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Papers In Press, published online ahead of print December 27, 2005
UFR Biomédicale des Saints-Pères, UPR2228-CNRS, 75270 PARIS, Cedex 06
Corresponding Author: ahmet.civas{at}univ-paris5.fr
Virus-induced expression of interferon (IFN)-A genes is regulated by two members of the IFN regulatory factor family, IRF-3 and IRF-7, which are activated by phosphorylation during viral infection by the IKK-related serine/threonine kinases TBK1 and IKKe. In this study, we demonstrate that three IRF-binding sites located in the virus responsive element mediate the transcriptional activation of the IFN-A4 promoter by IRF-3. The precise arrangement of these IRF-elements is required for synergistic activation of the IFN-A4 promoter following NDV infection or activation by TBK1 or IKKe. The ordered assembly of IRF-3 multimers on the promoter also determines cooperative recruitment of IRF-3 and CBP, and differential virus-induced expression of IFN-A4 gene promoter compared to IFN-A11. Naturally occurring nucleotide substitutions disrupt two of the IRF-elements in the IFN-A11 gene promoter, leading to a dramatic decrease in IRF-3 and CBP recruitment and in IRF-3-dependent transcription. Transcription of the IFN-A4 promoter by IRF-7 is mediated by two IRF-elements; promoter mutants that carry a reversed IRF-element retain the ability to respond to IKKe or TBK1 expression in the presence of IRF-7, but lose the capacity to respond to virus or kinase-induced IRF-3. Interestingly, IKKe or TBK1 stimulates the IRF-7-mediated transcription of IFN-A11, although at a lesser extent compared to IFN-A4. Our data indicate that virus-induced expression of IFN-A genes is dictated by the organization of IRF-elements within the IFN-A promoters and that the differential IFN-A gene expression, based on the IRF-3 responsiveness, is partially compensated in the presence of IRF-7 when both factors are activated by IKKe or TBK1.
J. Biol. Chem, 10.1074/jbc.M506812200
Submitted on June 22, 2005
Accepted on December 27, 2005
Promoter organization of the interferon-A genes differentially affects virus-induced expression and responsiveness to TBK1 and IKK
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