Interferon regulatory factor 3 is regulated by a dual phosphorylation-dependent switch.
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 epsilon 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 (Ser(396)-Ser(405)) alleviates autoinhibition to allow interaction with CBP (CREB-binding protein) and facilitates phosphorylation at site 1 (Ser(385) or Ser(386)). 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.
Panne
Daniel
D
Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
McWhirter
Sarah M
SM
Maniatis
Tom
T
Harrison
Stephen C
SC
D000818:Animals; D016367:Baculoviridae / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D019281:Dimerization; D006801:Humans; D006860:Hydrogen Bonding; D007313:Insecta; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human