Cullinan Sara B, Zhang Donna, Hannink Mark, Arvisais Edward, Kaufman Randal J, Diehl J Alan
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA.
Mol Cell Biol. 2003 Oct;23(20):7198-209. doi: 10.1128/MCB.23.20.7198-7209.2003.
Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate. In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/Keap1 complexes in vitro. Activation of PERK via agents that trigger the unfolded protein response is both necessary and sufficient for dissociation of cytoplasmic Nrf2/Keap1 and subsequent Nrf2 nuclear import. Finally, we demonstrate that cells harboring a targeted deletion of Nrf2 exhibit increased cell death relative to wild-type counterparts following exposure to ER stress. Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival.
内质网（ER）中未折叠蛋白积累后PERK的激活促进翻译抑制和细胞周期停滞。PERK功能对于细胞暴露于内质网应激后的存活至关重要，但PERK信号促进细胞存活的机制尚未完全了解。我们已将Nrf2转录因子鉴定为一种新的PERK底物。在未受应激的细胞中，Nrf2通过与Keap1结合而维持在细胞质中。PERK依赖性磷酸化触发Nrf2/Keap1复合物的解离，并在体外抑制Nrf2/Keap1复合物的重新结合。通过触发未折叠蛋白反应的试剂激活PERK对于细胞质Nrf2/Keap1的解离和随后的Nrf2核输入既是必要的也是充分的。最后，我们证明，与野生型细胞相比，靶向缺失Nrf2的细胞在暴露于内质网应激后表现出更高的细胞死亡率。我们的数据表明，Nrf2是PERK介导的细胞存活的关键效应因子。
