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.
Sci Signal. 2011 Nov 1;4(197):ra73. doi: 10.1126/scisignal.2001653.
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.
促炎细胞因子白细胞介素-17（IL-17）对于病原体的免疫反应很重要，也有助于各种炎症性疾病的发病机制。为了避免持续的炎症，IL-17 受体（IL-17R）的信号转导必须受到严格控制，该信号转导涉及衔接蛋白 Act1。在这里，我们报告说，持续刺激 HeLa 细胞的 IL-17 导致 Act1 的降解和 IL-17R 信号的脱敏。IL-17 刺激 Act1 的 Lys48 连接多泛素化和降解，这是磷酸化依赖性的，类似于核因子 κBα 抑制剂的 IL-17 依赖性降解。Act1 在细胞受到 IL-17 刺激后，以磷酸化依赖性方式被募集到含有 β-转导重复蛋白 1（β-TrCP1）或 β-TrCP2 的 SCF（Skp1-cullin-1-F-box）型 E3 泛素连接酶复合物中。显性失活的β-TrCP 或β-TrCP1 和β-TrCP2 的敲低显著减少了 IL-17 诱导的、磷酸化依赖性的 Act1 泛素化和降解。因此，我们的研究确定了一种以前未被描述的脱敏机制，涉及 SCFβ-TrCP 介导的 Act1 降解，该机制发生在持续刺激 IL-17 时。
