ER stress

Endoplasmic reticulum (ER) stress arises when the capacity of the ER to fold, modify, and quality-control secretory and membrane proteins is exceeded by the demand — triggered by misfolded protein accumulation, calcium depletion, lipid bilayer disequilibrium, or viral infection. Three ER-resident sensors — IRE1alpha, PERK, and ATF6 — detect luminal stress and activate the unfolded protein response (UPR) to restore ER homeostasis by attenuating global translation, upregulating chaperones, and expanding the ER. Chronic, unresolved ER stress, which increases with ageing due to diminished chaperone capacity and accumulated misfolded proteins, shifts UPR signalling toward pro-apoptotic and pro-inflammatory outputs, contributing to beta-cell loss in type 2 diabetes, neurodegeneration, and atherosclerosis.