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

Sci. Signal., 1 November 2011
Vol. 4, Issue 197, p. ra73
DOI: 10.1126/scisignal.2001653

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

  1. Peiqing Shi1,
  2. Shu Zhu1,
  3. Yingying Lin1,
  4. Yongfeng Liu1,
  5. Yan Liu1,
  6. Zhijian Chen2,
  7. Yufang Shi1, and
  8. Youcun Qian1,*
  1. 1The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  2. 2Department of Molecular Biology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  1. *To whom correspondence should be addressed. E-mail: ycqian{at}sibs.ac.cn

Abstract

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.

Citation:

P. Shi, S. Zhu, Y. Lin, Y. Liu, Y. Liu, Z. Chen, Y. Shi, and Y. Qian, Persistent Stimulation with Interleukin-17 Desensitizes Cells Through SCFβ-TrCP-Mediated Degradation of Act1. Sci. Signal. 4, ra73 (2011).

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