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J. Biol. Chem., Vol. 282, Issue 31, 22816-22822, August 3, 2007

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Interferon Regulatory Factor 3 Is Regulated by a Dual Phosphorylation-dependent Switch^*

Daniel Panne, Sarah M. McWhirter¹, Tom Maniatis, and Stephen C. Harrison²

From the Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115 and Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

The transcription factor interferon regulatory factor 3 (IRF-3) regulates genes in the innate immune response. IRF-3 is activated through phosphorylation by the kinases IKK and/or TBK1. Phosphorylation results in IRF-3 dimerization and removal of an autoinhibitory structure to allow interaction with the coactivators CBP/p300. The precise role of the different phosphorylation sites has remained controversial. Using purified proteins we show that TBK1 can directly phosphorylate full-length IRF-3 in vitro. Phosphorylation at residues in site 2 (Ser³⁹⁶—Ser⁴⁰⁵) alleviates autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitates phosphorylation at site 1 (Ser³⁸⁵ or Ser³⁸⁶). Phosphorylation at site 1 is, in turn, required for IRF-3 dimerization. The data support a two-step phosphorylation model for IRF-3 activation mediated by TBK1.

Received for publication, April 10, 2007 , and in revised form, May 23, 2007.

^* 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.

This article was selected as a Paper of the Week.

¹ Present address: Dept. of Molecular and Cell Biology, University of California, Berkeley, 415 Life Sciences Addition, Berkeley, CA 94720.

² To whom correspondence should be addressed. Tel.: 617-432-5607; Fax: 617-432-5600; E-mail: harrison{at}crystal.harvard.edu.

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