eIF2α kinases PERK and GCN2 act on FOXO to potentiate FOXO activity.

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.