HDAC6 |
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![](//upload.wikimedia.org/wikipedia/commons/thumb/f/fb/Protein_HDAC6_PDB_3C5K.png/250px-Protein_HDAC6_PDB_3C5K.png) |
PDBに登録されている構造 |
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PDB | オルソログ検索: RCSB PDBe PDBj |
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PDBのIDコード一覧 |
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3C5K, 3GV4, 3PHD, 5EDU, 5KH7 |
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識別子 |
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記号 | HDAC6, CPBHM, HD6, PPP1R90, JM21, histone deacetylase 6 |
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外部ID | OMIM: 300272 MGI: 1333752 HomoloGene: 31353 GeneCards: HDAC6 |
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遺伝子オントロジー |
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分子機能 | • ヒストンデアセチラーゼ結合 • misfolded protein binding • 金属イオン結合 • 酵素結合 • NAD-dependent histone deacetylase activity (H3-K14 specific) • beta-catenin binding • zinc ion binding • polyubiquitin modification-dependent protein binding • 血漿タンパク結合 • tau protein binding • dynein complex binding • Hsp90タンパク質結合 • histone deacetylase activity • microtubule binding • alpha-tubulin binding • ubiquitin binding • beta-tubulin binding • actin binding • 加水分解酵素活性 • ubiquitin protein ligase binding • tubulin deacetylase activity • RNA polymerase II cis-regulatory region sequence-specific DNA binding • protein deacetylase activity • acetylspermidine deacetylase activity
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細胞の構成要素 | • 細胞質基質 • perinuclear region of cytoplasm • カベオラ • 微小管 • 細胞核 • multivesicular body • cell projection • microtubule associated complex • アグリソーム • dynein complex • histone deacetylase complex • 細胞体 • 神経繊維 • 封入体 • 樹状突起 • cell leading edge • cytoplasmic microtubule • cell body • neuron projection • 核質 • 細胞質 • 高分子複合体
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生物学的プロセス | • Hsp90 deacetylation • protein quality control for misfolded or incompletely synthesized proteins • 有機物への反応 • cellular response to topologically incorrect protein • tubulin deacetylation • regulation of establishment of protein localization • ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway • response to growth factor • intracellular protein transport • aggresome assembly • negative regulation of proteolysis • histone H3 deacetylation • positive regulation of signal transduction • peptidyl-lysine deacetylation • response to misfolded protein • regulation of transcription, DNA-templated • タンパク質安定性の制御 • ubiquitin-dependent protein catabolic process • mitochondrion localization • positive regulation of epithelial cell migration • regulation of fat cell differentiation • transcription, DNA-templated • regulation of autophagy of mitochondrion • polyubiquitinated misfolded protein transport • 毒性物質への反応 • positive regulation of hydrogen peroxide-mediated programmed cell death • regulation of microtubule-based movement • regulation of signaling receptor activity • protein polyubiquitination • protein deacetylation • negative regulation of hydrogen peroxide metabolic process • regulation of autophagy • negative regulation of oxidoreductase activity • regulation of androgen receptor signaling pathway • negative regulation of transcription, DNA-templated • cellular response to misfolded protein • positive regulation of chaperone-mediated protein complex assembly • regulation of gene expression, epigenetic • negative regulation of protein-containing complex disassembly • オートファジー • negative regulation of microtubule depolymerization • lysosome localization • histone deacetylation • cellular response to hydrogen peroxide • collateral sprouting • dendritic spine morphogenesis • cilium assembly • regulation of macroautophagy • parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization • positive regulation of mitophagy in response to mitochondrial depolarization • chromatin organization • positive regulation of protein oligomerization • protein-containing complex disassembly • positive regulation of peptidyl-serine phosphorylation • polyamine deacetylation • spermidine deacetylation
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出典:Amigo / QuickGO |
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オルソログ |
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種 | ヒト | マウス |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNA) | NM_006044 NM_001321225 NM_001321226 NM_001321227 NM_001321228
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NM_001321229 NM_001321230 NM_001321231 |
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RefSeq (タンパク質) | NP_001308154 NP_001308155 NP_001308156 NP_001308157 NP_001308158
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NP_001308159 NP_001308160 NP_006035 |
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場所 (UCSC) | Chr X: 48.8 – 48.82 Mb | Chr X: 7.8 – 7.81 Mb |
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PubMed検索 | [3] | [4] |
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ウィキデータ |
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HDAC6(histone deacetylase 6)は、ヒトではHDAC6遺伝子にコードされる酵素である[5][6]。HDAC6の選択的阻害は、いくつかの種類のがんや神経変性疾患に対する治療として有望な戦略の1つとなっている[7]。
機能
ヒストンは転写調節、細胞周期の進行、発生上のイベントに重要な役割を果たしている。ヒストンのアセチル化/脱アセチル化はクロマチン構造を変化させ、転写に影響を及ぼす。HDAC6はヒストンデアセチラーゼ/acuc/aphaファミリーのクラスIIに属する。HDAC6には遺伝子内重複によって生じた2つの触媒ドメインが存在し、両者は互いに独立に機能しているようである。このタンパク質はヒストンデアセチラーゼ活性を有し、転写を抑制する[8]。
一方でHDAC6は主に細胞質に位置し、α-チューブリンの脱アセチル化を触媒して細胞の運動性を高める[9]。結果として、この酵素によってがん細胞の転移能は高まる[10]。また、HDAC6はTAK1のT178のアセチル化を除去してリン酸化を促進し、結腸がんにおけるマクロファージのM2極性化を高める[11]。
HDAC6はストレス顆粒(英語版)の形成に必要であり、HDAC6の薬理学的阻害や遺伝的除去によってストレス顆粒の形成は起こらなくなる[10]。また、ユビキチン化タンパク質に高い親和性で結合し、ストレス顆粒へのリクルートに関与していると考えられている[12]。
その他、HDAC6はレプチン感受性にも関与している[13]。
臨床的意義
HDAC6遺伝子の変異はアルツハイマー病と関連している[14]。
HDAC6の過剰発現は、腫瘍形成や細胞生存と相関している。また、HDAC6はがん細胞の転移を促進する[10]。
いくつかのがんや神経変性疾患ではHDAC6の調節不全が生じているため、この酵素特異的な薬理学的阻害は治療法としての高い可能性を有しており、また複数のHDACを標的とする汎HDAC阻害剤と関係した副作用を抑えられる可能性がある[7]。しかしながら、一部のHDAC6阻害剤がin vitroやin vivoで抗腫瘍活性を示すのは高濃度で投与された場合のみであり、こうした条件ではオフターゲット効果も生じているため、がん治療戦略としてのHDAC6選択的阻害の妥当性には議論がある。HDAC6選択的阻害剤の抗がん効果を明確に示すためにはさらなる研究が必要とされている[15]。
相互作用
HDAC6はHDAC11(英語版)[16]やZBTB16(英語版)[17]と相互作用することが示されている。また、ストレス顆粒タンパク質G3BP1(英語版)とも相互作用する[12]。
出典
- ^ a b c GRCh38: Ensembl release 89: ENSG00000094631 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031161 - Ensembl, May 2017
- ^ Human PubMed Reference:
- ^ Mouse PubMed Reference:
- ^ “Three proteins define a class of human histone deacetylases related to yeast Hda1p”. Proceedings of the National Academy of Sciences of the United States of America 96 (9): 4868–4873. (April 1999). Bibcode: 1999PNAS...96.4868G. doi:10.1073/pnas.96.9.4868. PMC 21783. PMID 10220385. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC21783/.
- ^ “Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro”. DNA Research 5 (6): 355–364. (December 1998). doi:10.1093/dnares/5.6.355. PMID 10048485.
- ^ a b “Identification of mercaptoacetamide-based HDAC6 inhibitors via a lean inhibitor strategy: screening, synthesis, and biological evaluation”. Chemical Communications 58 (42): 6239–6242. (May 2022). doi:10.1039/D2CC01550A. hdl:1854/LU-8752799. PMID 35510683. https://biblio.ugent.be/publication/8752799.
- ^ “Entrez Gene: HDAC6 histone deacetylase 6”. 2024年3月24日閲覧。
- ^ “Histone deacetylase 6 regulates growth factor-induced actin remodeling and endocytosis”. Molecular and Cellular Biology 27 (24): 8637–8647. (December 2007). doi:10.1128/MCB.00393-07. PMC 2169396. PMID 17938201. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2169396/.
- ^ a b c “The role of HDAC6 in cancer”. Journal of Biomedicine & Biotechnology 2011: 875824. (2011). doi:10.1155/2011/875824. PMC 2975074. PMID 21076528. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975074/.
- ^ “HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer”. Cell Death & Disease 13 (10): 888. (October 2022). doi:10.1038/s41419-022-05335-1. PMC 9587286. PMID 36270986. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587286/.
- ^ a b “The deacetylase HDAC6 is a novel critical component of stress granules involved in the stress response”. Genes & Development 21 (24): 3381–3394. (December 2007). doi:10.1101/gad.461107. PMC 2113037. PMID 18079183. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2113037/.
- ^ “Targeting an enzyme in fat cells drives rapid weight loss in obese mice” (英語). New Atlas (2022年1月18日). 2022年1月18日閲覧。
- ^ “Loss of HDAC6, a novel CHIP substrate, alleviates abnormal tau accumulation”. Human Molecular Genetics 21 (13): 2936–2945. (July 2012). doi:10.1093/hmg/dds125. PMC 3373241. PMID 22492994. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373241/.
- ^ “Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models”. International Journal of Cancer 145 (3): 735–747. (August 2019). doi:10.1002/ijc.32169. PMID 30694564.
- ^ “Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family”. The Journal of Biological Chemistry 277 (28): 25748–25755. (July 2002). doi:10.1074/jbc.M111871200. PMID 11948178.
- ^ “HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF”. Oncogene 23 (54): 8777–8784. (November 2004). doi:10.1038/sj.onc.1208128. PMID 15467736.
関連文献
- “What's up and down with histone deacetylation and transcription?”. Cell 89 (3): 325–328. (May 1997). doi:10.1016/S0092-8674(00)80211-1. PMID 9150131.
- “Transcriptional control. Sinful repression”. Nature 387 (6628): 16–17. (May 1997). doi:10.1038/387016a0. PMID 9139815.
- “BCoR, a novel corepressor involved in BCL-6 repression”. Genes & Development 14 (14): 1810–1823. (July 2000). doi:10.1101/gad.14.14.1810. PMC 316791. PMID 10898795. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC316791/.
- “Assignment of the human histone deacetylase 6 gene (HDAC6) to X chromosome p11.23 by in situ hybridization”. Cytogenetics and Cell Genetics 93 (1–2): 135–136. (2001). doi:10.1159/000056967. PMID 11474198.
- “Isolation and characterization of mammalian HDAC10, a novel histone deacetylase”. The Journal of Biological Chemistry 277 (1): 187–193. (January 2002). doi:10.1074/jbc.M108931200. PMID 11677242.
- “Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways”. Molecular and Cellular Biology 21 (23): 8035–8044. (December 2001). doi:10.1128/MCB.21.23.8035-8044.2001. PMC 99970. PMID 11689694. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC99970/.
- “Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain”. Nucleic Acids Research 30 (5): 1114–1123. (March 2002). doi:10.1093/nar/30.5.1114. PMC 101247. PMID 11861901. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC101247/.
- “Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family”. The Journal of Biological Chemistry 277 (28): 25748–25755. (July 2002). doi:10.1074/jbc.M111871200. PMID 11948178.
- “HDAC6 is a microtubule-associated deacetylase”. Nature 417 (6887): 455–458. (May 2002). Bibcode: 2002Natur.417..455H. doi:10.1038/417455a. PMID 12024216.
- “The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase”. The EMBO Journal 21 (11): 2682–2691. (June 2002). doi:10.1093/emboj/21.11.2682. PMC 125385. PMID 12032081. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125385/.
- “Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes”. Proceedings of the National Academy of Sciences of the United States of America 99 (21): 13425–13430. (October 2002). Bibcode: 2002PNAS...9913425H. doi:10.1073/pnas.172511699. PMC 129689. PMID 12354939. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC129689/.
- “Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter”. Molecular and Cellular Biology 22 (22): 7982–7992. (November 2002). doi:10.1128/MCB.22.22.7982-7992.2002. PMC 134736. PMID 12391164. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC134736/.
- “The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase”. Molecular Cell 11 (2): 437–444. (February 2003). doi:10.1016/S1097-2765(03)00038-8. PMID 12620231.
- “Cloning and structural characterization of the human histone deacetylase 6 gene”. International Journal of Molecular Medicine 12 (1): 87–93. (July 2003). doi:10.3892/ijmm.12.1.87. PMID 12792815.
- “Deactylase inhibitors disrupt cellular complexes containing protein phosphatases and deacetylases”. The Journal of Biological Chemistry 279 (9): 7685–7691. (February 2004). doi:10.1074/jbc.M310997200. PMID 14670976.
- “HDAC6 at the intersection of autophagy, the ubiquitin-proteasome system and neurodegeneration”. Autophagy 3 (6): 643–645. (Nov–Dec 2007). doi:10.4161/auto.5050. PMID 17912024.
- “HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS”. Nature 447 (7146): 859–863. (June 2007). Bibcode: 2007Natur.447..860P. doi:10.1038/nature05853. PMID 17568747.
関連項目
外部リンク