Control of protein synthesis (mRNA translation) plays key roles in shaping the proteome and in many physiological, including homeostatic, responses. One long-known translational control mechanism involves phosphorylation of initiation factor, eIF2, which is catalysed by any one of four protein kinases, which are generally activated in response to stresses. They form a key arm of the integrated stress response (ISR). Phosphorylated eIF2 inhibits eIF2B (the protein that promotes exchange of eIF2-bound GDP for GTP) and thus impairs general protein synthesis. However, this mechanism actually promotes translation of certain mRNAs by virtue of specific features they possess. Recent work has uncovered many previously unknown features of this regulatory system. Several studies have yielded crucial insights into the structure and control of eIF2, including that eIF2B is regulated by several metabolites. Recent studies also reveal that control of eIF2 and the ISR helps determine organismal lifespan and surprising roles in sensing mitochondrial stresses and in controlling the mammalian target of rapamycin (mTOR). The latter effect involves an unexpected role for one of the eIF2 kinases, HRI. Phosphoproteomic analysis identified new substrates for another eIF2 kinase, Gcn2, which senses the availability of amino acids. Several genetic disorders arise from mutations in genes for eIF2α kinases or eIF2B (i.e. vanishing white matter disease, VWM and microcephaly, epileptic seizures, microcephaly, hypogenitalism, diabetes and obesity, MEHMO). Furthermore, the eIF2-mediated ISR plays roles in cognitive decline associated with Alzheimer's disease. New findings suggest potential therapeutic value in interfering with the ISR in certain settings, including VWM, for example by using compounds that promote eIF2B activity.

中文翻译：

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eIF2磷酸化在细胞和有机体生理学中的作用：知名演员的新角色

控制蛋白质合成（mRNA 翻译）在塑造蛋白质组和许多生理反应（包括稳态反应）中起关键作用。一种众所周知的翻译控制机制涉及起始因子 eIF2 的磷酸化，它由四种蛋白激酶中的任何一种催化，这些蛋白激酶通常响应压力而被激活。它们构成了综合应激反应 (ISR) 的关键臂。磷酸化的 eIF2 抑制 eIF2B（促进 eIF2 结合的 GDP 与 GTP 交换的蛋白质），从而损害一般蛋白质合成。然而，这种机制实际上促进了某些 mRNA 的翻译，因为它们具有特定的特征。最近的工作揭示了该监管系统的许多以前未知的特征。几项研究对 eIF2 的结构和控制产生了重要的见解，包括 eIF2B 受几种代谢物的调节。最近的研究还表明，对 eIF2 和 ISR 的控制有助于确定生物体的寿命以及在感知线粒体压力和控制哺乳动物雷帕霉素靶标 (mTOR) 方面的惊人作用。后一种效应涉及 eIF2 激酶之一 HRI 的意外作用。磷酸蛋白质组学分析确定了另一种 eIF2 激酶 Gcn2 的新底物，它可以感知氨基酸的可用性。几种遗传疾病是由 eIF2α 激酶或 eIF2B 基因的突变引起的（即消失性白质病、VWM 和小头畸形、癫痫发作、小头畸形、生殖器低下、糖尿病和肥胖症、MEHMO）。此外，eIF2 介导的 ISR 在与阿尔茨海默病相关的认知衰退中发挥作用。