The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling

Abhishek V. Garg, Mushtaq Ahmed, Abbe N. Vallejo, Averil Ma, Sarah L. Gaffen

Research output: Contribution to journalArticle

71 Scopus citations

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.

Original languageEnglish
Article numberra44
JournalScience signaling
Volume6
Issue number278
DOIs
StatePublished - Jun 4 2013
Externally publishedYes

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