2. Academic Validation
  3. p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis

p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis

  • Mol Cell. 2018 May 17;70(4):663-678.e6. doi: 10.1016/j.molcel.2018.04.011.
He Huang 1,  Shuang Tang 2,  Ming Ji 2,  Zhanyun Tang 3,  Miho Shimada 3,  Xiaojing Liu 4,  Shankang Qi 1,  Jason W Locasale 4,  Robert G Roeder 3,  Yingming Zhao 5,  Xiaoling Li 6
Affiliations

Affiliations

  • 1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 2 Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
  • 3 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
  • 4 Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  • 5 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].
  • 6 Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: [email protected].
PMID: 29775581 DOI: 10.1016/j.molcel.2018.04.011
Abstract

Lysine 2-hydroxyisobutyrylation (Khib) is an evolutionarily conserved and widespread histone mark like lysine acetylation (Kac). Here we report that p300 functions as a lysine 2-hyroxyisobutyryltransferase to regulate glycolysis in response to nutritional cues. We discovered that p300 differentially regulates Khib and Kac on distinct lysine sites, with only 6 of the 149 p300-targeted Khib sites overlapping with the 693 p300-targeted Kac sites. We demonstrate that diverse cellular proteins, particularly glycolytic enzymes, are targeted by p300 for Khib, but not for Kac. Specifically, deletion of p300 significantly reduces Khib levels on several p300-dependent, Khib-specific sites on key glycolytic enzymes including ENO1, decreasing their catalytic activities. Consequently, p300-deficient cells have impaired glycolysis and are hypersensitive to glucose-depletion-induced cell death. Our study reveals an p300-catalyzed, Khib-specific molecular mechanism that regulates cellular glucose metabolism and further indicate that p300 has an intrinsic ability to select short-chain acyl-CoA-dependent protein substrates.

Keywords

EP300; cell survival; glycolysis; lysine 2-hydroxyisobutyrylation.

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