ERN1

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]

ERN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2HZ6, 3P23, 4U6R, 4Z7G, 4Z7H, 4YZC, 4YZ9, 4YZD, 5HGI
Identifiers
Aliases	ERN1, IRE1, IRE1P, IRE1a, hIRE1p, endoplasmic reticulum to nucleus signaling 1
External IDs	OMIM: 604033; MGI: 1930134; HomoloGene: 55580; GeneCards: ERN1; OMA:ERN1 - orthologs
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17q23.3 Start 64,039,080 bp[1] End 64,130,819 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 E1 Start 106,285,476 bp[2] End 106,378,678 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in parotid gland decidua amniotic fluid secondary oocyte right adrenal cortex seminal vesicula left adrenal cortex body of pancreas caput epididymis germinal epithelium Top expressed in secondary oocyte primary oocyte gastrula decidua seminal vesicula lacrimal gland submandibular gland adrenal gland zygote parotid gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding nucleotide binding ADP binding ribonuclease activity identical protein binding protein kinase activity transferase activity magnesium ion binding hydrolase activity Hsp70 protein binding kinase activity Hsp90 protein binding catalytic activity endonuclease activity ATP binding enzyme binding protein binding endoribonuclease activity protein serine/threonine kinase activity platelet-derived growth factor receptor binding protein homodimerization activity unfolded protein binding Cellular component AIP1-IRE1 complex cytoplasm integral component of membrane mitochondrion IRE1-TRAF2-ASK1 complex IRE1-RACK1-PP2A complex nuclear inner membrane Ire1 complex membrane integral component of endoplasmic reticulum membrane endoplasmic reticulum endoplasmic reticulum membrane Biological process positive regulation of endoplasmic reticulum unfolded protein response mRNA catabolic process transcription, DNA-templated insulin metabolic process peptidyl-serine autophosphorylation cellular response to vascular endothelial growth factor stimulus protein autophosphorylation metabolism apoptotic process mRNA splicing, via endonucleolytic cleavage and ligation intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress cellular response to glucose stimulus peptidyl-serine trans-autophosphorylation protein phosphorylation response to unfolded protein mRNA processing response to endoplasmic reticulum stress regulation of transcription, DNA-templated endothelial cell proliferation regulation of macroautophagy phosphorylation endoplasmic reticulum unfolded protein response positive regulation of vascular associated smooth muscle cell proliferation RNA phosphodiester bond hydrolysis, endonucleolytic positive regulation of RNA splicing IRE1-mediated unfolded protein response mRNA cleavage involved in mRNA processing mRNA cleavage Unfolded Protein Response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2081 78943 Ensembl ENSG00000178607 ENSMUSG00000020715 UniProt O75460 Q9EQY0 RefSeq (mRNA) NM_152461 NM_001433 NM_023913 RefSeq (protein) NP_001424 NP_076402 Location (UCSC) Chr 17: 64.04 – 64.13 Mb Chr 11: 106.29 – 106.38 Mb PubMed search [3] [4]
Wikidata
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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]