You Shiqiu, Li Huifang, Hu Zhubing, Zhang Wei
College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
College of Life Science, Nanjing Agricultural University, Nanjing, China.
Genes Cells. 2018 Sep;23(9):786-793. doi: 10.1111/gtc.12625. Epub 2018 Jul 24.
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 in Drosophila. 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.
PERK和GCN2是已知的真核起始因子2α（eIF2α）激酶，可介导内质网应激的作用并对一系列不同的应激刺激做出反应。此前，我们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胰岛素反应性。在这里，我们通过表明降低FOXO活性可改善果蝇中PERK功能获得性表型，进一步提供证据证明FOXO是PERK功能输出所必需的。更重要的是，我们展示的结果表明GCN2与PERK的作用类似，可促进FOXO活性。GCN2对FOXO的调节在进化上是保守的，并且可以由PERK代偿。这些机制的组合可能有助于PERK、GCN2和FOXO之间复杂的调控网络，这与多种疾病的发生和发展有关。
