An integrated stress response regulates amino acid metabolism and resistance to oxidative stress
An integrated stress response regulates amino acid metabolism and resistance to oxidative stress
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DOI：
10.1016/s1097-2765(03)00105-9
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发表时间：
2003-03-01
期刊：
影响因子：
16
通讯作者：
Ron, D
中科院分区：
文献类型：
--
作者：
Harding, HP;Zhang, YH;Ron, D
真核细胞通过磷酸化翻译起始因子2（eIF 2 α）的α亚基对内质网中的未折叠蛋白（ER应激）、氨基酸饥饿或氧化剂作出反应。这种适应抑制一般蛋白质合成，同时促进转录因子ATF 4的翻译和表达。atf 4（-/-）细胞在表达参与氨基酸输入、谷胱甘肽生物合成和抗氧化应激的基因方面受损。Perk（-/-）细胞，缺乏上游ER应激激活的eIF 2 α激酶，激活Atf 4，积累内源性过氧化物在ER应激，而干扰ER氧化酶ERO 1废除这种积累。由eIF 2 α磷酸化启动的信号通路通过促进氨基酸充足和抗氧化应激的相关过程来保护细胞免受ER氧化的代谢后果。
Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.