Integrated Stress Response and Unfolded Protein Response (ISR/UPR)

The Integrated Stress Response (ISR) and Unfolded Protein Response (UPR) are evolutionarily conserved intracellular signaling networks that maintain cellular proteostasis. The UPR specifically monitors the protein-folding capacity of the endoplasmic reticulum (ER) through three primary sensors: PERK, IRE1, and ATF6 (Walter & Ron, 2011, Science). The ISR is a broader pathway that responds to various stressors—including ER stress, amino acid deprivation, and viral infection—by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) (Costa-Mattioli & Walter, 2020, Science). Both pathways converge on the global reduction of protein synthesis while selectively increasing the translation of stress-adaptive genes like ATF4 to restore balance or trigger apoptosis if the stress is irremediable (Pakos-Zebrucka et al., 2016, EMBO reports). Dysregulation of these pathways is implicated in a wide range of pathologies, including neurodegenerative diseases like Alzheimer's and ALS, where chronic activation leads to persistent inhibition of protein synthesis, and cancer, where tumors hijack these pathways to survive (Hetz et al., 2020, Nature Reviews Molecular Cell Biology). Therapeutic strategies involve either inhibiting these pathways to restore translation or activating them to induce apoptosis in cancer cells.

Other names

Proteotoxic stress responseER stress responseeIF2α signaling pathwayStress-induced translation control

Modulation of eIF2α phosphorylation, inhibition of ER stress sensors (PERK, IRE1, ATF6), or chemical chaperoning to reduce protein misfolding.