Persistent stimulation with interleukin-17 desensitizes cells through SCF β-TrCP-mediated degradation of Act1

Peiqing Shi, Shu Zhu, Yingying Lin, Yongfeng Liu, Yan Liu, Zhijian Chen, Yufang Shi, Youcun Qian

Research output: Contribution to journalArticle

31 Scopus citations


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 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 SCF β-TrCP-mediated degradation of Act1, that occurs during persistent stimulation with IL-17.

Original languageEnglish (US)
Article numberra73
JournalScience Signaling
Issue number197
Publication statusPublished - Nov 1 2011


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this