title: IKKβ is an IRF5 kinase that instigates inflammation.
abstract: 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 IKKβ phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll-like receptors and retinoic acid-inducible gene I-like receptors. IKKβ 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 IKKβ phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production. Depletion or pharmacologic inhibition of IKKβ prevented IRF5 phosphorylation. These results indicate that IKKβ is an IRF5 kinase that instigates inflammation.
authors.affiliation: Department of Molecular Biology and.
authors.forename: Junyao
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Molecular Biology and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Zhijian.Chen@UTSouthwestern.edu.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000409:Alanine / Q000737:chemistry; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry
chemical_list: D016207:Cytokines; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D012694:Serine; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496562:Ikbkb protein, mouse; D000409:Alanine
keywords: IKK; IRF5; TLR; inflammation; phosphorylation