Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.
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.
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. yuyilin@ntu.edu.tw
Yu-yi
YY
Lin
Samara
S
Kiihl
Yasir
Y
Suhail
Shang-Yun
SY
Liu
Yi-hsuan
YH
Chou
Zheng
Z
Kuang
Jin-ying
JY
Lu
Chin Ni
CN
Khor
Chi-Long
CL
Lin
Joel S
JS
Bader
Rafael
R
Irizarry
Jef D
JD
Boeke
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D055162:Biocatalysis; D020134:Catalytic Domain; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D013379:Substrate Specificity; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D056284:Histone Deacetylase 1; D008239:Lysine; D017346:Protein Serine-Threonine Kinases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C109790:STK11 protein, human; C526180:PRKAA1 protein, human