Biology:ERN1
 Generic protein structure example |
The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.[1][2]
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.[2]
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.[3] 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, by which the accumulation of intracellular toxic proteins serves as one of the key pathogenic mechanisms.[4] IRE1 signalling is considered to be pathogenic in Alzheimer's disease,[5] Parkinson's disease[6] and amyotrophic lateral sclerosis.[7][8]
Research
ERN1 is overexpressed in the direct iPSC-derived motor neurons generated from familial ALS patients’ blood, and suppressing Ire1 in the C9orf72-ALS fly model impeded eye degeneration.[9]
Interactions
ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[10]
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,[11] 4μ8C,[12] MKC-3946,[13] STF-083010,[14] toyocamycin.[15]
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.[16]
References
- ↑ "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. June 1998. doi:10.1101/gad.12.12.1812. PMID 9637683.
- ↑ 2.0 2.1 "Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2081.
- ↑ "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature 415 (6867): 92–96. January 2002. doi:10.1038/415092a. PMID 11780124. Bibcode: 2002Natur.415...92C.
- ↑ "Cellular Proteostasis in Neurodegeneration". Molecular Neurobiology 56 (5): 3676–3689. May 2019. doi:10.1007/s12035-018-1334-z. PMID 30182337.
- ↑ "IRE1 signaling exacerbates Alzheimer's disease pathogenesis". Acta Neuropathologica 134 (3): 489–506. September 2017. doi:10.1007/s00401-017-1694-x. PMID 28341998.
- ↑ "IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease". Cell Death & Disease 10 (11): 800. October 2019. doi:10.1038/s41419-019-2039-6. PMID 31641108.
- ↑ "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. September 2018. doi:10.1007/s12192-018-0897-y. PMID 29725981.
- ↑ "Activation of the endoplasmic reticulum stress response in skeletal muscle of G93A*SOD1 amyotrophic lateral sclerosis mice". Frontiers in Cellular Neuroscience 9: 170. 2015-05-18. doi:10.3389/fncel.2015.00170. PMID 26041991.
- ↑ "Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics–An AI-Enabled Biological Target Discovery Platform.". Frontiers in Aging Neuroscience 14: 638. 2022. doi:10.3389/fnagi.2022.914017. PMID 35837482.
- ↑ "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Molecular and Cellular Biology 22 (24): 8506–8513. December 2002. doi:10.1128/MCB.22.24.8506-8513.2002. PMID 12446770.
- ↑ "Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease". The Journal of Biological Chemistry 286 (14): 12743–12755. April 2011. doi:10.1074/jbc.M110.199737. PMID 21303903.
- ↑ "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. April 2012. doi:10.1073/pnas.1115623109. PMID 22315414.
- ↑ "Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma". Blood 119 (24): 5772–5781. June 2012. doi:10.1182/blood-2011-07-366633. PMID 22538852.
- ↑ "Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma". Blood 117 (4): 1311–1314. January 2011. doi:10.1182/blood-2010-08-303099. PMID 21081713.
- ↑ "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. July 2012. doi:10.1038/bcj.2012.26. PMID 22852048.
- ↑ "Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors". Nature Chemical Biology 8 (12): 982–989. December 2012. doi:10.1038/nchembio.1094. PMID 23086298.
Further reading
- "Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response". Nature Cell Biology 1 (8): 479–485. December 1999. doi:10.1038/70265. PMID 10587643.
- "Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1". Science 287 (5453): 664–666. January 2000. doi:10.1126/science.287.5453.664. PMID 10650002. Bibcode: 2000Sci...287..664U.
- "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. March 2000. doi:10.1073/pnas.97.7.3491. PMID 10737800. Bibcode: 2000PNAS...97.3491D.
- "Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress". Nature Cell Biology 3 (2): 158–164. February 2001. doi:10.1038/35055065. PMID 11175748.
- "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. April 2001. doi:10.1074/jbc.M010677200. PMID 11278723.
- "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. February 2002. doi:10.1101/gad.964702. PMID 11850408.
- "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. May 2002. doi:10.1074/jbc.M112454200. PMID 11897784.
- "ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats". Genes & Development 16 (11): 1345–1355. June 2002. doi:10.1101/gad.992302. PMID 12050113.
- "Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha". Molecular and Cellular Biology 22 (24): 8506–8513. December 2002. doi:10.1128/MCB.22.24.8506-8513.2002. PMID 12446770.
- "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. December 2002. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M.
- "Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha". The Journal of Biological Chemistry 278 (20): 17680–17687. May 2003. doi:10.1074/jbc.M300418200. PMID 12637535.
- "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. July 2003. doi:10.1248/bpb.26.931. PMID 12843613.
- "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nature Genetics 36 (1): 40–45. January 2004. doi:10.1038/ng1285. PMID 14702039.
- "Discordance of UPR signaling by ATF6 and Ire1p-XBP1 with levels of target transcripts". Biochemical and Biophysical Research Communications 317 (2): 390–396. April 2004. doi:10.1016/j.bbrc.2004.03.058. PMID 15063770.
- "JAB1 participates in unfolded protein responses by association and dissociation with IRE1". Neurochemistry International 45 (5): 765–772. October 2004. doi:10.1016/j.neuint.2004.01.003. PMID 15234121.
- "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. September 2005. doi:10.1128/MCB.25.17.7522-7533.2005. PMID 16107700.
- "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. January 2006. doi:10.1101/gr.4039406. PMID 16344560.
- "Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha". Science 312 (5773): 572–576. April 2006. doi:10.1126/science.1123480. PMID 16645094. Bibcode: 2006Sci...312..572H.
- "Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1". Biochemical and Biophysical Research Communications 360 (1): 122–127. August 2007. doi:10.1016/j.bbrc.2007.06.020. PMID 17585877.
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