Fig. 1

Overview of the integrated stress response pathway. Distinct cellular stresses cause the phosphorylation and activation the eIF2α kinases PERK, PKR, GCN2 and HRI. The eIF2α kinases phosphorylate Ser51 of eIF2α which leads to suppression of global protein synthesis but selective enhancement of translation of some mRNAs, such as that encoding ATF4. ATF4 is a transcription factor that activates genes which regulate cellular responses to stress signals to determine cell fate. Additionally, in a negative feedback loop, ATF4 drives the expression of GADD34, a protein phosphatase 1 (PP1) regulatory subunit which forms a complex with the PP1 catalytic subunit (PP1c) to dephosphorylate and inactivate eIF2α. Another PP1 regulatory subunit, CReP, is constitutively expressed independent of ISR signaling and functions to maintain basal levels of de-phosphorylated eIF2α in the absence of stress. Created with BioRender.com