Translational control is required for the unfolded protein response and in vivo glucose homeostasis
Translational control is required for the unfolded protein response and in vivo glucose homeostasis
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DOI：
10.1016/s1097-2765(01)00265-9
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发表时间：
2001-06-01
期刊：
影响因子：
16
通讯作者：
Kaufman, RJ
中科院分区：
文献类型：
--
作者：
Scheuner, D;Song, BB;Kaufman, RJ
内质网（ER）中未折叠蛋白的积累通过真核翻译起始因子2（eIF2 α）的cu亚基在Ser51的磷酸化减弱蛋白质合成起始。随后，诱导编码包括葡萄糖调节蛋白的适应性功能的基因的转录。我们展示了eIF2 α。磷酸化是翻译减弱、转录诱导和响应ER应激的存活所必需的。在eIF2 α磷酸化位点（Ser51Ala）具有纯合突变的小鼠在出生后18小时内死于与发育缺陷相关的低血糖。此外，纯合子突变胚胎和新生儿显示胰腺P细胞缺乏。结果表明，通过eIF2 α磷酸化调节翻译对于ER应激反应和体内葡萄糖稳态是必不可少的。
The accumulation of unfolded protein in the endoplasmic reticulum (ER) attenuates protein synthesis initiation through phosphorylation of the cu subunit of eukaryotic translation initiation factor 2 (eIF2 alpha) at Ser51. Subsequently, transcription of genes encoding adaptive functions including the glucose-regulated proteins is induced. We show that eIF2 alpha. phosphorylation is required for translation attenuation, transcriptional induction, and survival in response to ER stress. Mice with a homozygous mutation at the eIF2 alpha phosphorylation site (Ser51Ala) died within 18 hr after birth due to hypoglycemia associated with defective gluconeogenesis. In addition, homozygous mutant embryos and neonates displayed a deficiency in pancreatic P cells. The results demonstrate that regulation of translation through eIF2 alpha phosphorylation is essential for the ER stress response and in vivo glucose homeostasis.