Research ArticleImmunology

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

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

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Limiting Persistent Inflammation

Interleukin-17 (IL-17) is a proinflammatory cytokine that is required for immune responses to extracellular pathogens, but it is also implicated in autoimmune disorders and inflammatory diseases. Signaling through the IL-17 receptor (IL-17R) requires the adaptor protein Act1 and leads to activation of the transcription factor NF-κB. Shi et al. found that persistent stimulation of HeLa cells with IL-17 led to a loss of Act1 protein and inhibited responses of the cells to subsequent exposure to the cytokine. Stimulation with IL-17 led to phosphorylation, ubiquitination, and proteasomal degradation of Act1. The authors identified SCFβ-TrCP as the E3 ubiquitin ligase complex responsible for Act1 ubiquitination. SCFβ-TrCP is also required for IL-17–dependent degradation of the inhibitor of κB (IκB) protein to enable NF-κB activation, positioning SCFβ-TrCP as both a positive and a negative regulator of IL-17 signaling.