ERN1
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(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.