title: IκB kinase α phosphorylation of TRAF4 downregulates innate immune signaling.
abstract: Despite their homology, IκB kinase α (IKKα) and IKKβ have divergent roles in NF-κB signaling. IKKβ strongly activates NF-κB while IKKα can downregulate NF-κB under certain circumstances. Given this, identifying independent substrates for these kinases could help delineate their divergent roles. Peptide substrate array technology followed by bioinformatic screening identified TRAF4 as a substrate for IKKα. Like IKKα, TRAF4 is atypical within its family because it is the only TRAF family member to negatively regulate innate immune signaling. IKKα's phosphorylation of serine-426 on TRAF4 was required for this negative regulation. Binding to the Crohn's disease susceptibility protein, NOD2, is required for TRAF4 phosphorylation and subsequent inhibition of NOD2 signaling. Structurally, serine-426 resides within an exaggerated β-bulge in TRAF4 that is not present in the other TRAF proteins, and phosphorylation of this site provides a structural basis for the atypical function of TRAF4 and its atypical role in NOD2 signaling.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Marinis
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Hutti
authors.forename: Craig R
authors.initials: CR
authors.lastname: Homer
authors.forename: Brian A
authors.initials: BA
authors.lastname: Cobb
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Christine
authors.initials: C
authors.lastname: McDonald
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007113:Immunity, Innate; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D010766:Phosphorylation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity; D053449:TNF Receptor-Associated Factor 4 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human; C506368:Traf4 protein, mouse; D012694:Serine; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase