ERN1
Protein-coding gene in the species Homo sapiens
From Wikipedia, the free encyclopedia
The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.[5][6]
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.[6]
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.[7] XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress.
Clinical significance
As IRE1α is a primary sensor for unfolded protein response, its disruption could be linked with neurodegenerative diseases, wherein 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]
Interactions
ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[13]
Inhibitors
Two types of inhibitors exist targeting either the catalytic core of the RNase domain or the ATP-binding pocket of the kinase domain.
RNase domain inhibitors
Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde,[14] 4μ8C,[15] MKC-3946[16]), STF-083010,[17] toyocamycin.[18]
ATP-binding pocket
Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain.
Compound 3 prevents kinase activity, oligomerization and RNase activity.[19]
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. [20] 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. [21]