Editors' ChoiceCell Biology

Screening for Interactions

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Science Signaling  14 Feb 2012:
Vol. 5, Issue 211, pp. ec52
DOI: 10.1126/scisignal.2002956

Although best known for their regulation of the reversible acetylation of lysine residues on histone proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) also modify many nonhistone proteins that are involved in cellular processes such as metabolism. To investigate the functional specificity and substrates of individual KDACs, Lin et al. performed an RNA interference (RNAi)–based screen in a cultured human cell line by individually targeting 12 critical KDACs and examining the effects of KDAC knockdown on gene expression with microarrays. The authors validated more than 800 genetic interactions, and gene ontology analysis showed that genes affected by KDAC knockdown included those that encoded products involved in the regulation of cell cycle control and metabolism. The authors also identified enzyme-substrate relationships between KDACs and their targets, which were validated with in vitro deacetylation assays. One such relationship was that between HDAC1 and the energy-sensing protein adenosine monophosphate–activated protein kinase (AMPK). AMPK is phosphorylated and activated by the kinase LKB1 in response to stresses such as glucose deprivation, and it targets downstream proteins to regulate metabolism. The authors found that HDAC1, but not other KDACs, deacetylated the catalytic subunit of AMPK, and they identified p300 as the major acetyltransferase for AMPK. Acetylation and phosphorylation of AMPK were inversely correlated, and acetylation of AMPK inhibited its activation and that of its downstream targets. Deacetylation of AMPK increased its physical interaction with LKB1 and led to increased phosphorylation and activation of AMPK. Together, these data suggest that HDAC1 plays an important regulatory role in metabolism by controlling the activation of AMPK in response to nutrient deprivation. The authors suggest that use of similar RNAi-based screens and gene interaction analyses may reveal other specific KDAC-substrate relationships that might be targeted therapeutically.

Y.-y. Lin, S. Kiihl, Y. Suhail, S.-Y. Liu, Y.-h. Chou, Z. Kuang, J.-y. Lu, C. N. Khor, C.-L. Lin, J. S. Bader, R. Irizarry, J. D. Boeke, Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK. Nature 482, 251–255 (2012). [PubMed]

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