Integrated stress response pathway (ISR)

The Integrated Stress Response pathway is a fundamental, evolutionarily conserved signaling network that enables eukaryotic cells to sense and respond to a variety of stressors, including nutrient deprivation, viral infection, hypoxia, and protein misfolding. Its core event is the phosphorylation of eIF2α by one of four sensor kinases: PERK (ER stress), GCN2 (amino acid deprivation), PKR (viral infection/double-stranded RNA), and HRI (heme depletion or mitochondrial stress). Phosphorylated eIF2α leads to global inhibition of protein synthesis and selective translation of adaptive genes, notably ATF4. This program helps restore cellular homeostasis or, under prolonged or severe stress, triggers apoptosis. Individual components of the ISR, especially its sensor kinases and regulatory effectors, are clinically relevant as therapeutic targets in cancer, neurodegeneration, infection, and other diseases, whereas the pathway as a whole is not a single druggable target.

Other names

Integrated stress responseeIF2α phosphorylation pathwayeIF2 signalingISR pathway

Inhibition or activation of eIF2α kinases (PERK, GCN2, PKR, HRI) to modulate eIF2α phosphorylation Modulation of translation initiation and selective mRNA translation Induction or blockade of ATF4 and downstream cytoprotective, pro-apoptotic, or immune regulatory pathways