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

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

doi:10.1126/scisignal.2001653

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

Sci Signal. 2011 Nov 1;4(197):ra73. doi: 10.1126/scisignal.2001653.

Authors

Peiqing Shi¹, Shu Zhu, Yingying Lin, Yongfeng Liu, Yan Liu, Zhijian Chen, Yufang Shi, Youcun Qian

Affiliation

¹ The 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.

PMID: 22045853
DOI: 10.1126/scisignal.2001653

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Blotting, Western
Cell Line, Tumor
Cells, Cultured
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
HEK293 Cells
HeLa Cells
Humans
Interleukin-17 / pharmacology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation / drug effects
Protein Binding / drug effects
Proteolysis / drug effects
RNA Interference
Receptors, Interleukin-17 / genetics
Receptors, Interleukin-17 / metabolism
Signal Transduction / drug effects
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination / drug effects
beta-Transducin Repeat-Containing Proteins / genetics
beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

Adaptor Proteins, Signal Transducing
BTRC protein, human
FBXW11 protein, human
IL17RA protein, human
Interleukin-17
Receptors, Interleukin-17
TRAF3IP2 protein, human
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
beta-Transducin Repeat-Containing Proteins
Ubiquitin-Protein Ligases