In:
Science Signaling, American Association for the Advancement of Science (AAAS), Vol. 4, No. 197 ( 2011-11)
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 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.
Type of Medium:
Online Resource
ISSN:
1945-0877
,
1937-9145
DOI:
10.1126/scisignal.2001653
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2011
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