Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells.
Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells.
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DOI：
10.1016/j.cmet.2009.06.002
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发表时间：
2009-07
期刊：
影响因子：
29
通讯作者：
Kaufman RJ
中科院分区：
文献类型：
--
作者：
Back SH;Scheuner D;Han J;Song B;Ribick M;Wang J;Gildersleeve RD;Pennathur S;Kaufman RJ
内质网（ER）管腔内未折叠蛋白的积累通过激活蛋白激酶PERK和随后α亚基（eIF2α） Ser51上真核起始因子2的磷酸化来减弱mRNA的翻译。在人类和小鼠中，PERK/eIF2α通路的遗传破坏会产生严重的胰腺β细胞缺乏和产后死亡。为了阐明eIF2α磷酸化在β细胞中的作用，我们通过表达一个loxp -翼的野生型eIF2α转基因，挽救了纯合子eIF2α Ser51Ala小鼠的致病性。β细胞特异性转基因缺失以防止eIF2α磷酸化导致严重的糖尿病表型，原因是胰岛素原翻译升高，不受调节，分泌和质膜蛋白在细胞内运输缺陷，氧化损伤增加，应激反应和β细胞特异性基因表达减少，以及细胞凋亡。然而，通过抗氧化处理，这些小鼠的葡萄糖耐受不良和β细胞死亡有所减轻。我们得出结论，eIF2α的磷酸化协同减弱mRNA翻译，防止氧化应激，并优化内质网蛋白折叠，以支持β细胞中胰岛素的产生。这些发现表明胰岛素原合成增加导致氧化应激导致β细胞衰竭，这可能反映了2型糖尿病中与胰岛素抵抗相关的β细胞损失事件。
Accumulation of unfolded protein within the endoplasmic reticulum (ER) lumen attenuates mRNA translation through activation of the protein kinase PERK and subsequent phosphorylation of eukaryotic initiation factor 2 on Ser51 of the alpha subunit (eIF2α). Genetic disruption of the PERK/eIF2α pathway in humans and mice produces severe pancreatic beta cell deficiency and post-natal lethality. To elucidate the role of eIF2α phosphorylation in beta cells, we have rescued the lethality of homozygous eIF2α Ser51Ala mice by expression of a loxP-flanked wild-type eIF2α transgene. Beta cell-specific transgene deletion to prevent eIF2α phosphorylation caused a severe diabetic phenotype due to heightened, unregulated proinsulin translation, defective intracellular trafficking of secretory and plasma membrane proteins, increased oxidative damage, reduced expression of stress response and beta cell-specific genes, and apoptosis. However, glucose intolerance and beta cell death in these mice were attenuated by antioxidant treatment. We conclude that phosphorylation of eIF2α coordinately attenuates mRNA translation, prevents oxidative stress, and optimizes ER protein folding to support insulin production in the beta cell. These findings that show increased proinsulin synthesis causes oxidative stress leading to beta cell failure may reflect events in the beta cell loss associated with insulin resistance in type 2 diabetes.
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影响因子：
4.1
作者：
Gomez, Edith;Powell, Mike L.;Herbert, Terence P.
通讯作者：
Herbert, Terence P.
影响因子：
11.4
作者：
Lee, AH;Chu, GC;Glimcher, LH
通讯作者：
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影响因子：
16
作者：
Harding, HP;Novoa, I;Ron, D
通讯作者：
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DOI：
10.1073/pnas.0602956103
发表时间：
2006-06-13
影响因子：
11.1
作者：
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通讯作者：
Mauvais-Jarvis, Franck
影响因子：
64.8
作者：
Dor, Y;Brown, J;Melton, DA
通讯作者：
Melton, DA