title: Persistent stimulation with interleukin-17 desensitizes cells through SCFβ-TrCP-mediated degradation of Act1.
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.
authors: 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.
authors: Peiqing
authors: P
authors: Shi
authors: Shu
authors: S
authors: Zhu
authors: Yingying
authors: Y
authors: Lin
authors: Yongfeng
authors: Y
authors: Liu
authors: Yan
authors: Y
authors: Liu
authors: Zhijian
authors: Z
authors: Chen
authors: Yufang
authors: Y
authors: Shi
authors: Youcun
authors: Y
authors: Qian
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C471644:BTRC protein, human; C471645:FBXW11 protein, human; C109985:IL17RA protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; C414202:TRAF3IP2 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D044767:Ubiquitin-Protein Ligases