Unfolded protein response pathway sensors (UPR sensors)

The Unfolded Protein Response (UPR) pathway sensors are a group of three primary transmembrane proteins—Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6)—located in the endoplasmic reticulum (ER) membrane (Hetz et al., 2020). These sensors detect the accumulation of unfolded or misfolded proteins within the ER lumen and initiate signaling cascades to restore proteostasis by increasing chaperone production, inhibiting general translation, and enhancing ER-associated degradation (Walter & Ron, 2011). In conditions of chronic stress, the UPR switches to a pro-apoptotic signaling mode, often mediated by the transcription factor CHOP (Wang & Kaufman, 2016). This pathway is a critical therapeutic target in oncology, where tumors utilize UPR to survive hypoxia, and in neurodegeneration, where protein aggregation overwhelms cellular defenses. While specific inhibitors for individual sensors are in development, many compounds are characterized as UPR modulators based on phenotypic effects before their exact molecular binding site on a specific sensor is confirmed.

Other names

ER stress sensorsUPR signaling componentsIRE1-PERK-ATF6 triadEndoplasmic reticulum stress sensors

Modulation of endoplasmic reticulum stress sensors (IRE1, PERK, or ATF6) to either restore protein folding homeostasis or selectively induce apoptosis in stressed cells.