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首页> 外文期刊>Molecular and Cellular Biology >Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery
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Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery

机译：蛋白质错误折叠通过展开的蛋白质反应机制的子集诱导低氧预处理

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Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe hypoxia can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein response pathway (UPR) has been known for some time to respond to hypoxia and regulate hypoxic sensitivity; however, the role of the UPR, if any, in HP essentially has been unexplored. We have shown previously that a sublethal hypoxic exposure of the nematode Caenorhabditis elegans induces a protein chaperone component of the UPR (L. L. Anderson, X. Mao, B. A. Scott, and C. M. Crowder, Science >323:630-633, 2009). Here, we show that HP induces the UPR and that the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6. HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP. The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP. These data suggest a model where hypoxia-induced misfolded proteins trigger the activation of IRE-1, which along with GCN-2 controls an adaptive response that is essential to HP.
机译：长时间的细胞缺氧会导致能量衰竭，并最终导致细胞死亡。但是，严重程度较低的缺氧可以诱导称为低氧预处理（HP）的细胞保护反应。展开的蛋白质反应途径（UPR）已知对缺氧有反应并调节缺氧敏感性。但是，UPR在HP中的作用（如果有的话）基本上尚未被开发。先前我们已经证明线虫秀丽隐杆线虫的亚致死性低氧暴露诱导了UPR的蛋白伴侣成分（LL Anderson，X. Mao，BA Scott，and CM Crowder，Science > 323： 630-633，2009）。在这里，我们表明HP诱导了UPR，并且折叠错误的蛋白质的药理作用本身足以刺激对需要UPR途径蛋白质IRE-1，XBP-1和ATF-6的低氧损伤的延迟保护反应。惠普还需要IRE-1，但不需要XBP-1或ATF-6。相反，HP需要GCN-2，该蛋白在UPR激活或氨基酸剥夺条件下可抑制翻译并诱导适应性转录反应。 HP不需要翻译因子eIF2α的磷酸化，这是已建立的GCN-2介导的翻译抑制机制。这些数据提出了一个模型，在该模型中，低氧诱导的错折叠蛋白触发了IRE-1的激活，IRE-1与GCN-2一起控制了HP必需的适应性反应。

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