Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Nat Cell Biol. 2013 May;15(5):481-90. doi: 10.1038/ncb2738. Epub 2013 Apr 28.
Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.
内质网（ER）中的蛋白质错误折叠会导致细胞死亡，这是通过 PERK 介导的 eIF2α 磷酸化实现的，但具体机制尚不清楚。激活转录因子 4（ATF4）和 C/EBP 同源蛋白（CHOP）的 ChIP-seq 和 mRNA-seq 研究表明，它们作为 p-eIF2α 的下游关键转录因子相互作用，直接诱导编码蛋白质合成和未折叠蛋白反应的基因，但不诱导细胞凋亡。强制表达 ATF4 和 CHOP 会增加蛋白质合成并导致 ATP 耗竭、氧化应激和细胞死亡。增加的蛋白质合成和氧化应激是细胞死亡的必要信号。我们发现，eIF2α 磷酸化减弱了蛋白质合成，而非 Atf4 mRNA 翻译，促进了细胞存活。这些结果表明，通过 ATF4 和 CHOP 的转录诱导增加了蛋白质合成，导致氧化应激和细胞死亡。这些发现提示，限制蛋白质合成可能对 ER 中蛋白质错误折叠引起的疾病具有治疗作用。
