Endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) (IRE1α)

Endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) is a type I transmembrane protein located in the endoplasmic reticulum (ER) membrane that serves as a primary sensor for the unfolded protein response (UPR) (UniProt: P51367). It possesses dual enzymatic activities: a cytoplasmic serine/threonine kinase domain and an endoribonuclease (RNase) domain (PubMed: 24553141). Upon sensing ER stress caused by the accumulation of unfolded proteins, IRE1α undergoes oligomerization and autophosphorylation, which activates its RNase domain to catalyze the unconventional splicing of XBP1 mRNA into its active form (XBP1s) and initiate regulated IRE1-dependent decay (RIDD) of various mRNAs (PubMed: 18425123). In disease contexts, chronic activation of IRE1α is linked to cancer cell survival, inflammatory signaling, and neurodegeneration, making it a significant therapeutic target (PubMed: 30305440). Pharmacological strategies include small-molecule inhibitors targeting either the ATP-binding pocket of the kinase domain (Kinase-Inhibiting RNase Attenuators or KIRAs) or the RNase catalytic site to modulate UPR signaling (PubMed: 25129134).

Other names

ERN1hIRE1pInositol-requiring protein 1Serine/threonine-protein kinase/endoribonuclease IRE1

Inhibition of the kinase domain (KIRA) or the endoribonuclease domain to modulate the unfolded protein response and downstream XBP1 splicing.