RT Journal Article
SR Electronic
T1 The Deubiquitinase A20 Mediates Feedback Inhibition of Interleukin-17 Receptor Signaling
JF Science Signaling
JO Sci. Signal.
FD American Association for the Advancement of Science
SP ra44
OP ra44
DO 10.1126/scisignal.2003699
VO 6
IS 278
A1 Garg, Abhishek V.
A1 Ahmed, Mushtaq
A1 Vallejo, Abbe N.
A1 Ma, Averil
A1 Gaffen, Sarah L.
YR 2013
UL http://stke.sciencemag.org/content/6/278/ra44.abstract
AB 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.