Unfolded Protein Response

Synonyms: UPR

Increased protein secretion or disrupted ER protein folding can cause accumulation of unfolded or misfolded proteins in the ER lumen — a condition referred to as ‘ER stress’. To ensure protein folding fidelity and to maintain ER functions, the unfolded protein response (UPR) of eukaryotic cells evolved to a network of signal transduction pathways to reprogramme gene transcription, mRNA translation and protein modifications to relieve the load of unfolded or misfolded proteins and restore protein homeostasis (proteostasis).

ER stress activates the stress sensors ATF6, IRE1, and PERK, representing the three branches of the UPR. Activation of each sensor produces a transcription factor (ATF6, XBP1, and ATF4, respectively) that activates genes to increase the protein-folding capacity in the ER. IRE1 (via RIDD) and PERK (via eIF2a phosphorylation) also decrease the load of proteins entering the ER. Both outcomes work as feedback loops that mitigate ER stress. If cells cannot reestablish homeostasis but continue to experience prolonged and unmitigated ER stress (depicted by the timer), they apoptose.