Unfolded protein response pathway components (UPR)

The Unfolded Protein Response (UPR) is a complex cellular surveillance mechanism located in the endoplasmic reticulum (ER) that maintains protein homeostasis (proteostasis) by responding to the accumulation of misfolded proteins (Hetz et al., 2020). It is mediated by three primary transmembrane sensors: Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like ER kinase (PERK), and Activating transcription factor 6 (ATF6), which collectively coordinate a program to reduce protein synthesis, enhance folding capacity, and clear defective proteins (Walter & Ron, 2011). While the UPR is initially cytoprotective, chronic or overwhelming ER stress shifts the signaling toward a pro-apoptotic program, often involving the upregulation of CHOP and the activation of caspases (Oakes & Papa, 2015). In various diseases, the UPR is either pathologically suppressed or hyperactivated; for instance, cancer cells often hijack UPR signaling to survive harsh microenvironments, whereas in neurodegenerative diseases, the UPR may fail to clear toxic aggregates (Marciniak et al., 2022). Consequently, "unspecified UPR-related targets" encompasses a variety of enzymes and transcription factors within this pathway that are being investigated as therapeutic nodes for small-molecule inhibitors or activators (Adams et al., 2019).

Other names

Endoplasmic reticulum stress responseER stress pathwayIntegrated stress response componentsUPR pathway

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