Unfolded Protein Response (UPR)

The unfolded protein response (UPR) is an adaptive signalling programme activated when misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER), engaging three parallel branches initiated by the sensors IRE1alpha, PERK, and ATF6. Collectively, these branches attenuate global cap-dependent translation via eIF2alpha phosphorylation, transcriptionally upregulate ER-resident chaperones and folding enzymes, and expand ER-associated protein degradation (ERAD) to clear aberrant proteins. When ER stress is resolved, the UPR is switched off and homeostasis is restored; when stress is chronic and irresolvable — a condition increasingly common with ageing — the UPR shifts its output to activate NF-kB-driven inflammation and CHOP-dependent apoptosis, coupling proteostatic failure to tissue degeneration.