title: The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling.
abstract: The proinflammatory cytokine interleukin-17 (IL-17) is the signature cytokine of the T helper 17 (TH17) subset of CD4(+) T cells, and antibodies targeting IL-17 or the IL-17 receptor (IL-17R) show clinical efficacy in several autoimmune diseases. Although important for protective immunity against microorganisms, IL-17 causes collateral damage in inflammatory settings. TNFAIP3 encodes the deubiquitinase A20 and is genetically linked to numerous autoimmune syndromes. A20, a potent inhibitor of tumor necrosis factor-α signaling, removes ubiquitin from signaling intermediates upstream of nuclear factor κB (NF-κB), thereby dampening NF-κB-mediated inflammation. We demonstrated that IL-17 stimulates TNFAIP3 expression. Enhanced IL-17-mediated induction of genes encoding proinflammatory factors, including IL-6 and various chemokines, occurred upon knockdown of A20 with short inhibitory RNA or in A20(-/-) cells. A20 associated with the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor-associated factor 6) in an IL-17-dependent manner and restricted the IL-17-dependent activation of NF-κB and mitogen-activated protein kinases. A20 interacted directly with the distal domain of IL-17RA, a previously defined inhibitory domain. Together, these data describe a mechanism of restraining IL-17 signaling and reveal an aspect of A20 activity that may help to explain its role in autoimmunity in humans.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Abhishek V
authors.initials: AV
authors.lastname: Garg
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Abbe N
authors.initials: AN
authors.lastname: Vallejo
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D053722:Receptors, Interleukin-17; D048029:TNF Receptor-Associated Factor 6; D064570:Ubiquitin-Specific Proteases