https://scholars.lib.ntu.edu.tw/handle/123456789/511433
標題: | Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK | 作者: | Lin Y.-Y. Kiihl S. Suhail Y. Liu S.-Y. Chou Y.-H. Kuang Z. JIN-YING LU Khor C.N. Lin C.-L. Bader J.S. Irizarry R. Boeke J.D. |
公開日期: | 2012 | 出版社: | Nature Publishing Group | 卷: | 482 | 期: | 7384 | 起(迄)頁: | 251-255 | 來源出版物: | Nature | 摘要: | First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications. ? 2012 Macmillan Publishers Limited. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84863012559&doi=10.1038%2fnature10804&partnerID=40&md5=068396c9f356cde8eb34e779a0e72187 https://scholars.lib.ntu.edu.tw/handle/123456789/511433 |
ISSN: | 0028-0836 | DOI: | 10.1038/nature10804 | SDG/關鍵字: | adenylate kinase; enzyme; histone deacetylase 1; lysine deacetylase; protein kinase LKB1; protein p300; unclassified drug; disease treatment; enzyme activity; eukaryote; genetic analysis; genome; hominid; metabolism; molecular analysis; nutrient availability; protein; acetylation; article; cell cycle progression; controlled study; deacetylation; development; enzyme activity; enzyme phosphorylation; enzyme specificity; enzyme substrate; enzyme substrate complex; enzyme subunit; gene interaction; high throughput screening; human; human cell; metabolism; nucleotide sequence; priority journal; protein function; protein protein interaction; screening; Eukaryota |
顯示於: | 醫學系 |
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