牛皮癣与T辅助细胞17(TH17)响应增强有关。来自美国克里夫兰医学中心勒纳研究所的Li及其同事发现IL-17R信号通路中的适配体蛋白Act1需要分子伴侣hsp90。若该途径发生缺陷则会导致IL-22过度生成及促进牛皮癣发病。相关的研究论文于2012年12月2日在线发表在《Nature Immunology》杂志上。

-2013年1月《自然-免疫》

中文翻译


【题目】Act1与D10N变体使得分子伴侣hsp90的调控失效

【译文】Act1是白细胞介素17(IL-17)介导的信号通路的必需适配体蛋白,细胞受IL-17刺激后,Act1会被招募充当IL-17的受体。本研究发现Act1是分子伴侣hsp90的客户蛋白。Act1的D10N变体(Act1(D10N))与牛皮癣的易感性有关,该变体不能与hsp90的互作,导致Act1丧失全部功能。Act1缺陷小鼠能够模拟Act1功能丧失与牛皮癣易感性的联系特点。尽管Act1是IL-17介导的炎症所需的蛋白,但Act1缺陷的小鼠对T辅助细胞的TH17细胞亚类具有极其活跃的响应,同时该小鼠还患上自发性IL-22依赖的皮肤炎症。在IL-17缺乏的情况下,IL-22是皮肤炎症的主要参与因子,这为Act1(D10N)与牛皮癣易感性的关联性提供分子机制。

英文原稿


[Title]: The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90  

[Authors]:Chenhui Wang, Ling Wu, Katarzyna Bulek, Bradley N Martin, Jarod A Zepp, Zizhen Kang, Caini Liu, Tomasz Herjan, Saurav Misra, Julie A Carman, Ji Gao, Ashok Dongre, Shujie Han, Kevin D Bunting, Jennifer S Ko, Hui Xiao, Vijay K Kuchroo, Wenjun Ouyang & Xiaoxia Li

[Abstract]: 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 TH17 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.

原文地址

http://www.nature.com/ni/journal/v14/n1/full/ni.2479.html

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