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

Nature volume 482, pages 251–255 (2012)Cite this article

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A Retraction to this article was published on 06 November 2013

Abstract

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 proteins1. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms2,3,4,5,6, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs7 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 screen8,9,10,11,12,13 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 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.

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Figure 1: Overview of human KDAC genetic interaction screen.
Figure 2: Negative genetic interactions and enzyme–substrate relationship between HDAC1 and PRKAA1.
Figure 3: Deacetylation of PRKAA1 increases its phosphorylation and activity.
Figure 4: Deacetylation of PRKAA1 specifically enhances its physical interaction with LKB1 kinase.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data were deposited in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE29662.

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Acknowledgements

We thank H. Zhu, S.-L. Yu and L.-P. Chow for gifts of reagents, J. Lu for IMR-90 cells, Department of Medical Science, National Taiwan University for technical help with sequencing, and the National RNAi Core Facility, Academia Sinica for reagents and technical support with RNAi screen. We are grateful to P. Meluh and members of the Lin and Boeke laboratories for discussions. We thank D. Root for discussions. This study was supported by National Science Council grants NSC 98-2320-B-002-057-, NSC 99-2320-B-002-057- and NSC 100-2325-002-044- (Y.-y.L.), National Taiwan University Frontier and Innovative Research 99R71424 (Y.-y.L.), National Taiwan University College of Medicine and National Taiwan University Hospital Excellent Translational Medicine Research Project 99C101-603 (Y.-y.L. and J.-y.L.), National Health Research Institutes Career Development grant NHRI-EX100-10017BC (Y.-y.L.), Liver Disease Prevention and Treatment Research Foundation (Y.-y.L. and J.-y.L.) and NIH Common Fund grant U54 RR 020839 (J.D.B.).

Author information

Author notes

  1. Samara Kiihl and Yasir Suhail: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan,

    Yu-yi Lin, Shang-Yun Liu & Yi-hsuan Chou

  2. Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan,

    Yu-yi Lin & Jin-ying Lu

  3. Department of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan,

    Yu-yi Lin

  4. Department of Biostatistics, Johns Hopkins Bloomberg, School of Public Health, Baltimore, 21231, Maryland, USA

    Samara Kiihl & Rafael Irizarry

  5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Yasir Suhail & Joel S. Bader

  6. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Zheng Kuang & Jef D. Boeke

  7. The High Throughput Biology Center, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Zheng Kuang & Jef D. Boeke

  8. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan,

    Jin-ying Lu

  9. National RNAi Core Facility, Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan,

    Chin Ni Khor & Chi-Long Lin

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Contributions

Y.-y.L. and J.D.B. designed the experiments, with help from J.-y.L. Y.-y.L. and Y.-h.C. performed the primary screens, with help from C.N.K. and C.-L.L. Validation and further functional categorization experiments were performed by Y.-y.L., S.-Y.L. and Z.K. S.K. and Y.S. performed computational analyses, supervised by R.I. and J.S.B., respectively. Y.-y.L., J.-y.L. and J.D.B. wrote the manuscript. All authors discussed results and edited the manuscript.

Corresponding authors

Correspondence to Yu-yi Lin or Jef D. Boeke.

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The authors declare no competing financial interests.

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Lin, Yy., Kiihl, S., Suhail, Y. et al. Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. Nature 482, 251–255 (2012). https://doi.org/10.1038/nature10804

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