Integrated Stress Response (ISR)

The integrated stress response (ISR) is a conserved eukaryotic signalling programme that converges on phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α) by any of four stress-sensing kinases — HRI (haem deficiency), PKR (double-stranded RNA), PERK (ER unfolded proteins) and GCN2 (uncharged tRNAs / amino acid deprivation). eIF2α phosphorylation globally suppresses cap-dependent translation while selectively enhancing translation of stress-response mRNAs containing upstream open reading frames, most notably ATF4, which orchestrates transcriptional adaptation to the specific stress. The ISR supports short-term adaptation but, when chronically active — as seen in neurodegenerative disease, obesity and ageing — impairs synaptic plasticity, memory, and protein synthesis capacity in post-mitotic tissues; small-molecule ISR inhibitors such as ISRIB, which antagonise the inhibitory effect of phospho-eIF2α on eIF2B thereby restoring translation capacity, show efficacy in preclinical models of neurodegeneration and cognitive decline.