Serine/threonine-protein kinase/endoribonuclease IRE1 (IRE1 (or ERN1 for IRE1α isoform))

Serine/threonine-protein kinase/endoribonuclease IRE1 is a dual-function enzyme and transmembrane receptor that resides in the endoplasmic reticulum (ER) membrane[2][3][6]. It is a central sensor of ER stress and a key mediator of the unfolded protein response (UPR) in eukaryotic cells. Structurally, IRE1 contains: - An N-terminal luminal domain for detecting misfolded proteins, - A single-pass transmembrane segment, - A cytoplasmic serine/threonine kinase domain, and - A C-terminal RNase domain[2][3][6]. Upon sensing unfolded proteins, IRE1 dimerizes and oligomerizes, leading to kinase domain autophosphorylation and activation of its RNase activity[1][2][3][4][6]. This triggers unconventional splicing of XBP1 mRNA, producing XBP1s, a transcription factor that induces UPR target genes[3]. IRE1 signaling can promote cell survival by restoring ER function but, upon prolonged or excessive activation, can switch to promote apoptosis. IRE1 is a validated therapeutic target, especially in cancers with high secretory burdens, and is actively investigated for drug development[1][3].

Other names

Inositol-requiring enzyme 1Endoplasmic reticulum to nucleus signaling 1 (ERN1)IRE1α (ubiquitous isoform)IRE1β (intestinal epithelium–restricted isoform)ERN1 (gene symbol for human IRE1α)

ATP-competitive inhibition of kinase activity leading to reduction of RNase-mediated XBP1 mRNA splicing Modulation of unfolded protein response by affecting ER stress signaling Dual manipulation: pro-survival (adaptive UPR) or pro-apoptotic (terminal UPR) depending on activity level[1][2][3]