IRE1

IRE1, or inositol-requiring enzyme 1, is a conserved endoplasmic reticulum (ER) membrane sensor of the unfolded protein response (UPR) in eukaryotic cells. In humans it exists as two paralogs, IRE1α (ERN1) and IRE1β (ERN2). The protein is a type I membrane protein with a lumenal domain that detects misfolded proteins, a single transmembrane helix, and cytosolic kinase and endoribonuclease (RNase) domains. Upon ER stress, conformational changes promote IRE1 oligomerization and trans-autophosphorylation, activating its RNase.

The primary signaling output in vertebrates is unconventional splicing of XBP1 mRNA by the RNase, producing XBP1s, a transcription factor that upregulates genes involved in protein folding, ER-associated degradation (ERAD), lipid synthesis, and ER expansion. In yeast, the analogous reaction splices HAC1 mRNA. In addition to XBP1 splicing, IRE1 drives regulated IRE1-dependent decay (RIDD) of select mRNAs, reducing the protein-folding load and tuning the response. IRE1 can also recruit TRAF2 to activate ASK1 and JNK signaling, linking ER stress to apoptotic pathways during prolonged stress.

Functionally, IRE1 helps restore ER homeostasis but can contribute to cell death if stress persists. Its activity is context-dependent, with IRE1α expressed broadly and IRE1β mainly in mucosal epithelia. Dysregulation of IRE1 signaling is associated with metabolic disorders, neurodegenerative diseases, inflammatory conditions, and cancer. Therapeutically, small-molecule modulators of IRE1’s kinase or RNase activities are being explored to adjust UPR signaling in disease.