Inositol-requiring enzyme 1 alpha (IRE1α) (IRE1α)

Inositol-requiring enzyme 1 alpha (IRE1α), encoded by the ERN1 gene, is a type I transmembrane protein and the most evolutionarily conserved sensor of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) [1, 10]. It possesses a luminal domain that detects misfolded proteins and a cytosolic region containing both a serine/threonine kinase domain and an endoribonuclease (RNase) domain [1, 4]. Upon activation by ER stress, IRE1α undergoes dimerization and trans-autophosphorylation, which induces a conformational change that activates its RNase domain [7, 10]. This domain is responsible for the non-conventional splicing of XBP1 mRNA into its active form (XBP1s) and the degradation of various ER-localized mRNAs through a process called Regulated IRE1-Dependent Decay (RIDD) [1, 15]. These pathways collectively regulate cell survival, protein folding capacity, and apoptosis, making the IRE1α RNase domain a high-priority therapeutic target in cancers (such as multiple myeloma and triple-negative breast cancer), neurodegenerative diseases, and metabolic disorders [3, 4, 12]. Pharmacological modulation involves direct RNase inhibitors that bind the catalytic site (e.g., 4μ8C, STF-083010) and allosteric kinase inhibitors (KIRAs) that prevent RNase activation [1, 6, 14].

Other names

ERN1Endoplasmic reticulum to nucleus signaling 1hIRE1pIRE1IRE1PInositol-requiring protein 1

Direct inhibition of the RNase catalytic site or allosteric inhibition via the kinase domain to prevent RNase activation and subsequent XBP1 splicing and RIDD activity.