CrossRef] [Google Scholar]
  6. Dao, C. T. & Zhang, D. E.(2005). ISG15: ubiquitin-like enigma. Regulation of ISG15 expression and conjugation. Front Biosci 10, 2701–2722.[CrossRef] [Google Scholar]
  7. D’Cunha, J., Knight, E., Haas, A. L., Truitt, R. L. & Borden, E. C.(1996a). Immunoregulatory properties of ISG15, an interferon-induced cytokine. Proc Natl Acad Sci U S A 93, 211–215.[CrossRef] [Google Scholar]
  8. D’Cunha, J., Ramanujam, S., Wagner, R. J., Witt, P. L., Knight, E. & Borden, E. C.(1996b).In vitro and in vivo secretion of human ISG15. J Immunol 157, 4100–4108. [Google Scholar]
  9. Duex, J. E. & Sorkin, A.(2009). RNA interference screen identifies Usp18 as a regulator of epidermal growth factor receptor synthesis. Mol Biol Cell 20, 1833–1844.[CrossRef] [Google Scholar]
  10. Feld, J. J., Nanda, S., Huang, Y., Chen, W., Cam, M., Pusek, S. N., Schweigler, L. M., Theodore, D., Zacks, S. L. & other authors(2007). Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepatology 46, 1548–1563.[CrossRef] [Google Scholar]
  11. Kim, K. I., Yan, M., Malakhova, O., Luo, J. K., Shen, M. F., Zou, W., de la Torre, J. C. & Zhang, D. E.(2006). Ube1L and protein ISGylation are not essential for alpha/beta interferon signaling. Mol Cell Biol 26, 472–479.[CrossRef] [Google Scholar]
  12. Kim, J. H., Luo, J. K. & Zhang, D. E.(2008a). The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression. J Immunol 181, 6467–6472.[CrossRef] [Google Scholar]
  13. Kim, M. J., Hwang, S. Y., Imaizumi, T. & Yoo, J. Y.(2008b). Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol 82, 1474–1483.[CrossRef] [Google Scholar]
  14. Knobeloch, K. P., Utermöhlen, O., Kisser, A., Prinz, M. & Horak, I.(2005). Reexamination of the role of ubiquitin-like modifier ISG15 in the phenotype of UBP43-deficient mice. Mol Cell Biol 25, 11030–11034.[CrossRef] [Google Scholar]
  15. Lai, C., Struckhoff, J. J., Schneider, J., Martinez-Sobrido, L., Wolff, T., García-Sastre, A., Zhang, D. E. & Lenschow, D. J.(2009). Mice lacking the ISG15 E1 enzyme UbE1L demonstrate increased susceptibility to both mouse-adapted and non-mouse-adapted influenza B virus infection. J Virol 83, 1147–1151.[CrossRef] [Google Scholar]
  16. Lenschow, D. J., Giannakopoulos, N. V., Gunn, L. J., Johnston, C., O'Guin, A. K., Schmidt, R. E., Levine, B. & Virgin, H. W., IV(2005). Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol 79, 13974–13983.[CrossRef] [Google Scholar]
  17. Lenschow, D. J., Lai, C., Frias-Staheli, N., Giannakopoulos, N. V., Lutz, A., Wolff, T., Osiak, A., Levine, B., Schmidt, R. E. & other authors(2007). IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A 104, 1371–1376.[CrossRef] [Google Scholar]
  18. Li, K., Foy, E., Ferreon, J. C., Nakamura, M., Ferreon, A. C., Ikeda, M., Ray, S. C., Gale, M., Jr & Lemon, S. M.(2005). Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A 102, 2992–2997.[CrossRef] [Google Scholar]
  19. Lindenbach, B. D., Evans, M. J., Syder, A. J., Wölk, B., Tellinghuisen, T. L., Liu, C. C., Maruyama, T., Hynes, R. O., Burton, D. R. & other authors(2005). Complete replication of hepatitis C virus in cell culture. Science 309, 623–626.[CrossRef] [Google Scholar]
  20. Loeb, K. R. & Haas, A. L.(1992). The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem 267, 7806–7813. [Google Scholar]
  21. Loo, Y. M., Owen, D. M., Li, K., Erickson, A. K., Johnson, C. L., Fish, P. M., Carney, D. S., Wang, T., Ishida, H. & other authors(2006). Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection. Proc Natl Acad Sci U S A 103, 6001–6006.[CrossRef] [Google Scholar]
  22. Lu, G., Reinert, J. T., Pitha-Rowe, I., Okumura, A., Kellum, M., Knobeloch, K. P., Hassel, B. & Pitha, P. M.(2006). ISG15 enhances the innate antiviral response by inhibition of IRF-3 degradation. Cell Mol Biol (Noisy-le-grand) 52, 29–41. [Google Scholar]
  23. Malakhov, M. P., Malakhova, O. A., Kim, K. I., Ritchie, K. J. & Zhang, D. E.(2002). UBP43 (USP18) specifically removes ISG15 from conjugated proteins. J Biol Chem 277, 9976–9981.[CrossRef] [Google Scholar]
  24. Malakhova, O. A. & Zhang, D. E.(2008). ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J Biol Chem 283, 8783–8787.[CrossRef] [Google Scholar]
  25. Malakhova, O. A., Malakhov, M. P., Hetherington, C. & Zhang, D. E.(2002). Lipopolysaccharide activates the expression of ISG15-specific protease UBP43 via interferon regulatory factor 3. J Biol Chem 277, 14703–14711.[CrossRef] [Google Scholar]
  26. Malakhova, O. A., Yan, M., Malakhov, M. P., Yuan, Y., Ritchie, K. J., Kim, K. I., Peterson, L. F., Shuai, K. & Zhang, D. E.(2003). Protein ISGylation modulates the JAK-STAT signaling pathway. Genes Dev 17, 455–460.[CrossRef] [Google Scholar]
  27. Malakhova, O. A., Kim, K. I., Luo, J. K., Zou, W., Kumar, K. G., Fuchs, S. Y., Shuai, K. & Zhang, D. E.(2006). UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J 25, 2358–2367.[CrossRef] [Google Scholar]
  28. Okumura, A., Lu, G., Pitha-Rowe, I. & Pitha, P. M.(2006). Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15. Proc Natl Acad Sci U S A 103, 1440–1445.[CrossRef] [Google Scholar]
  29. Okumura, A., Pitha, P. M. & Harty, R. N.(2008). ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proc Natl Acad Sci U S A 105, 3974–3979.[CrossRef] [Google Scholar]
  30. Osiak, A., Utermöhlen, O., Niendorf, S., Horak, I. & Knobeloch, K. P.(2005). ISG15, an interferon-stimulated ubiquitin-like protein, is not essential for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus. Mol Cell Biol 25, 6338–6345.[CrossRef] [Google Scholar]
  31. Randall, G., Chen, L., Panis, M., Fischer, A. K., Lindenbach, B. D., Sun, J., Heathcote, J., Rice, C. M., Edwards, A. M. & other authors(2006). Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology 131, 1584–1591.[CrossRef] [Google Scholar]
  32. Recht, M., Borden, E. C. & Knight, E.(1991). A human 15-kDa IFN-induced protein induces the secretion of IFN-γ. J Immunol 147, 2617–2623. [Google Scholar]
  33. Ritchie, K. J., Malakhov, M. P., Hetherington, C. J., Zhou, L., Little, M. T., Malakhova, O. A., Sipe, J. C., Orkin, S. H. & Zhang, D. E.(2002). Dysregulation of protein modification by ISG15 results in brain cell injury. Genes Dev 16, 2207–2212.[CrossRef] [Google Scholar]
  34. Sarasin-Filipowicz, M., Oakeley, E. J., Duong, F. H., Christen, V., Terracciano, L., Filipowicz, W. & Heim, M. H.(2008). Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 105, 7034–7039.[CrossRef] [Google Scholar]
  35. Sumpter, R., Jr, Loo, Y. M., Foy, E., Li, K., Yoneyama, M., Fujita, T., Lemon, S. M. & Gale, M., Jr(2005). Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J Virol 79, 2689–2699.[CrossRef] [Google Scholar]
  36. Yuan, W. & Krug, R. M.(2001). Influenza B virus NS1 protein inhibits conjugation of the interferon-induced ubiquitin-like ISG15 protein. EMBO J 20, 362–371.[CrossRef] [Google Scholar]
  37. Zhang, Y., Burke, C. W., Ryman, K. D. & Klimstra, W. B.(2007). Identification and characterization of interferon-induced proteins that inhibit alphavirus replication. J Virol 81, 11246–11255.[CrossRef] [Google Scholar]
  38. Zhao, C., Denison, C., Huibregtse, J. M., Gygi, S. & Krug, R. M.(2005). Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A 102, 10200–10205.[CrossRef] [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.015388-0
Loading
/content/journal/jgv/10.1099/vir.0.015388-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error