Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.
Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.
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DOI：
10.1038/nature10804
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发表时间：
2012-02-08
期刊：
影响因子：
64.8
通讯作者：
Boeke, Jef D.
中科院分区：
文献类型：
--
作者：
Lin, Yu-yi;Kiihl, Samara;Suhail, Yasir;Liu, Shang-Yun;Chou, Yi-hsuan;Kuang, Zheng;Lu, Jin-ying;Khor, Chin Ni;Lin, Chi-Long;Bader, Joel S.;Irizarry, Rafael;Boeke, Jef D.
赖氨酸乙酰转移酶（KATs）和去乙酰化酶（kdac）最初被认为是组蛋白修饰蛋白，它们通过修饰组蛋白中赖氨酸残基的侧链而相互拮抗。在真核生物中，许多参与染色质、代谢或细胞骨架调节的非组蛋白的（去）乙酰化被进一步发现，但相应的修饰酶和修饰的底物特异性功能尚不清楚。此外，单个KDAC的功能特异性机制仍然是谜，每个KDAC的底物光谱缺乏全面的定义。在这里，我们在培养的人类细胞中使用全基因组合成致死性筛选来剖析12个关键的人类kdac的功能特异性。遗传相互作用谱揭示了单个kdac与许多重要底物之间的酶-底物关系，这些底物控制着广泛的生物过程，包括代谢、发育和细胞周期进程。我们进一步证实了腺苷单磷酸活化蛋白激酶（AMPK）的催化亚基的（去）乙酰化是由HDAC1和p300相反的催化活性控制的，AMPK是一种关键的细胞能量感应蛋白激酶复合物。其去乙酰化增强了与上游激酶LKB1的物理相互作用，进而导致AMPK磷酸化和激活，导致人肝细胞脂质分解。这些发现为以前被低估的HDAC1在协调营养可用性和AMPK上游细胞反应中的代谢调节作用提供了新的见解，并证明了高通量遗传相互作用谱在阐明个体人类kdac的功能特异性和关键底物方面的重要性，这些kdac具有潜在的治疗应用价值。
First identified as histone-modifying proteins, lysine acetyltranferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. (De)acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding modifying enzymes and substrate-specific functions of the modification 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 twelve 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 (de)acetylation 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. Its deacetylation enhances physical interaction with the upstream kinase LKB1, in turn leading to AMPK phosphorylation and activation, resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolism-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.
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作者：
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通讯作者：
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作者：
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通讯作者：
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DOI：
10.1073/pnas.0903139106
发表时间：
2009-05-12
影响因子：
11.1
作者：
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通讯作者：
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