title: A cytosolic heat shock protein 90 and cochaperone CDC37 complex is required for RIP3 activation during necroptosis.
abstract: 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.
authors: Graduate Program, Beijing Normal University, Beijing 100875, China; National Institute of Biological Sciences, Beijing 102206, China; and.
authors: Dianrong
authors: D
authors: Li
authors: National Institute of Biological Sciences, Beijing 102206, China; and.
authors: Tao
authors: T
authors: Xu
authors: National Institute of Biological Sciences, Beijing 102206, China; and.
authors: Yang
authors: Y
authors: Cao
authors: National Institute of Biological Sciences, Beijing 102206, China; and.
authors: Huayi
authors: H
authors: Wang
authors: National Institute of Biological Sciences, Beijing 102206, China; and.
authors: Lin
authors: L
authors: Li
authors: National Institute of Biological Sciences, Beijing 102206, China; and.
authors: She
authors: S
authors: Chen
authors: National Institute of Biological Sciences, Beijing 102206, China; and Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China wangxiaodong@nibs.ac.cn shenzhirong@nibs.ac.cn.
authors: Xiaodong
authors: X
authors: Wang
authors: National Institute of Biological Sciences, Beijing 102206, China; and Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China wangxiaodong@nibs.ac.cn shenzhirong@nibs.ac.cn.
authors: Zhirong
authors: Z
authors: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D018833:Chaperonins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; C570693:MLKL protein, human; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018833:Chaperonins
keywords: CDC37; HSP90; RIP3; kinase; necrosis