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Journal of Virology, October 2007, p. 10950-10960, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00183-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Binding of Kaposi's Sarcoma-Associated Herpesvirus K-bZIP to Interferon-Responsive Factor 3 Elements Modulates Antiviral Gene Expression{triangledown}

Sylvain Lefort,1 Anton Soucy-Faulkner,2 Nathalie Grandvaux,2 and Louis Flamand1*

Laboratory of Virology, Rheumatology and Immunology Research Center, CHUQ Research Center, and Faculty of Medicine, Laval University, Quebec, Quebec, Canada,1 Department of Biochemistry, Faculty of Medicine, University of Montreal, and CHUM Research Center, St. Luc Hospital, Montreal, Quebec, Canada2

Received 26 January 2007/ Accepted 16 July 2007

Kaposi's sarcoma-associated herpesvirus encodes numerous regulatory proteins capable of modulating viral and cellular gene expression and affecting host cell functions. K-bZIP, a leucine zipper-containing transcription factor encoded by ORFK8, is one such protein. During infection, transcription of the ORFK8 early gene is turned on by the immediate-early replication and transcription factor activator (RTA). One described function of the K-bZIP nuclear protein is to interact with and repress RTA-mediated transactivation of viral promoters, including that of the K8 gene. In the present work, we provide evidence that the expression of K-bZIP results in the activation of the ifn-ß gene. Of interest, ifn-ß gene activation by K-bZIP is independent of interferon (IFN)-responsive factor 3 (IRF-3) and nuclear factor {kappa}B (NF-{kappa}B) activation. Using a DNA binding affinity assay and electromobility shift assay, we report that K-bZIP binds efficiently to the PRDIII-I region of the beta IFN (IFN-ß) promoter, and, in doing so, it prevents the attachment of activated IRF-3 but not that of NF-{kappa}B or ATF2/c-Jun to the IFN-ß promoter sequence. As a consequence, ifn-ß gene activation in response to IFN inducers such as Sendai virus infection or expression of retinoic acid-inducible gene I, mitochondrial antiviral signaling protein, or TANK-binding kinase 1 (TBK-1) is severely impaired (>90%) by the presence of K-bZIP. K-bZIP also prevents the activation of RANTES and CXCL11, whose promoters are also regulated by IRF-3. Lysine 158 (target for SUMO conjugation), threonine 111, and serine 167 (targets for phosphorylation) mutants of K-bZIP were equally effective as wild-type K-bZIP in mediating the repression of TBK-1-activated ifn-ß gene expression. Lastly, the overexpression of CREB binding protein could not reverse the K-bZIP repression of TBK-1-activated ifn-ß gene expression. In all, our results indicate that K-bZIP binds directly to the PRDIII-I region of the IFN-ß promoter and, as a consequence, causes a low level of ifn-ß gene transcription. In doing so, K-bZIP prevents IRF-3 from binding to the IFN-ß promoter and precludes the formation of the enhanceosome, which is required for maximal ifn-ß gene transcription. A new role for K-bZIP as a protein involved in immune evasion is therefore uncovered.

* Corresponding author. Mailing address: Rheumatology and Immunology Research Center, Room T1-49, 2705 Laurier Blvd., Quebec, Quebec G1V 4G2, Canada. Phone: (418) 656-4141, ext. 46164. Fax: (418) 654-2765. E-mail: Louis.Flamand{at}crchul.ulaval.ca

{triangledown} Published ahead of print on 25 July 2007.

Journal of Virology, October 2007, p. 10950-10960, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.00183-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lefort, S., Flamand, L. (2009). Kaposi's Sarcoma-Associated Herpesvirus K-bZIP Protein Is Necessary for Lytic Viral Gene Expression, DNA Replication, and Virion Production in Primary Effusion Lymphoma Cell Lines. J. Virol. 83: 5869-5880 [Abstract] [Full Text]  
  • Wang, J.-T., Doong, S.-L., Teng, S.-C., Lee, C.-P., Tsai, C.-H., Chen, M.-R. (2009). Epstein-Barr Virus BGLF4 Kinase Suppresses the Interferon Regulatory Factor 3 Signaling Pathway. J. Virol. 83: 1856-1869 [Abstract] [Full Text]  


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