ERN1 explained

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.

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]}

Interactions

ERN1 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1.^[9]

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,^[10] 4μ8C,^[11] MKC-3946,^[12] STF-083010,^[13] toyocamycin.^[14]

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.^[15]

Specific roles in the brain

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. ^[16] 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. ^[17]

Further reading

• Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M . 6 . Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response . Nature Cell Biology . 1 . 8 . 479–485 . December 1999 . 10587643 . 10.1038/70265 . vanc . 30259483 .
• Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D . Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1 . Science . 287 . 5453 . 664–666 . January 2000 . 10650002 . 10.1126/science.287.5453.664 . 2000Sci...287..664U . vanc . 9154084 .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . 6 . 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 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . 2000PNAS...97.3491D . vanc . free .
• Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, Tsuru A, Kohno K . 6 . Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress . Nature Cell Biology . 3 . 2 . 158–164 . February 2001 . 11175748 . 10.1038/35055065 . vanc . 7756732 .
• Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M . 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 . 11278723 . 10.1074/jbc.M010677200 . vanc . free .
• Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ . 6 . 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 . 11850408 . 155339 . 10.1101/gad.964702 . vanc .
• Liu CY, Wong HN, Schauerte JA, Kaufman RJ . 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 . 11897784 . 10.1074/jbc.M112454200 . free .
• Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H . 6 . ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats . Genes & Development . 16 . 11 . 1345–1355 . June 2002 . 12050113 . 186318 . 10.1101/gad.992302 . vanc .
• Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L . Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha . Molecular and Cellular Biology . 22 . 24 . 8506–8513 . December 2002 . 12446770 . 139892 . 10.1128/MCB.22.24.8506-8513.2002 . vanc .
• Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA . 6 . 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 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . vanc . free .
• Liu CY, Xu Z, Kaufman RJ . Structure and intermolecular interactions of the luminal dimerization domain of human IRE1alpha . The Journal of Biological Chemistry . 278 . 20 . 17680–17687 . May 2003 . 12637535 . 10.1074/jbc.M300418200 . free .
• Kaneko M, Niinuma Y, Nomura Y . 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 . 12843613 . 10.1248/bpb.26.931 . free .
• Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S . 6 . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nature Genetics . 36 . 1 . 40–45 . January 2004 . 14702039 . 10.1038/ng1285 . vanc . free .
• Shang J, Lehrman MA . 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 . 15063770 . 10.1016/j.bbrc.2004.03.058 .
• Oono K, Yoneda T, Manabe T, Yamagishi S, Matsuda S, Hitomi J, Miyata S, Mizuno T, Imaizumi K, Katayama T, Tohyama M . 6 . JAB1 participates in unfolded protein responses by association and dissociation with IRE1 . Neurochemistry International . 45 . 5 . 765–772 . October 2004 . 15234121 . 10.1016/j.neuint.2004.01.003 . vanc . 11627892 .
• Huang ZM, Tan T, Yoshida H, Mori K, Ma Y, Yen TS . 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 . 16107700 . 1190304 . 10.1128/MCB.25.17.7522-7533.2005 . vanc .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . 6 . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 . vanc .
• Oikawa D, Tokuda M, Iwawaki T . Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1 . Biochemical and Biophysical Research Communications . 360 . 1 . 122–127 . August 2007 . 17585877 . 10.1016/j.bbrc.2007.06.020 .

Notes and References

1. Tirasophon W, Welihinda AA, Kaufman RJ . 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 . 9637683 . 316900 . 10.1101/gad.12.12.1812 .
2. Web site: Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1.
3. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D . 6 . IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA . Nature . 415 . 6867 . 92–96 . January 2002 . 11780124 . 10.1038/415092a . 2002Natur.415...92C . 4319118 .
4. Kurtishi A, Rosen B, Patil KS, Alves GW, Møller SG . Cellular Proteostasis in Neurodegeneration . Molecular Neurobiology . 56 . 5 . 3676–3689 . May 2019 . 30182337 . 10.1007/s12035-018-1334-z . 52158118 .
5. Duran-Aniotz C, Cornejo VH, Espinoza S, Ardiles ÁO, Medinas DB, Salazar C, Foley A, Gajardo I, Thielen P, Iwawaki T, Scheper W, Soto C, Palacios AG, Hoozemans JJ, Hetz C . 6 . IRE1 signaling exacerbates Alzheimer's disease pathogenesis . Acta Neuropathologica . 134 . 3 . 489–506 . September 2017 . 28341998 . 10.1007/s00401-017-1694-x . 9380354 .
6. Yan C, Liu J, Gao J, Sun Y, Zhang L, Song H, Xue L, Zhan L, Gao G, Ke Z, Liu Y, Liu J . 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 . 31641108 . 6805898 . 10.1038/s41419-019-2039-6 .
7. Montibeller L, de Belleroche J . 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 . 29725981 . 6111088 . 10.1007/s12192-018-0897-y .
8. Chen D, Wang Y, Chin ER . 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 . 26041991 . 4435075 . 10.3389/fncel.2015.00170 . free .
9. Marcu MG, Doyle M, Bertolotti A, Ron D, Hendershot L, Neckers L . Heat shock protein 90 modulates the unfolded protein response by stabilizing IRE1alpha . Molecular and Cellular Biology . 22 . 24 . 8506–8513 . December 2002 . 12446770 . 139892 . 10.1128/MCB.22.24.8506-8513.2002 .
10. 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 . 6 . Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease . The Journal of Biological Chemistry . 286 . 14 . 12743–12755 . April 2011 . 21303903 . 3069474 . 10.1074/jbc.M110.199737 . free .
11. Cross BC, Bond PJ, Sadowski PG, Jha BK, Zak J, Goodman JM, Silverman RH, Neubert TA, Baxendale IR, Ron D, Harding HP . 6 . 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 . 22315414 . 3326519 . 10.1073/pnas.1115623109 . free .
12. 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 . 6 . Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma . Blood . 119 . 24 . 5772–5781 . June 2012 . 22538852 . 3382937 . 10.1182/blood-2011-07-366633 .
13. Papandreou I, Denko NC, Olson M, Van Melckebeke H, Lust S, Tam A, Solow-Cordero DE, Bouley DM, Offner F, Niwa M, Koong AC . 6 . Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma . Blood . 117 . 4 . 1311–1314 . January 2011 . 21081713 . 3056474 . 10.1182/blood-2010-08-303099 .
14. 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 . 6 . 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 . 22852048 . 3408640 . 10.1038/bcj.2012.26 .
15. Wang L, Perera BG, Hari SB, Bhhatarai B, Backes BJ, Seeliger MA, Schürer SC, Oakes SA, Papa FR, Maly DJ . 6 . Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors . Nature Chemical Biology . 8 . 12 . 982–989 . December 2012 . 23086298 . 3508346 . 10.1038/nchembio.1094 .
16. 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 . en . 20 . 8 . 942–953 . 10.1038/s41556-018-0141-0 . 30013108 . 1465-7392.
17. 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 . en . 15 . 1 . 4879 . 10.1038/s41467-024-49198-w . 2041-1723 . 11161512 . 38849354.