ERN1とは - わかりやすく解説 Weblio辞書 (original) (raw)

ERN1
PDBに登録されている構造PDBオルソログ検索: RCSB PDBe PDBj PDBのIDコード一覧2HZ6, 3P23, 4U6R, 4Z7G, 4Z7H, 4YZC, 4YZ9, 4YZD, 5HGI
識別子
記号	ERN1, IRE1, IRE1P, IRE1a, hIRE1p, endoplasmic reticulum to nucleus signaling 1
外部ID	OMIM: 604033 MGI: 1930134 HomoloGene: 55580 GeneCards: ERN1
遺伝子の位置 (ヒト)染色体17番染色体 (ヒト)[1]バンドデータ無し開始点64,039,080 bp[1]終点64,130,819 bp[1]
遺伝子の位置 (マウス)染色体11番染色体 (マウス)[2]バンドデータ無し開始点106,285,476 bp[2]終点106,378,678 bp[2]
RNA発現パターンさらなる参照発現データ
遺伝子オントロジー分子機能• 金属イオン結合• ヌクレオチド結合• ADP binding• ribonuclease activity• identical protein binding• protein kinase activity• トランスフェラーゼ活性• magnesium ion binding• 加水分解酵素活性• Hsp70タンパク質結合• キナーゼ活性• Hsp90タンパク質結合• 触媒活性• エンドヌクレアーゼ活性• ATP binding• 酵素結合• 血漿タンパク結合• endoribonuclease activity• protein serine/threonine kinase activity• platelet-derived growth factor receptor binding• protein homodimerization activity• unfolded protein binding細胞の構成要素• AIP1-IRE1 complex• 細胞質• integral component of membrane• ミトコンドリア• IRE1-TRAF2-ASK1 complex• IRE1-RACK1-PP2A complex• 核内膜• Ire1 complex• 膜• integral component of endoplasmic reticulum membrane• 小胞体• endoplasmic reticulum membrane生物学的プロセス• positive regulation of endoplasmic reticulum unfolded protein response• mRNA異化プロセス• transcription, DNA-templated• insulin metabolic process• peptidyl-serine autophosphorylation• cellular response to vascular endothelial growth factor stimulus• 自己リン酸化• 代謝• アポトーシス• mRNA splicing, via endonucleolytic cleavage and ligation• intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress• cellular response to glucose stimulus• peptidyl-serine trans-autophosphorylation• タンパク質リン酸化• response to unfolded protein• mRNA processing• response to endoplasmic reticulum stress• regulation of transcription, DNA-templated• endothelial cell proliferation• regulation of macroautophagy• リン酸化• 小胞体ストレス• positive regulation of vascular associated smooth muscle cell proliferation• RNA phosphodiester bond hydrolysis, endonucleolytic• positive regulation of RNA splicing• IRE1-mediated unfolded protein response• mRNA cleavage involved in mRNA processing• mRNA cleavage• Unfolded Protein Response出典:Amigo / QuickGO
オルソログ
種	ヒト	マウス
Entrez	2081	78943
Ensembl	ENSG00000178607	ENSMUSG00000020715
UniProt	O75460	Q9EQY0
RefSeq(mRNA)	NM_152461NM_001433	NM_023913
RefSeq(タンパク質)	NP_001424	NP_076402
場所(UCSC)	Chr 17: 64.04 – 64.13 Mb	Chr 17: 106.29 – 106.38 Mb
PubMed検索	[3]	[4]
ウィキデータ
閲覧/編集 ヒト閲覧/編集 マウス

ERN1（endoplasmic reticulum to nucleus signaling 1）またはIRE1α（inositol-requiring enzyme 1 alpha）は、ヒトでは_ERN1_遺伝子にコードされる酵素（プロテインキナーゼ・リボヌクレアーゼ）である[5][6]。

機能

ERN1_遺伝子にコードされるERN1タンパク質は酵母のIre1のホモログである。このタンパク質はキナーゼ活性とエンドリボヌクレアーゼ活性を有する。小胞体においてストレスシグナル（unfolded protein response）のセンサーとして機能し、XBP1_のmRNAのスプライシングと活性化に関与している[6]。

シグナル伝達

IRE1αは、トランス自己リン酸化を行うキナーゼドメイン、エンドヌクレアーゼドメインという2つの機能的酵素ドメインを有する。活性化に伴ってIRE1αはオリゴマー化し、非典型的なRNAスプライシング活性を示す。IRE1αは_XBP1_のmRNAからイントロンを除去し、機能的な転写因子であるXBP1sへの翻訳を可能にする[7]。XBP1sは小胞体のシャペロンや小胞体関連分解（ERAD）に関する遺伝子をアップレギュレーションし、小胞体ストレスからの回復を促進する。

臨床的意義

IRE1αはunfolded protein responseの主要なセンサーであり、IRE1αの破壊は、細胞内の毒性タンパク質の蓄積が主要な発症機構の1つとなっている神経変性疾患と関連づけられている[8]。IRE1シグナルは、アルツハイマー病[9]、パーキンソン病[10]、筋萎縮性側索硬化症[11][12]の発症に関与していると考えられている。

相互作用

ERN1はHSP90AA1と相互作用することが示されている[13]。

阻害剤

IRE1を標的とした阻害剤には、リボヌクレアーゼドメインの触媒コアを標的としたもの、キナーゼドメインのATP結合ポケットを標的したものの2種類がある。

リボヌクレアーゼドメイン阻害剤

サリチルアルデヒド類（3-methoxy-6-bromosalicylaldehyde[14]、4μ8C[15]、MKC-3946[16]、STF-083010[17]）、トヨカマイシン（toyocamycin）[18]

ATP結合ポケット阻害剤

スニチニブとAPY29はATP結合ポケットを標的として阻害するが、IRE1αのリボヌクレアーゼドメインをアロステリックに活性化する。

キナーゼ活性、オリゴマー化、リボヌクレアーゼ活性を阻害する化合物（compund 3）も得られている[19]。

出典

1. ^ a b c GRCh38: Ensembl release 89: ENSG00000178607 - Ensembl, May 2017
2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020715 - Ensembl, May 2017
3. ^ Human PubMed Reference:
4. ^ Mouse PubMed Reference:
5. ^ “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. PMC 316900. PMID 9637683. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316900/.
6. ^ a b “Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1”. 2024年2月12日閲覧。
7. ^ “IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA”. Nature 415 (6867): 92–96. (January 2002). Bibcode: 2002Natur.415...92C. doi:10.1038/415092a. PMID 11780124.
8. ^ “Cellular Proteostasis in Neurodegeneration”. Molecular Neurobiology 56 (5): 3676–3689. (May 2019). doi:10.1007/s12035-018-1334-z. PMID 30182337.
9. ^ “IRE1 signaling exacerbates Alzheimer's disease pathogenesis”. Acta Neuropathologica 134 (3): 489–506. (September 2017). doi:10.1007/s00401-017-1694-x. PMID 28341998.
10. ^ “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. PMC 6805898. PMID 31641108. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805898/.
11. ^ “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. PMC 6111088. PMID 29725981. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111088/.
12. ^ “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. PMC 4435075. PMID 26041991. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435075/.
13. ^ “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. PMC 139892. PMID 12446770. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139892/.
14. ^ “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. PMC 3069474. PMID 21303903. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069474/.
15. ^ “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. PMC 3326519. PMID 22315414. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326519/.
16. ^ “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. PMC 3382937. PMID 22538852. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382937/.
17. ^ “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. PMC 3056474. PMID 21081713. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056474/.
18. ^ “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. PMC 3408640. PMID 22852048. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408640/.
19. ^ “Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors”. Nature Chemical Biology 8 (12): 982–989. (December 2012). doi:10.1038/nchembio.1094. PMC 3508346. PMID 23086298. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508346/.

関連文献

• “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). Bibcode: 2000Sci...287..664U. doi:10.1126/science.287.5453.664. PMID 10650002.
• “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). Bibcode: 2000PNAS...97.3491D. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC16267/.
• “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. PMC 155339. PMID 11850408. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC155339/.
• “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. PMC 186318. PMID 12050113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC186318/.
• “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. PMC 139892. PMID 12446770. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139892/.
• “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). Bibcode: 2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139241/.
• “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. PMC 1190304. PMID 16107700. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1190304/.
• “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. PMC 1356129. PMID 16344560. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1356129/.
• “Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha”. Science 312 (5773): 572–576. (April 2006). Bibcode: 2006Sci...312..572H. doi:10.1126/science.1123480. PMID 16645094.
• “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.