IKKβ is an IRF5 kinase that instigates inflammation

The transcription factor interferon regulatory factor 5 (IRF5) is essential for the induction of inflammatory cytokines, but the mechanism by which IRF5 is activated is not well understood. Here we present evidence that the kinase IKK beta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll-like receptors and retinoic acidinducible gene I-like receptors. IKK beta phosphorylates mouse IRF5 at specific residues, including serine 445 (S446 in human IRF5 isoform 1), as evidenced by mass spectrometry analysis and detection with a phosphospecific antibody. Recombinant IKK beta phosphorylated IRF5 at Ser-445 in vitro, and a pointmutation of this serine abolished IRF5 activation and cytokine production. Depletion or pharmacologic inhibition of IKK beta prevented IRF5 phosphorylation. These results indicate that IKK beta is an IRF5 kinase that instigates inflammation.