Research ArticleImmunology

The Deubiquitinase A20 Mediates Feedback Inhibition of Interleukin-17 Receptor Signaling

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Sci. Signal.  04 Jun 2013:
Vol. 6, Issue 278, pp. ra44
DOI: 10.1126/scisignal.2003699

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A20 Targets a Cytokine Receptor to Limit Inflammation

The cytokine interleukin-17 (IL-17) mediates immunity against various microorganisms; however, it also causes inflammatory tissue damage in autoimmune disorders, such as rheumatoid arthritis (RA). Garg et al. found that IL-17 stimulated the production of the deubiquitinase A20, an inhibitor of nuclear factor κB (NF-κB) activation downstream of the tumor necrosis factor receptor and Toll-like receptors. Mutations in the gene encoding A20 are associated with RA in some patients. Knockdown of A20 in human fibroblast-like synoviocytes resulted in enhanced IL-17–dependent production of the inflammatory cytokine IL-6. IL-17 stimulated an association between A20, the IL-17R, and the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor–associated factor 6) to inhibit IL-17–dependent signaling. In addition to demonstrating the direct recruitment of A20 to a cytokine receptor, these results may partly explain the association of mutations in A20 with susceptibility to RA.