ERN1

The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 αあるふぁ (IRE1αあるふぁ) is an enzyme that in humans is encoded by the ERN1 gene.

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) Band 17q23.3 Start 64,039,080 bp End 64,130,819 bp
Gene location (Mouse) Chr. Chromosome 11 (mouse) Band 11|11 E1 Start 106,285,476 bp End 106,378,678 bp
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
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.

Signaling

IRE1αあるふぁ possesses two functional enzymatic domains, an endonuclease and a trans-autophosphorylation kinase domain. Upon activation, IRE1αあるふぁ 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.

Clinical significance

As IRE1αあるふぁ 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. IRE1 signalling is considered to be pathogenic in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Interactions

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

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, 4μ8C, MKC-3946, STF-083010, toyocamycin.

ATP-binding pocket

Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1αあるふぁ 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あるふぁ 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あるふぁ controls cytoskeletal remodeling and cell migration during brain development. Additionally, IRE1αあるふぁ regulates protein synthesis rates in the developing murine cortex in a mechanism involving translation initiation and elongation. Loss of IRE1αあるふぁ leads to ribosomal stalling, and loss of upper layer Satb2-expressing neurons at the expense of deeper layer, CTIP2-expressing ones. Moreover, IRE1αあるふぁ controls the proteostasis of eIF4A1 to drive translation of neuronal subtype determinants.

Further reading

• Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, et al. (December 1999). "Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response". Nature Cell Biology. 1 (8): 479–485. doi:10.1038/70265. PMID 10587643. S2CID 30259483.
• Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (January 2000). "Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1". Science. 287 (5453): 664–666. Bibcode:2000Sci...287..664U. doi:10.1126/science.287.5453.664. PMID 10650002. S2CID 9154084.
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, et al. (March 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–3496. Bibcode:2000PNAS...97.3491D. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
• Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, et al. (February 2001). "Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress". Nature Cell Biology. 3 (2): 158–164. doi:10.1038/35055065. PMID 11175748. S2CID 7756732.
• Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (April 2001). "Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress". The Journal of Biological Chemistry. 276 (17): 13935–13940. doi:10.1074/jbc.M010677200. PMID 11278723.
• Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, et al. (February 2002). "IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response". Genes & Development. 16 (4): 452–466. doi:10.1101/gad.964702. PMC 155339. PMID 11850408.
• Liu CY, Wong HN, Schauerte JA, Kaufman RJ (May 2002). "The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain". The Journal of Biological Chemistry. 277 (21): 18346–18356. doi:10.1074/jbc.M112454200. PMID 11897784.
• Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, et al. (June 2002). "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats". Genes & Development. 16 (11): 1345–1355. doi:10.1101/gad.992302. PMC 186318. PMID 12050113.
• Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L (December 2002). "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Molecular and Cellular Biology. 22 (24): 8506–8513. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–16903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Liu CY, Xu Z, Kaufman RJ (May 2003). "Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha". The Journal of Biological Chemistry. 278 (20): 17680–17687. doi:10.1074/jbc.M300418200. PMID 12637535.
• Kaneko M, Niinuma Y, Nomura Y (July 2003). "Activation signal of nuclear factor-kappa B in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2". Biological & Pharmaceutical Bulletin. 26 (7): 931–935. doi:10.1248/bpb.26.931. PMID 12843613.
• Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, et al. (January 2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nature Genetics. 36 (1): 40–45. doi:10.1038/ng1285. PMID 14702039.
• Shang J, Lehrman MA (April 2004). "Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts". Biochemical and Biophysical Research Communications. 317 (2): 390–396. doi:10.1016/j.bbrc.2004.03.058. PMID 15063770.
• Oono K, Yoneda T, Manabe T, Yamagishi S, Matsuda S, Hitomi J, et al. (October 2004). "JAB1 participates in unfolded protein responses by association and dissociation with IRE1". Neurochemistry International. 45 (5): 765–772. doi:10.1016/j.neuint.2004.01.003. PMID 15234121. S2CID 11627892.
• Huang ZM, Tan T, Yoshida H, Mori K, Ma Y, Yen TS (September 2005). "Activation of hepatitis B virus S promoter by a cell type-restricted IRE1-dependent pathway induced by endoplasmic reticulum stress". Molecular and Cellular Biology. 25 (17): 7522–7533. doi:10.1128/MCB.25.17.7522-7533.2005. PMC 1190304. PMID 16107700.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Oikawa D, Tokuda M, Iwawaki T (August 2007). "Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1". Biochemical and Biophysical Research Communications. 360 (1): 122–127. doi:10.1016/j.bbrc.2007.06.020. PMID 17585877.