p300-Mediated Lysine 2-Hydroxyisobutyrylation Regulates Glycolysis

Abstract

Lysine 2-hydroxyisobutyrylation (Khib) is an evolutionarily conserved and widespread histone mark like lysine acetylation (Kac). Here we report that EP300 functions as a lysine 2-hyroxyisobutyryltransferase to regulate glycolysis in response to nutritional cues. We discovered that EP300 differentially regulates Khib and Kac on distinct lysine sites, with only 6 of the 149 EP300-targeted Khib sites overlapping with the 693 EP300-targeted Kac sites. We demonstrate that diverse cellular proteins, particularly glycolytic enzymes, are targeted by EP300 for Khib, but not for Kac. Specifically, deletion of EP300 significantly reduces Khib levels on several EP300-dependent, Khib-specific sites on key glycolytic enzymes including ENO1, decreasing their catalytic activities. Consequently, EP300-deficient cells have impaired glycolysis and are hypersensitive to glucose-depletion-induced cell death. Our study reveals an EP300-catalyzed, Khib-specific molecular mechanism that regulates cellular glucose metabolism and further indicate that EP300 has an intrinsic ability to select short-chain acyl-CoA-dependent protein substrates.

Short-chain fatty acid, acylation and cardiovascular diseases

“…A total of 6548 Khib sites on 1725 substrate proteins were reported, which suggested an essential role of Khib in diverse biological processes [167]. Tip60 and p300 are lysine 2-hyroxyisobutyryltransferase, while HDAC2 and HDAC3 act as the vital enzymes to remove Khib [168,169]. p300-catalyzed Khib of metabolic enzymes (e.g., ENO1) regulates cellular glucose metabolism [168].…”

“…Tip60 and p300 are lysine 2-hyroxyisobutyryltransferase, while HDAC2 and HDAC3 act as the vital enzymes to remove Khib [168,169]. p300-catalyzed Khib of metabolic enzymes (e.g., ENO1) regulates cellular glucose metabolism [168].…”

Global Profiling of 2-hydroxyisobutyrylome in Common Wheat

“…Over the past several years, many regulatory enzymes (writers and erasers) have 95 been identified [36]. A recent study indicated that histone deacetylase 2 (HDAC2) and 96 histone deacetylase 3 (HDAC3) were acting as "erasers" in mammalian cells, and Esa1p 97 and its homologue Tip60 were discovered to be "writers" in budding yeast and in 98 human cells, respectively [37]. Another recent study identified the histone lysine 99 acetyltransferase (HAT) EP300 was a ''writer'' for Khib in mammalian cells, and that 100 EP300 was able to regulate glycolysis through Khib of glycolytic enzymes, as well as 101 mediate cell survival via nutritional regulation through glycolysis [37].…”

“…Total word count: 5864 24 Total references: 62 25 References from 2014: 32 26 Total tables: 1 27 Total figures: 8 28 Total supplementary figures: 10 29 Total supplementary tables: 17 30 Total supplementary files: 3 31 We conducted a structural analysis of all identified proteins using NetSurfP. Results 162 indicated that 26.3% and 6.8% of the Khib sites were located in the α-helix and β-strand, 163 respectively, while 6.7% of the Khib sites were located in disordered coils 164 ( Supplemental Table S2; Figure 2F).…”

Reciprocal Regulation of Metabolic Reprogramming and Epigenetic Modifications in Cancer

“…Upon DNA damage, nuclear ACLY is phosphorylated, which enhances its ability to synthesize the nuclear acetyl-CoA pool and increases histone acetylation required for efficient double-strand break repair by homologous recombination ( Sivanand et al, 2017 ). Huang et al found that p300 functions as a lysine 2-hydroxyisobutyryl transferase to regulate glycolysis in response to nutritional cues ( Huang et al, 2018 ). p300 catalyzes lysine 2-hydroxyisobutyrylation on glycolytic enzymes, i.e., ENO1 to enhance their catalytic activity and knockout of p300 leads to impaired glycolysis and reduced growth of cancer cells when cultured in glucose-depleted medium ( Huang et al, 2018 ).…”