Li Dianrong, Xu Tao, Cao Yang, Wang Huayi, Li Lin, Chen She, Wang Xiaodong, Shen Zhirong
Graduate Program, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; and.
National Institute of Biological Sciences, Beijing 102206, China; and.
Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):5017-22. doi: 10.1073/pnas.1505244112. Epub 2015 Apr 7.
Receptor-interacting protein kinase 3, RIP3, and a pseudokinase mixed lineage kinase-domain like protein, MLKL, constitute the core components of the necroptosis pathway, which causes programmed necrotic death in mammalian cells. Latent RIP3 in the cytosol is activated by several upstream signals including the related kinase RIP1, which transduces signals from the tumor necrosis factor (TNF) family of cytokines. We report here that RIP3 activation following the induction of necroptosis requires the activity of an HSP90 and CDC37 cochaperone complex. This complex physically associates with RIP3. Chemical inhibitors of HSP90 efficiently block necroptosis by preventing RIP3 activation. Cells with knocked down CDC37 were unable to respond to necroptosis stimuli. Moreover, an HSP90 inhibitor that is currently under clinical development as a cancer therapy was able to prevent systemic inflammatory response syndrome in rats treated with TNF-α. HSP90 and CDC37 cochaperone complex-mediated protein folding is thus an important part of the RIP3 activation process during necroptosis.
受体相互作用蛋白激酶3（RIP3）和一种假激酶混合谱系激酶结构域样蛋白（MLKL）构成坏死性凋亡途径的核心成分，该途径导致哺乳动物细胞发生程序性坏死死亡。胞质溶胶中的潜伏RIP3被包括相关激酶RIP1在内的几种上游信号激活，RIP1转导来自细胞因子肿瘤坏死因子（TNF）家族的信号。我们在此报告，坏死性凋亡诱导后RIP3的激活需要热休克蛋白90（HSP90）和细胞周期蛋白依赖性激酶37（CDC37）伴侣蛋白复合物的活性。该复合物与RIP3发生物理结合。HSP90的化学抑制剂通过阻止RIP3激活有效阻断坏死性凋亡。敲低CDC37的细胞无法对坏死性凋亡刺激作出反应。此外，一种目前正在作为癌症治疗药物进行临床开发的HSP90抑制剂能够预防用TNF-α治疗的大鼠的全身炎症反应综合征。因此，HSP90和CDC37伴侣蛋白复合物介导的蛋白质折叠是坏死性凋亡过程中RIP3激活过程的重要组成部分。
