Figure 1. Schematic of the integrated stress response (ISR).

Four eIF2α kinases (GCN2, PKR, PERK, and/or HRI) are specifically activated under certain stress conditions. A high level of phosphorylated eIF2α leads to global repression of protein synthesis and to translational induction of ATF4. These responses alleviate the burden of the stress factor and activate genes for stress resistance. On the other hand, dephosphorylation of eIF2α is regulated by Ppp1r15a and/or Ppp1r15b.