ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death.
ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death.
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DOI：
10.1038/ncb2738
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发表时间：
2013-05
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
内质网（ER）中的蛋白质错误折叠通过perk介导的eIF2α磷酸化导致细胞死亡，尽管其机制尚不清楚。活化转录因子4 （ATF4）和C/EBP同源蛋白（CHOP）是p-eIF2α下游的关键转录因子，其ChIP-seq和mRNA-seq结果表明，它们相互作用直接诱导编码蛋白合成和未折叠蛋白应答的基因，而不是细胞凋亡。ATF4和CHOP的强制表达增加了蛋白质合成，引起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eif2 α-磷酸化减毒蛋白合成，而不是Atf4 mRNA翻译，促进细胞存活。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。研究结果表明，限制蛋白质合成将对内质网蛋白质错误折叠引起的疾病有治疗作用。
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.
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影响因子：
3
作者：
Bailey TL;Bodén M;Whitington T;Machanick P
通讯作者：
Machanick P
影响因子：
2.7
作者：
Hettmann, T;Barton, K;Leiden, TM
通讯作者：
Leiden, TM
DOI：
10.1126/science.1166175
发表时间：
2009-01-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anderson LL;Mao X;Scott BA;Crowder CM
通讯作者：
Crowder CM
DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
5.3
作者：
Galehdar, Zohreh;Swan, Patrick;Cregan, Sean P.
通讯作者：
Cregan, Sean P.