Inositol-requiring enzyme 1 alpha and Protein kinase RNA-like endoplasmic reticulum kinase (IRE1α and PERK)

Inositol-requiring enzyme 1 alpha (IRE1α) and Protein kinase RNA-like endoplasmic reticulum kinase (PERK) are the primary transmembrane sensors of the unfolded protein response (UPR) located in the endoplasmic reticulum (ER) (UniProt O75460, Q9NZJ5). They detect the accumulation of misfolded proteins and initiate signaling cascades to restore proteostasis or, under chronic stress, trigger apoptosis (PubMed: 33762516). IRE1α is a dual-function enzyme with kinase and endoribonuclease activities that facilitate the splicing of XBP1 mRNA, while PERK is a kinase that phosphorylates eIF2α to attenuate global protein translation (PubMed: 33664244). These sensors are critically involved in the pathogenesis of various diseases, including cancer, where they support tumor survival under hypoxic conditions, and neurodegenerative disorders, where they respond to protein aggregation (PubMed: 33664244). Pharmacological modulation of IRE1α and PERK is a major area of drug development, with inhibitors like MKC8866 and GSK2606414 being explored to sensitize cancer cells or protect neurons (PubMed: 24046371). However, therapeutic targeting faces challenges such as pancreatic toxicity associated with PERK inhibition and the complex dual roles of these sensors in cell survival versus death (PubMed: 24046371).

Other names

ERN1EIF2AK3hIRE1pInositol-requiring protein 1 alphaPEKPKR-like ER kinase

Inhibition of IRE1α endoribonuclease activity, inhibition of PERK kinase activity, and prevention of eIF2α phosphorylation and XBP1 splicing.