Fig. 1

The integrated stress response signaling pathway. The ISR can be initiated upon sensing ER stress, dsRNA, amino acid deprivation, and heme depletion, which are recognized by PERK, PKR, GCN2, and HRI respectively. Once activated, the four kinases converge in the phosphorylation of eIF2α that then activates ATF4. ATF4 translocate to the nucleus in which promotes the translation of stress response genes. Evidence shows regulation of ISR through “negative feedback”. ATF4 induces the expression of GADD34, which promotes the dephosphorylation of eIF2α by recruiting CReP and PP1c, hence restoring protein synthesis. Figure was created in BioRender