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Journal of Virology, February 2009, p. 1856-1869, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01099-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus BGLF4 Kinase Suppresses the Interferon Regulatory Factor 3 Signaling Pathway{triangledown} ,{dagger}

Jiin-Tarng Wang, Shin-Lian Doong, Shu-Chun Teng, Chung-Pei Lee, Ching-Hwa Tsai, and Mei-Ru Chen*

Graduate Institute and Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan

Received 24 May 2008/ Accepted 25 November 2008

The BGLF4 protein kinase of Epstein-Barr virus (EBV) is a member of the conserved family of herpesvirus protein kinases which, to some extent, have a function similar to that of the cellular cyclin-dependent kinase in regulating multiple cellular and viral substrates. In a yeast two-hybrid screening assay, a splicing variant of interferon (IFN) regulatory factor 3 (IRF3) was found to interact with the BGLF4 protein. This interaction was defined further by coimmunoprecipitation in transfected cells and glutathione S-transferase (GST) pull-down in vitro. Using reporter assays, we show that BGLF4 effectively suppresses the activities of the poly(I:C)-stimulated IFN-β promoter and IRF3-responsive element. Moreover, BGLF4 represses the poly(I:C)-stimulated expression of endogenous IFN-β mRNA and the phosphorylation of STAT1 at Tyr701. In searching for a possible mechanism, BGLF4 was shown not to affect the dimerization, nuclear translocation, or CBP recruitment of IRF3 upon poly(I:C) treatment. Notably, BGLF4 reduces the amount of active IRF3 recruited to the IRF3-responsive element containing the IFN-β promoter region in a chromatin immunoprecipitation assay. BGLF4 phosphorylates GST-IRF3 in vitro, but Ser339-Pro340 phosphorylation-dependent, Pin1-mediated downregulation is not responsible for the repression. Most importantly, we found that three proline-dependent phosphorylation sites at Ser123, Ser173, and Thr180, which cluster in a region between the DNA binding and IRF association domains of IRF3, contribute additively to the BGLF4-mediated repression of IRF3(5D) transactivation activity. IRF3 signaling is activated in reactivated EBV-positive NA cells, and the knockdown of BGLF4 further stimulates IRF3-responsive reporter activity. The data presented here thus suggest a novel mechanism by which herpesviral protein kinases suppress host innate immune responses and facilitate virus replication.

* Corresponding author. Mailing address: R714, No. 1, 1st Sec. Jen-Ai Road, Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Phone: 886-2-23123456, ext. 88298. Fax: 886-2-23915293. E-mail: mrc{at}ntu.edu.tw

{triangledown} Published ahead of print on 3 December 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, February 2009, p. 1856-1869, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01099-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, F.-Z., Roy, D., Gershburg, E., Whitehurst, C. B., Dittmer, D. P., Pagano, J. S. (2009). Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication. J. Virol. 83: 12108-12117 [Abstract] [Full Text]  
  • Feederle, R., Mehl-Lautscham, A. M., Bannert, H., Delecluse, H.-J. (2009). The Epstein-Barr Virus Protein Kinase BGLF4 and the Exonuclease BGLF5 Have Opposite Effects on the Regulation of Viral Protein Production. J. Virol. 83: 10877-10891 [Abstract] [Full Text]  


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