FIGURE 1.

Integrated stress responses signaling pathway. ER stress, mitochondria stress or heme depletion, amino acid deficiency and ds-RNA virus infection activate PERK, HRI, GCN2 and PKR sensor kinases, leading to phosphorylation of eIF2α. eIF2α phosphorylation causes global inhibition of protein synthesis but selective translation of ATF4 mRNA. ATF4 binds to DNA targets to regulate the expression of genes that promote cellular adaptation, survival and apoptosis. Feedback regulation of ISR is regulated by constitutively expressed phosphatase complex CReP-PP1 and inducible phosphatase GADD34-PP1, which dephosphorylate eIF2α and attenuate or terminate ISR. AA, Amino acid; ER, Endoplasmic reticulum.