Unfolded protein response sensors (UPR sensors)

The Unfolded Protein Response (UPR) sensors and signaling components are a group of endoplasmic reticulum (ER) resident proteins that monitor and maintain protein folding quality (NIH, 2024). The three primary sensors—Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6)—detect the accumulation of misfolded proteins in the ER lumen (UniProt, 2024). Upon activation, they initiate a coordinated signaling network that reduces protein synthesis, increases the expression of molecular chaperones, and promotes the degradation of defective proteins (PubMed, 2011). While the UPR initially serves a pro-survival, homeostatic function, chronic or excessive ER stress can trigger a terminal UPR that leads to programmed cell death (Nature, 2014). This dual role makes the UPR a significant therapeutic target in various pathologies, including cancer, where tumor cells exploit the pathway for survival, and neurodegenerative diseases, where protein aggregation causes chronic stress (Frontiers in Oncology, 2019). Pharmacological modulation of these sensors, such as through IRE1 or PERK inhibitors, is currently being explored to selectively induce apoptosis in cancer cells or protect vulnerable neurons from proteotoxicity (Journal of Clinical Investigation, 2022). Key signaling components also include the chaperone BiP (GRP78), which acts as the master regulator, and downstream transcription factors like XBP1, ATF4, and CHOP (R&D Systems, 2024). Therapeutic strategies involve both the inhibition of these sensors to overcome chemoresistance in cancer and their activation to enhance proteostasis in protein-misfolding disorders (NIH, 2015).

Other names

Unfolded Protein Response sensors and signaling componentsER stress sensorsUPR transducersIRE1-PERK-ATF6 signaling componentsEndoplasmic reticulum stress sensors

Inhibition of IRE1α endoribonuclease activity, inhibition of PERK-mediated eIF2α phosphorylation, inhibition of ATF6 Golgi translocation and proteolytic cleavage, and activation of ATF6-mediated adaptive proteostasis.