Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Nat Immunol. 2013 Jan;14(1):72-81. doi: 10.1038/ni.2479. Epub 2012 Dec 2.
Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a 'client' protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis was defective in its interaction with hsp90, which resulted in a global loss of Act1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the T(H)17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17 signaling, IL-22 was the main contributor to skin inflammation, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.
Act1 是白细胞介素 17（IL-17）介导的信号转导中的一个必需衔接蛋白，在受到 IL-17 刺激后被募集到 IL-17 受体。在这里，我们发现 Act1 是分子伴侣 hsp90 的“客户”蛋白。与银屑病易感性相关的 Act1（Act1(D10N)）的 D10N 变体与 hsp90 的相互作用存在缺陷，导致 Act1 功能全面丧失。Act1 缺陷型小鼠模拟了 Act1 功能丧失与银屑病易感性之间的机制联系。虽然 Act1 对于 IL-17 介导的炎症是必需的，但 Act1 缺陷型小鼠的辅助性 T 细胞 T(H)17 亚群的反应过度，并自发发生依赖于 IL-22 的皮肤炎症。在没有 IL-17 信号的情况下，IL-22 是皮肤炎症的主要贡献者，这为 Act1(D10N)与银屑病易感性相关提供了分子机制。
