Publications

• Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway.

  Huang H., Luo Z., Qi S., Huang J., Xu P., Wang X., Gao L., Li F., Wang J., Zhao W., Gu W., Chen Z., Dai L., Dai J., Zhao Y.

  Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine ... >> More

  Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation (K_hib) that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone K_hib has been shown to be associated with active gene expression in spermatogenic cells. However, the key elements that regulate this post-translational lysine acylation pathway remain unknown. This has hindered characterization of the mechanisms by which this modification exerts its biological functions. Here we show that Esa1p in budding yeast and its homologue Tip60 in human could add K_hib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major enzymes to remove K_hib. Moreover, we report the first global profiling of K_hib proteome in mammalian cells, identifying 6 548 K_hib sites on 1 725 substrate proteins. Our study has thus discovered both the "writers" and "erasers" for histone K_hib marks, and major K_hib protein substrates. These results not only illustrate the landscape of this new lysine acylation pathway, but also open new avenues for studying diverse functions of cellular metabolites associated with this pathway. << Less

  Cell Res. 28:111-125(2018) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.

• p300-mediated lysine 2-hydroxyisobutyrylation regulates glycolysis.

  Huang H., Tang S., Ji M., Tang Z., Shimada M., Liu X., Qi S., Locasale J.W., Roeder R.G., Zhao Y., Li X.

  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 differential ... >> More

  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. << Less

  Mol. Cell 70:663-678(2018) [PubMed] [EuropePMC]