The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1gene.
Function
The protein encoded by this gene is the ER to nucleus signalling 1 protein, a human homologue of the yeast Ire1 gene product. This protein possesses intrinsic kinase activity and an endoribonuclease activity and it is important in altering gene expression as a response to endoplasmic reticulum-based stress signals (mainly the unfolded protein response). Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.
Signaling
IRE1α possesses two functional enzymatic domains, an endonuclease and a trans-autophosphorylation kinase domain. Upon activation, IRE1α oligomerizes and carries out an unconventional RNA splicing activity, removing an intron from the X-box binding protein 1 (XBP1) mRNA, and allowing it to become translated into a functional transcription factor, XBP1s. XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress.
Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain.
Compound 3 prevents kinase activity, oligomerization and RNase activity.
Specific roles in the brain
Apart from its function as the main regulator of cellular stress and the Unfolded Protein Response pathway, IRE1α also has its non-canonical roles in the brain. For one, it has been shown to act as a scaffold, which recruits and regulates filamin A. This way, IRE1α controls cytoskeletal remodeling and cell migration during brain development. Additionally, IRE1α regulates protein synthesis rates in the developing murine cortex in a mechanism involving translation initiation and elongation. Loss of IRE1α leads to ribosomal stalling, and loss of upper layer Satb2-expressing neurons at the expense of deeper layer, CTIP2-expressing ones. Moreover, IRE1α controls the proteostasis of eIF4A1 to drive translation of neuronal subtype determinants.
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