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
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesERN1, IRE1, IRE1P, IRE1a, hIRE1p, endoplasmic reticulum to nucleus signaling 1
External IDsOMIM: 604033; MGI: 1930134; HomoloGene: 55580; GeneCards: ERN1; OMA:ERN1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_152461
NM_001433

NM_023913

RefSeq (protein)

NP_001424

NP_076402

Location (UCSC)Chr 17: 64.04 – 64.13 MbChr 11: 106.29 – 106.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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

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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

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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

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

Inhibitors

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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

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Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde,[14] 4μ8C,[15] MKC-3946,[16] STF-083010,[17] toyocamycin.[18]

ATP-binding pocket

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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

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000178607Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020715Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Tirasophon W, Welihinda AA, Kaufman RJ (June 1998). "A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells". Genes & Development. 12 (12): 1812–1824. doi:10.1101/gad.12.12.1812. PMC 316900. PMID 9637683.
  6. ^ a b "Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1".
  7. ^ Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, et al. (January 2002). "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature. 415 (6867): 92–96. Bibcode:2002Natur.415...92C. doi:10.1038/415092a. PMID 11780124. S2CID 4319118.
  8. ^ Kurtishi A, Rosen B, Patil KS, Alves GW, Møller SG (May 2019). "Cellular Proteostasis in Neurodegeneration". Molecular Neurobiology. 56 (5): 3676–3689. doi:10.1007/s12035-018-1334-z. PMID 30182337. S2CID 52158118.
  9. ^ Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles ÁO, Medinas DB, Salazar C, et al. (September 2017). "IRE1 signaling exacerbates Alzheimer's disease pathogenesis". Acta Neuropathologica. 134 (3): 489–506. doi:10.1007/s00401-017-1694-x. PMID 28341998. S2CID 9380354.
  10. ^ Yan C, Liu J, Gao J, Sun Y, Zhang L, Song H, et al. (October 2019). "IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease". Cell Death & Disease. 10 (11): 800. doi:10.1038/s41419-019-2039-6. PMC 6805898. PMID 31641108.
  11. ^ Montibeller L, de Belleroche J (September 2018). "Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes". Cell Stress & Chaperones. 23 (5): 897–912. doi:10.1007/s12192-018-0897-y. PMC 6111088. PMID 29725981.
  12. ^ Chen D, Wang Y, Chin ER (2015-05-18). "Activation of the endoplasmic reticulum stress response in skeletal muscle of G93A*SOD1 amyotrophic lateral sclerosis mice". Frontiers in Cellular Neuroscience. 9: 170. doi:10.3389/fncel.2015.00170. PMC 4435075. PMID 26041991.
  13. ^ 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.
  14. ^ Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, et al. (April 2011). "Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease". The Journal of Biological Chemistry. 286 (14): 12743–12755. doi:10.1074/jbc.M110.199737. PMC 3069474. PMID 21303903.
  15. ^ Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, et al. (April 2012). "The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule". Proceedings of the National Academy of Sciences of the United States of America. 109 (15): E869–E878. doi:10.1073/pnas.1115623109. PMC 3326519. PMID 22315414.
  16. ^ Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, et al. (June 2012). "Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma". Blood. 119 (24): 5772–5781. doi:10.1182/blood-2011-07-366633. PMC 3382937. PMID 22538852.
  17. ^ Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, et al. (January 2011). "Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma". Blood. 117 (4): 1311–1314. doi:10.1182/blood-2010-08-303099. PMC 3056474. PMID 21081713.
  18. ^ Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, et al. (July 2012). "Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing". Blood Cancer Journal. 2 (7): e79. doi:10.1038/bcj.2012.26. PMC 3408640. PMID 22852048.
  19. ^ Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, et al. (December 2012). "Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors". Nature Chemical Biology. 8 (12): 982–989. doi:10.1038/nchembio.1094. PMC 3508346. PMID 23086298.
  20. ^ Urra, Hery; Henriquez, Daniel R.; Cánovas, José; Villarroel-Campos, David; Carreras-Sureda, Amado; Pulgar, Eduardo; Molina, Emiliano; Hazari, Younis M.; Limia, Celia M.; Alvarez-Rojas, Sebastián; Figueroa, Ricardo; Vidal, Rene L.; Rodriguez, Diego A.; Rivera, Claudia A.; Court, Felipe A. (August 2018). "IRE1α governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A". Nature Cell Biology. 20 (8): 942–953. doi:10.1038/s41556-018-0141-0. ISSN 1465-7392. PMID 30013108.
  21. ^ Borisova, Ekaterina; Newman, Andrew G.; Couce Iglesias, Marta; Dannenberg, Rike; Schaub, Theres; Qin, Bo; Rusanova, Alexandra; Brockmann, Marisa; Koch, Janina; Daniels, Marieatou; Turko, Paul; Jahn, Olaf; Kaplan, David R.; Rosário, Marta; Iwawaki, Takao (2024-06-07). "Protein translation rate determines neocortical neuron fate". Nature Communications. 15 (1): 4879. doi:10.1038/s41467-024-49198-w. ISSN 2041-1723. PMC 11161512. PMID 38849354.

Further reading

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