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J. Biol. Chem., Vol. 281, Issue 8, 4856-4866, February 24, 2006

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Promoter Organization of the Interferon-A Genes Differentially Affects Virus-induced Expression and Responsiveness to TBK1 and IKK^*

Ahmet Civas¹, Pierre Génin, Pierre Morin, Rongtuan Lin², and John Hiscott³

From the UPR 2228-CNRS, Laboratoire de Régulation Transcriptionnelle et Maladies Génétiques, UFR Biomédicale des Saints-Pères, Université Paris V, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France and Lady Davis Institute for Medical Research and Departments of Microbiology, Immunology, and Medicine, McGill University, Montréal, Quebec H3T 1E2, Canada

Virus-induced expression of interferon (IFN)-A genes is regulated by two members of the IFN regulatory factor (IRF) family, IRF-3 and IRF-7, which are activated by phosphorylation during viral infection by the IKK-related serine/threonine kinases TBK1 and IB kinase (IKK). 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 Newcastle disease virus infection or activation by TBK1 or IKK. The ordered assembly of IRF-3 multimers on the promoter also determines cooperative recruitment of IRF-3 and CREB-binding protein and differential virus-induced expression of IFN-A4 gene promoter compared with 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 CREB-binding protein 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 IKK or TBK1 expression in the presence of IRF-7 but lose the capacity to respond to virus or kinase-induced IRF-3. Interestingly, IKK or TBK1 stimulates the IRF-7-mediated transcription of IFN-A11, although at a lesser extent compared with 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 IKK or TBK1.

Received for publication, June 22, 2005 , and in revised form, November 28, 2005.

^* This work was supported by the Centre National de la Recherche Scientifique, the Université Paris V, and grants from the Association pour la Recherche sur le Cancer (Contrat ARC 5828 and 3236) from the Ligue Régionale contre le Cancer (Contrat 75/01-RS/44 and R04–75/81). This work was also supported by grants (to J. H.) from the Canadian Institutes of Health Research (CIHR), the National Cancer Institute of Canada with funds from the Canadian Cancer Society, and the Canadian Network for Vaccines and Immunotherapeutics. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported by a Fonds pour la Recherche Scientifique du Québec chercheur boursier.

³ Supported by a CIHR Senior Investigator Award.

¹ To whom correspondence should be addressed. Tel.: 33-1-42-86-22-84; Fax: 33-1-42-86-20-42; E-mail: ahmet.civas{at}univ-paris5.fr.

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