Research ArticleImmunology

Persistent Stimulation with Interleukin-17 Desensitizes Cells Through SCFβ-TrCP-Mediated Degradation of Act1

Sci. Signal.  01 Nov 2011:
Vol. 4, Issue 197, pp. ra73
DOI: 10.1126/scisignal.2001653

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The proinflammatory cytokine interleukin-17 (IL-17) is important for the immune response to pathogens and also contributes to the pathogenesis of various inflammatory diseases. To avoid persistent inflammation, signaling by the IL-17 receptor (IL-17R), which involves the adaptor protein Act1, must be tightly controlled. Here, we report that persistent stimulation of HeLa cells with IL-17 resulted in degradation of Act1 and desensitization of IL-17R signaling. IL-17 stimulated the Lys48-linked polyubiquitination and degradation of Act1, which was phosphorylation-dependent, similar to the IL-17–dependent degradation of inhibitor of nuclear factor κB α. Act1 was recruited to SCF (Skp1–cullin-1–F-box)–type E3 ubiquitin ligase complexes containing β-transducin repeat–containing protein 1 (β-TrCP1) or β-TrCP2 in a phosphorylation-dependent manner upon stimulation of cells with IL-17. Dominant-negative β-TrCP or knockdown of β-TrCP1 and β-TrCP2 markedly reduced IL-17–induced, phosphorylation-dependent ubiquitination and degradation of Act1. Thus, our studies identify a previously uncharacterized desensitization mechanism, involving the SCFβ-TrCP-mediated degradation of Act1, that occurs during persistent stimulation with IL-17.

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