ERN1

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.[6]

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.[7] XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress.

As IRE1α is a primary sensor for unfolded protein response, its disruption could be linked with neurodegenerative diseases, by which the accumulation of intracellular toxic proteins serves as one of the key pathogenic mechanisms.[8] IRE1 signalling is considered to be pathogenic in Alzheimer's disease,[9] Parkinson's disease[10] and amyotrophic lateral sclerosis.[11][12]

ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[13]

Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain.