Biology:ERN1

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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

  1. ↑ "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. ↑ 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. 
  3. ↑ "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. 
  4. ↑ "Cellular Proteostasis in Neurodegeneration". Molecular Neurobiology 56 (5): 3676–3689. May 2019. doi:10.1007/s12035-018-1334-z. PMID 30182337. 
  5. ↑ "IRE1 signaling exacerbates Alzheimer's disease pathogenesis". Acta Neuropathologica 134 (3): 489–506. September 2017. doi:10.1007/s00401-017-1694-x. PMID 28341998. 
  6. ↑ "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. 
  7. ↑ "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. 
  8. ↑ "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. 
  9. ↑ "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. 
  10. ↑ "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. 
  11. ↑ "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. 
  12. ↑ "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. 
  13. ↑ "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. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ "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




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