Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK

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(1). (De)acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms(2–6), but the corresponding modifying enzymes and substrate-specific functions of the modification are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs(7) 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(8–13) 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.