title: IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms.
abstract: Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-κB is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-κB activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.
authors.affiliation: Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20852, USA.
authors.forename: Søren Ulrik
authors.initials: SU
authors.lastname: Sønder
authors.forename: Sun
authors.initials: S
authors.lastname: Saret
authors.forename: Wanhu
authors.initials: W
authors.lastname: Tang
authors.forename: Dan E
authors.initials: DE
authors.lastname: Sturdevant
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siebenlist
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C515963:Traf3ip2 protein, mouse