ERN1

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)
終点	64,130,819 bp
遺伝子の位置 (マウス)
染色体	11番染色体 (マウス)
終点	106,378,678 bp
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
	2081
	78943
	ENSG00000178607
	ENSMUSG00000020715
	O75460
	Q9EQY0
	NM_152461; NM_001433
	NM_023913
	NP_001424
	NP_076402
	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]。

機能編集

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]。

シグナル伝達編集

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（英語版）（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。

臨床的意義編集

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。

相互作用編集

ERN1はHSP90AA1と相互作用することが示されている^[13]。

阻害剤編集

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編集

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編集

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]。

出典編集

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000178607 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000020715 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ “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.
^ ^a ^b “Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1”. 2024年2月12日閲覧。
^ “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.
^ “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. PMC 6805898. 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. PMC 6111088. 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. PMC 4435075. PMID 26041991.
^ “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.
^ “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.
^ “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.
^ “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.
^ “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.
^ “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.
^ “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.

関連文献編集

“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.
“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.
“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.
“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.
“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.
“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.
“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.
“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.

この項目は、生物学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:生命科学／Portal:生物学）。

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000178607 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000020715 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[pmid9637683-5] “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.

[entrez-6] “Entrez Gene: ERN1 endoplasmic reticulum to nucleus signalling 1”. 2024年2月12日閲覧。

[pmid11780124-7] “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.

[:0-8] “Cellular Proteostasis in Neurodegeneration”. Molecular Neurobiology 56 (5): 3676–3689. (May 2019). doi:10.1007/s12035-018-1334-z. PMID 30182337.

[:1-9] “IRE1 signaling exacerbates Alzheimer's disease pathogenesis”. Acta Neuropathologica 134 (3): 489–506. (September 2017). doi:10.1007/s00401-017-1694-x. PMID 28341998.

[:2-10] “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.

[:3-11] “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.

[:4-12] “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.

[pmid12446770-13] “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.

[pmid21303903-14] “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.

[pmid22315414-15] “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.

[pmid22538852-16] “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.

[pmid21081713-17] “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.

[pmid22852048-18] “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.

[pmid23086298-19] “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.

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ERN1

機能 編集

シグナル伝達 編集

臨床的意義 編集

相互作用 編集

阻害剤 編集

リボヌクレアーゼドメイン阻害剤 編集

ATP結合ポケット阻害剤 編集

出典 編集

関連文献 編集