In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis (1).The ISR can be stimulated by a range of physiological or pathological stimuli including hypoxia, amino acid deprivation, glucose/nutrition deprivation, viral infection and intrinsic endoplasmic reticulum (ER) stress (3).
ER stress, viral infection, and other cellular stress signals activate PERK, PKR, HRI, and GCN2 kinases that converge on phosphorylation of eIF2α, the core of ISR. This leads to global attenuation of Cap‐dependent translation while concomitantly initiates the preferential translation of ISR‐specific mRNAs, such as ATF4. ATF4 is the main effector of the ISR. It forms homo‐ and heterodimers that bind to DNA targets to control the expression of genes involved in cellular adaptation. Termination of the ISR is regulated by the constitutively expressed CReP and stress‐inducible phosphatase GADD34 that dephosphorylate eIF2α. For more details, see main text and Table 1. Arrows denote activation or induction, while blunt lines indicate inhibition.