炎症性细胞因子白介素-17单独诱导，或与其它炎症因子（如TNF）协调诱导炎症性细胞因子、趋化因子等基因表达来发挥炎症效应，在宿主防御系统以及炎症性疾病中都发挥重要作用。快速的炎症对机体的正常生理功能如抗感染具有重要作用，而持续或慢性炎症会引发机体病理反应，需得到有效的控制。目前还不清楚机体是否存在对连续白介素-17刺激的调控作用以避免持续性炎症。
11月1日，Science子刊《科学—信号传导》（Science Signaling）发表了中科院上海生命科学研究院/上海交大医学院健康所钱友存研究组关于持续炎症调控的新机制（Persistent Stimulation with Interleukin-17 Desensitizes Cells Through SCFβ-TrCP-Mediated Degradation of Act1）。
该研究发现，持续白介素-17刺激引起细胞脱敏，避免了持续的炎症效应。机制研究发现，连续白介素-17刺激导致其信号通路中关键分子Act1的磷酸化、泛素化及蛋白酶体介导的降解，从而引起细胞脱敏。
白介素-17刺激通过E3复合体（SCFb-TrCP）泛素化IkBa（inhibitor of NFkBa）及随后蛋白酶体介导的IkBa降解而激活NFkB通路，在炎症信号激活后，又通过SCFb-TrCP泛素化Act1及随后的蛋白酶体介导的Act1降解从而终止炎症信号的进一步激活，表明机体对信号激活与终止存在有效的耦联机制。
该工作主要由博士生施沛青在钱友存研究员的指导下完成。该课题获得国家自然科学基金委、国家科技部、中国科学院和上海市科委的经费资助。（生物探索）
相关英文论文摘要：
Persistent Stimulation with Interleukin-17 Desensitizes Cells Through SCFβ-TrCP-Mediated Degradation of Act1
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 B 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.
英文论文链接：https://stke.sciencemag.org/cgi/content/abstract/sigtrans;4/197/ra73
