TY - JOUR
T1 - Persistent stimulation with interleukin-17 desensitizes cells through SCF β-TrCP-mediated degradation of Act1
AU - Shi, Peiqing
AU - Zhu, Shu
AU - Lin, Yingying
AU - Liu, Yongfeng
AU - Liu, Yan
AU - Chen, Zhijian
AU - Shi, Yufang
AU - Qian, Youcun
PY - 2011/11/1
Y1 - 2011/11/1
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.2001653
DO - 10.1126/scisignal.2001653
M3 - Article
C2 - 22045853
AN - SCOPUS:80455163028
SN - 1945-0877
VL - 4
JO - Science signaling
JF - Science signaling
IS - 197
M1 - ra73
ER -