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

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 Lys(48)-linked polyubiquitination and degradation of Act1, which was phosphorylation-dependent, similar to the IL-17-dependent degradation of inhibitor of nuclear factor kappa B alpha. Act1 was recruited to SCF (Skp1-cullin-1-F-box)-type E3 ubiquitin ligase complexes containing beta-transducin repeat-containing protein 1 (beta-TrCP1) or beta-TrCP2 in a phosphorylation-dependent manner upon stimulation of cells with IL-17. Dominant-negative beta-TrCP or knockdown of beta-TrCP1 and beta-TrCP2 markedly reduced IL-17-induced, phosphorylation-dependent ubiquitination and degradation of Act1. Thus, our studies identify a previously uncharacterized desensitization mechanism, involving the SCF beta-TrCP-mediated degradation of Act1, that occurs during persistent stimulation with IL-17.