1887

Abstract

Previous studies have suggested that hepatitis B virus (HBV) blocks expression of the alpha interferon (IFN-)-inducible myeloid differential primary response protein (MyD88) gene. To study the molecular mechanism(s) of the inhibition of MyD88 expression by HBV, MyD88 promoter reporter plasmids and vectors expressing different HBV viral proteins were constructed. Co-transfection experiments showed that IFN-induced MyD88 promoter activity was inhibited by HBV polymerase expression in a dose-dependent manner and that the terminal protein (TP) domain of HBV polymerase was responsible for this antagonistic activity. Analysis of site mutants showed that the region targeted by the polymerase protein contained the signal transducer and activator of transcription (Stat) binding site. Chromatin immunoprecipitation analysis showed that the IFN-induced DNA-binding activity of Stat1 was affected. Further study demonstrated that the HBV polymerase protein inhibited the Stat1 nuclear translocation induced by IFN-, but did not induce Stat1 degradation nor interfere with its phosphorylation. In addition, HBV polymerase could inhibit the transcriptional activity of other IFN-stimulated response element-driven promoters and the expression of interferon-stimulated genes (ISGs), such as Stat1 and ISG15. In summary, these results indicate that HBV polymerase is a general inhibitor of IFN signalling and can inhibit IFN-inducible MyD88 expression by inhibiting the activity of the MyD88 promoter through blocking the nuclear translocation of Stat1.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.82959-0
2007-12-01
2024-04-10
Loading full text...

Full text loading...

/deliver/fulltext/jgv/88/12/3260.html?itemId=/content/journal/jgv/10.1099/vir.0.82959-0&mimeType=html&fmt=ahah

References

  1. Bonnert T. P., Garka K. E., Parnet P., Sonoda G., Testa J. R., Sims J. E. 1997; The cloning and characterization of human MyD88: a member of an IL-1 receptor related family. FEBS Lett 402:81–84 [CrossRef]
    [Google Scholar]
  2. Brzozka K., Finke S., Conzelmann K. K. 2006; Inhibition of interferon signaling by rabies virus phosphoprotein P: activation-dependent binding of STAT1 and STAT2. J Virol 80:2675–2683 [CrossRef]
    [Google Scholar]
  3. Cao F., Tavis J. E. 2004; Detection and characterization of cytoplasmic hepatitis B virus reverse transcriptase. J Gen Virol 85:3353–3360 [CrossRef]
    [Google Scholar]
  4. Cao F., Tavis J. E. 2006; Suppression of mRNA accumulation by the duck hepatitis B virus reverse transcriptase. Virology 350:475–483 [CrossRef]
    [Google Scholar]
  5. Choi J., Chang J. S., Song M. S., Ahn B. Y., Park Y., Lim D. S., Han Y. S. 2003; Association of hepatitis B virus polymerase with promyelocytic leukemia nuclear bodies mediated by the S100 family protein p11. Biochem Biophys Res Commun 305:1049–1056 [CrossRef]
    [Google Scholar]
  6. Christen V., Duong F., Bernsmeier C., Sun D., Nassal M., Heim M. H. 2007; Inhibition of alpha interferon signaling by hepatitis B virus. J Virol 81:159–165 [CrossRef]
    [Google Scholar]
  7. Fernandez M., Quiroga J. A., Carreno V. 2003; Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins. J Gen Virol 84:2073–2082 [CrossRef]
    [Google Scholar]
  8. Foster G. R., Ackrill A. M., Goldin R. D., Kerr I. M., Thomas H. C., Stark G. R. 1991; Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons α and γ and double-stranded RNA. Proc Natl Acad Sci U S A 88:2888–2892 [CrossRef]
    [Google Scholar]
  9. Foster G. R., Ackrill A. M., Goldin R. D., Kerr I. M., Thomas H. C., Stark G. R. 1995; Corrections: expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons α and γ and double-stranded RNA. Proc Natl Acad Sci U S A 92:3632
    [Google Scholar]
  10. Guan R. 2000; Interferon monotherapy in chronic hepatitis B. J Gastroenterol Hepatol 15:Suppl.E34–E40 [CrossRef]
    [Google Scholar]
  11. Harroch S., Gothelf Y., Revel M., Chebath J. 1995; 5′ upstream sequences of MyD88, an IL-6 primary response gene in M1 cells: detection of functional IRF-1 and Stat factors binding sites. Nucleic Acids Res 23:3539–3546 [CrossRef]
    [Google Scholar]
  12. Karayiannis P. 2003; Hepatitis B virus: old, new and future approaches to antiviral treatment. J Antimicrob Chemother 51:761–785 [CrossRef]
    [Google Scholar]
  13. Krastev Z. A. 2006; The “return” of hepatitis B. World J Gastroenterol 12:7081–7086
    [Google Scholar]
  14. Manns M. P. 2002; Current state of interferon therapy in the treatment of chronic hepatitis B. Semin Liver Dis 22 (Suppl. 1):7–13 [CrossRef]
    [Google Scholar]
  15. Munoz-Jordan J. L., Sanchez-Burgos G. G., Laurent-Rolle M., Garcia-Sastre A. 2003; Inhibition of interferon signaling by dengue virus. Proc Natl Acad Sci U S A 100:14333–14338 [CrossRef]
    [Google Scholar]
  16. Oda K., Kitano H. 2006; A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol 2: 2006.0015
    [Google Scholar]
  17. Palosaari H., Parisien J. P., Rodriguez J. J., Ulane C. M., Horvath C. M. 2003; STAT protein interference and suppression of cytokine signal transduction by measles virus V protein. J Virol 77:7635–7644 [CrossRef]
    [Google Scholar]
  18. Rahmouni S., Vang T., Alonso A., Williams S., van Stipdonk M., Soncini C., Moutschen M., Schoenberger S. P., Mustelin T. 2005; Removal of C-terminal SRC kinase from the immune synapse by a new binding protein. Mol Cell Biol 25:2227–2241 [CrossRef]
    [Google Scholar]
  19. Reid S. P., Leung L. W., Hartman A. L., Martinez O., Shaw M. L., Carbonnelle C., Volchkov V. E., Nichol S. T., Basler C. F. 2006; Ebola virus VP24 binds karyopherin α 1 and blocks STAT1 nuclear accumulation. J Virol 80:5156–5167 [CrossRef]
    [Google Scholar]
  20. Rodriguez J. J., Horvath C. M. 2004; Host evasion by emerging paramyxoviruses: Hendra virus and Nipah virus V proteins inhibit interferon signaling. Viral Immunol 17:210–219 [CrossRef]
    [Google Scholar]
  21. Seeger C., Mason W. S. 2000; Hepatitis B virus biology. Microbiol Mol Biol Rev 64:51–68 [CrossRef]
    [Google Scholar]
  22. Shaw M. L., Garcia-Sastre A., Palese P., Basler C. F. 2004; Nipah virus V and W proteins have a common STAT1-binding domain yet inhibit STAT1 activation from the cytoplasmic and nuclear compartments, respectively. J Virol 78:5633–5641 [CrossRef]
    [Google Scholar]
  23. Staeheli P. 1990; Interferon-induced proteins and the antiviral state. Adv Virus Res 38:147–200
    [Google Scholar]
  24. Thomas H., Foster G., Platis D. 2003; Mechanisms of action of interferon and nucleoside analogues. J Hepatol 39 (Suppl. 1):S93–S98
    [Google Scholar]
  25. Xiong W., Wang X., Liu X. Y., Xiang L., Zheng L. J., Liu J. X., Yuan Z. H. 2003; Analysis of gene expression in hepatitis B virus transfected cell line induced by interferon. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai) 35:1053–1060
    [Google Scholar]
  26. Xiong W., Wang X., Liu X., Xiang L., Zheng L., Yuan Z. 2004; Interferon-inducible MyD88 protein inhibits hepatitis B virus replication. Virology 319:306–314 [CrossRef]
    [Google Scholar]
  27. Yao E., Tavis J. E. 2003; Kinetics of synthesis and turnover of the duck hepatitis B virus reverse transcriptase. J Biol Chem 278:1201–1205 [CrossRef]
    [Google Scholar]
  28. Yao E., Gong Y., Chen N., Tavis J. E. 2000; The majority of duck hepatitis B virus reverse transcriptase in cells is nonencapsidated and is bound to a cytoplasmic structure. J Virol 74:8648–8657 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.82959-0
Loading
/content/journal/jgv/10.1099/vir.0.82959-0
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