IRE1 alpha

Inositol-requiring protein 1/IRE1 alpha (also called Endoplasmic Reticulum to Nucleus Signaling 1/ERN1; predicted mol wt 110 kDa) is a serine-threonine protein kinase/endoribonuclease which plays a highly critical role in unfolded protein response/UPR signaling, a mechanism by which eukaryotic cells sense and deal with ER stress. The latter triggers growth arrest and apoptosis in cells with misfolded proteins.

Despite in depth characterization of the role of IRE1 alpha (inositol-requiring enzyme 1 alpha) in activating the unfolded protein response (UPR) in the ER - little is known about the molecular mechanisms by which this ER protein has shown to regulate intracellular calcium levels and subsequent apoptosis. Intracellular calcium homeostasis is fundamental to many physiological processes, and an increase in Ca2+ is associated with both the early and late stages of apoptosis.

The unfolded protein response (UPR) is a eukaryotic cell process that addresses ER stress. UPR is initiated by three ER-localized sensors: PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 alpha (IRE1 alpha). UPR-downstream signaling is modulated by the ATF6 and IRE1-XBP1 pathways.

Inositol Requiring Enzyme 1 alpha (IRE1 alpha) is a transmembrane-RNase with an endoplasmic reticulum (ER) luminal sensor domain and cytosolic kinase and ribonuclease domains. IRE1 also plays a central role in the ER stress response (1).