title: TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation.
abstract: Interleukin-17 (IL-17) is critically involved in the pathogenesis of various inflammatory disorders. IL-17 receptor (IL-17R)-proximal signaling complex (IL-17R-Act1-TRAF6) is essential for IL-17-mediated NF-κB activation, while IL-17-mediated mRNA stability is TRAF6 independent. Recently, inducible IκB kinase (IKKi) has been shown to phosphorylate Act1 on Ser 311 to mediate IL-17-induced mRNA stability. Here we show that TANK binding kinase 1 (TBK1), the other IKK-related kinase, directly phosphorylated Act1 on three other Ser sites to suppress IL-17R-mediated NF-κB activation. IL-17 stimulation activated TBK1 and induced its association with Act1. IKKi also phosphorylated Act1 on the three serine sites and played a redundant role with TBK1 in suppressing IL-17-induced NF-κB activation. Act1 phosphorylation on the three sites inhibited its association with TRAF6 and consequently NF-κB activation in IL-17R signaling. Interestingly, TRAF6, but not TRAF3, which is the upstream adaptor of the IKK-related kinases in antiviral signaling, was critical for IL-17-induced Act1 phosphorylation. TRAF6 was essential for IL-17-induced TBK1 activation, its association with Act1, and consequent Act1 phosphorylation. Our findings define a new role for the IKK-related kinases in suppressing IL-17-mediated NF-κB activation through TRAF6-dependent Act1 phosphorylation.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Qu
authors.forename: Hanchao
authors.initials: H
authors.lastname: Gao
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.forename: Peiqing
authors.initials: P
authors.lastname: Shi
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
mesh_terms: D000818:Animals; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: C541130:ACT1 protein; D018031:Connexin 43; D020381:Interleukin-17; D010446:Peptide Fragments; D053722:Receptors, Interleukin-17; D048029:TNF Receptor-Associated Factor 6; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase