eIF2 kinases PERK and GCN2 act on FOXO to potentiate FOXO activity
eIF2 kinases PERK and GCN2 act on FOXO to potentiate FOXO activity
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eIF2 激酶 PERK 和 GCN2 作用于 FOXO 以增强 FOXO 活性
DOI：
10.1111/gtc.12625
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发表时间：
2018
期刊：
影响因子：
2.1
通讯作者：
Zhang Wei
中科院分区：
文献类型：
--
作者：
You Shiqiu;Li Huifang;Hu Zhubing;Zhang Wei
PERK和GCN2是已知的eIF2α激酶，它们介导内质网应激的效应，并对一系列不同的应激刺激做出反应。此前，我们曾报道内质网应激通过PERK介导的FOXO磷酸化增强胰岛素抵抗。抑制PERK可在FOXO活性水平上改善细胞的胰岛素反应。在这里，我们提供了进一步的证据，表明FOXO是PERK功能输出所必需的，因为降低FOXO活性可以改善果蝇的PERK功能获得表型。更重要的是，我们提供的结果表明，GCN2的作用类似于PERK，以促进FOXO活性。GCN2对FOXO的调节在进化上是保守的，可以通过PERK来补偿。这些机制的结合可能有助于PERK、GCN2和FOXO之间的复杂调控网络，该网络已参与多种疾病的发生和发展。
PERK and GCN2 are eIF2α kinases known to mediate the effects of ER stress and respond to an array of diverse stress stimuli. Previously, we reported that ER stress potentiates insulin resistance through PERK‐mediated FOXO phosphorylation. Inhibition of PERK improves cellular insulin responsiveness at the level of FOXO activity. Here we provide further evidence that FOXO is required for the functional output of PERK by showing that lowering FOXO activity ameliorates a PERK gain‐of‐function phenotype inDrosophila. More importantly, we present results demonstrating that GCN2 acts similarly to PERK to promote FOXO activity. Regulation of FOXO by GCN2 is evolutionarily conserved and can be compensated for by PERK. The combination of these mechanisms may contribute to the complex regulatory network between PERK, GCN2, and FOXO, which has been implicated in the development and progression of a variety of diseases.