AI Article Synopsis
- PERK and GCN2 are eIF2α kinases that help cells respond to ER stress and other stress signals, influencing insulin resistance through the phosphorylation of FOXO.
- Lowering FOXO activity can reduce negative effects linked to increased PERK activity, as shown in studies with Drosophila.
- GCN2 also promotes FOXO activity in a way similar to PERK, suggesting a complex regulatory relationship between these proteins, which may play a role in various diseases.
Article Abstract
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.
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| http://dx.doi.org/10.1111/gtc.12625 | DOI Listing |
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