Unfolded protein response signaling pathway (UPR)

The endoplasmic reticulum (ER) stress-related signaling pathway, also known as the unfolded protein response (UPR), is a conserved cellular mechanism that reacts to the accumulation of misfolded or unfolded proteins in the ER. The UPR comprises three principal branches controlled by ER-resident sensor proteins: inositol-requiring enzyme 1 alpha (IRE1α), protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). When activated, the UPR temporarily reduces general protein synthesis, increases expression of molecular chaperones (like BiP/GRP78), and enhances protein degradation machinery. If ER homeostasis cannot be restored, chronic signaling through these branches activates cell death pathways (such as CHOP-mediated apoptosis). Dysregulation of ER stress signaling is implicated in a wide range of diseases, including cancer, neurodegeneration, metabolic diseases (e.g., diabetes), inflammatory diseases, and others. Modulating components of the ER stress signaling pathway is currently under investigation as a therapeutic approach for these disorders, but presents complex safety and biomarker challenges.

Other names

Endoplasmic reticulum stress responseER stress signalingER stress pathwaysUnfolded protein response (UPR)UPR signaling

Chaperone upregulation; Inhibition of PERK or IRE1α kinase/endoribonuclease activity; Regulation of protein degradation; Restoration of proteostasis; Attenuation of protein synthesis; Apoptosis induction (via terminal UPR)