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Protein ERN1 PDB 2hz6.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesERN1, IRE1, IRE1P, IRE1a, hIRE1p, endoplasmic reticulum to nucleus signaling 1
External IDsOMIM: 604033 MGI: 1930134 HomoloGene: 55580 GeneCards: ERN1
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 17: 64.04 – 64.13 Mbn/a
PubMed search[2][3]
View/Edit HumanView/Edit Mouse

The serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α (IRE1α) is an enzyme that in humans is encoded by the ERN1 gene.[4][5]


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.[5]


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.[6] XBP1s upregulates ER chaperones and endoplasmic reticulum associated degradation (ERAD) genes that facilitate recovery from ER stress.


ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.[7]


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[edit]

Salicylaldehydes (3-methoxy-6-bromosalicylaldehyde,[8] 4μ8C,[9] MKC-3946,[10] STF-083010,[11] toyocamycin.[12]

ATP-binding pocket[edit]

Sunitinib and APY29 inhibit the ATP-binding pocket but allosterically activate the IRE1α RNase domain.

Compound 3 prevents kinase activity, oligomerization and RNase activity.[13]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000178607 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ Tirasophon W, Welihinda AA, Kaufman RJ (Jul 1998). "A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells". Genes Dev. 12 (12): 1812–24. doi:10.1101/gad.12.12.1812. PMC 316900. PMID 9637683.
  5. ^ a b "Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1".
  6. ^ Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (January 2002). "IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA". Nature. 415 (6867): 92–6. doi:10.1038/415092a. PMID 11780124. S2CID 4319118.
  7. ^ 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". Mol. Cell. Biol. 22 (24): 8506–13. doi:10.1128/MCB.22.24.8506-8513.2002. PMC 139892. PMID 12446770.
  8. ^ Volkmann K, Lucas JL, Vuga D, Wang X, Brumm D, Stiles C, Kriebel D, Der-Sarkissian A, Krishnan K, Schweitzer C, Liu Z, Malyankar UM, Chiovitti D, Canny M, Durocher D, Sicheri F, Patterson JB (April 2011). "Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease". J. Biol. Chem. 286 (14): 12743–55. doi:10.1074/jbc.M110.199737. PMC 3069474. PMID 21303903.
  9. ^ Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP (April 2012). "The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule". Proc. Natl. Acad. Sci. U.S.A. 109 (15): E869–78. doi:10.1073/pnas.1115623109. PMC 3326519. PMID 22315414.
  10. ^ Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H, Kiziltepe T, Ikeda H, Kawano Y, French M, Blumenthal M, Tam V, Kertesz NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC (June 2012). "Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma". Blood. 119 (24): 5772–81. doi:10.1182/blood-2011-07-366633. PMC 3382937. PMID 22538852.
  11. ^ Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC (January 2011). "Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma". Blood. 117 (4): 1311–4. doi:10.1182/blood-2010-08-303099. PMC 3056474. PMID 21081713.
  12. ^ Ri M, Tashiro E, Oikawa D, Shinjo S, Tokuda M, Yokouchi Y, Narita T, Masaki A, Ito A, Ding J, Kusumoto S, Ishida T, Komatsu H, Shiotsu Y, Ueda R, Iwawaki T, Imoto M, Iida S (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 J. 2 (7): e79. doi:10.1038/bcj.2012.26. PMC 3408640. PMID 22852048.
  13. ^ Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ (December 2012). "Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors". Nat. Chem. Biol. 8 (12): 982–9. doi:10.1038/nchembio.1094. PMC 3508346. PMID 23086298.

Further reading[edit]