The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR
The Hsp90 chaperone complex is both a facilitator and a repressor of the dsRNA-dependent kinase PKR
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DOI：
10.1093/emboj/20.14.3771
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发表时间：
2001-07-16
期刊：
影响因子：
11.4
通讯作者：
Picard, D
中科院分区：
文献类型：
--
作者：
Donzé, O;Abbas-Terki, T;Picard, D
PKR是真核细胞起始因子2 α（eIF-2 α）激酶家族的成员，介导宿主的抗病毒反应，并与肿瘤抑制和细胞凋亡有关。在这里，我们表明，PKR的调节热休克蛋白90（Hsp 90）分子伴侣复合物。在芽殖酵母中表达的哺乳动物PKR依赖于Hsp 90复合物的几种组分的积累和活性。在哺乳动物细胞中，格尔德霉素（GA）在PKR从头合成过程中抑制Hsp 90功能也会干扰其积累和活性。热休克蛋白90及其共伴侣蛋白p23通过其N-末端双链RNA结合区以及通过其激酶结构域与PKR结合。dsRNA和GA均诱导Hsp 90和p23从成熟PKR快速解离，在体内和体外激活PKR，并在几分钟内触发PKR底物eIF-2 α的磷酸化。短期暴露于Hsp 90抑制剂GA或根赤霉素的细胞不仅去抑制PKR，而且激活Raf-MAPK通路。这表明，热休克蛋白90复合物可能更普遍地帮助激酶和其他热休克蛋白90底物的调节结构域。
PKR, a member of the eukaryotic initiation-factor 2 alpha (eIF-2 alpha) kinase family, mediates the host antiviral response and is implicated in tumor suppression and apoptosis. Here we show that PKR is regulated by the heat shock protein 90 (Hsp90) molecular chaperone complex. Mammalian PKR expressed in budding yeast depends on several components of the Hsp90 complex for accumulation and activity. In mammalian cells, inhibition of Hsp90 function with geldanamycin (GA) during de novo synthesis of PKR also interferes with its accumulation and activity. Hsp90 and its co-chaperone p23 bind to PKR through its N-terminal double-stranded (ds) RNA binding region as well as through its kinase domain. Both dsRNA and GA induce the rapid dissociation of Hsp90 and p23 from mature PKR, activate PKR both in vivo and in vitro and within minutes trigger the phosphorylation of the PKR substrate eIF-2 alpha. A short-term exposure of cells to the Hsp90 inhibitors GA or radicicol not only derepresses PKR, but also activates the Raf-MAPK pathway. This suggests that the Hsp90 complex may more generally assist the regulatory domains of kinases and other Hsp90 substrates.