Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mol Cell Biol. 2010 Nov;30(21):5033-42. doi: 10.1128/MCB.00922-10. Epub 2010 Aug 23.
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.
细胞长期缺氧会导致能量衰竭，最终导致细胞死亡。然而，较轻程度的缺氧可以诱导一种称为缺氧预处理（HP）的细胞保护反应。一段时间以来， unfolded protein response pathway（UPR）一直被认为可以对缺氧做出反应并调节缺氧敏感性；然而，UPR 是否在 HP 中发挥作用基本上尚未得到探索。我们之前已经表明，线虫秀丽隐杆线虫的亚致死缺氧暴露会诱导 UPR 的蛋白质伴侣成分（L. L. Anderson，X. Mao，B. A. Scott 和 C. M. Crowder，Science 323：630-633，2009）。在这里，我们表明 HP 诱导 UPR，并且错误折叠蛋白的药理学诱导本身足以刺激对缺氧损伤的延迟保护反应，这需要 UPR 途径蛋白 IRE-1、XBP-1 和 ATF-6。HP 还需要 IRE-1，但不需要 XBP-1 或 ATF-6；相反，已知在 UPR 激活或氨基酸剥夺条件下抑制翻译并诱导适应性转录反应的 GCN-2 是 HP 所必需的。翻译因子 eIF2α 的磷酸化，这是 GCN-2 介导的翻译抑制的一种既定机制，对于 HP 来说并不是必需的。这些数据表明了一种模型，即缺氧诱导的错误折叠蛋白触发 IRE-1 的激活，IRE-1 与 GCN-2 一起控制适应性反应，这对于 HP 至关重要。
