Unfolded protein response (UPR) pathway components (UPR)

The Unfolded Protein Response (UPR) is a conserved adaptive signaling pathway triggered by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), a condition termed ER stress (Hetz et al., 2020, Nature Reviews Molecular Cell Biology). It is regulated by three primary sensors: Inositol-requiring enzyme 1 alpha (IRE1α), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6) (Walter & Ron, 2011, Science). Under physiological conditions, these sensors are kept inactive by the chaperone BiP; upon stress, BiP dissociates, allowing the sensors to initiate downstream signaling to restore proteostasis (Wang & Kaufman, 2016, Nature). Initially, the UPR acts to reduce protein translation and increase the ER's folding capacity and degradation machinery. If ER stress is prolonged or severe, the UPR transitions from a cytoprotective role to a pro-apoptotic one, often involving the upregulation of CHOP (DDIT3). Dysregulation of the UPR is implicated in various pathologies, including cancer, where it supports tumor survival, and neurodegenerative diseases, where it contributes to neuronal loss. Pharmacological intervention targets these components using inhibitors like GSK2606414 (PERK) or KIRA6 (IRE1) to modulate cell fate in disease contexts (Grootjans et al., 2016, Gene Expression).

Other names

Endoplasmic reticulum stress pathwayER stress responseUPR signaling pathwayProteotoxic stress response

Modulation of ER stress sensors (PERK, IRE1, ATF6) to either restore proteostasis or trigger apoptosis in diseased cells.