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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.