2. Academic Validation
  3. Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway

Landscape of the regulatory elements for lysine 2-hydroxyisobutyrylation pathway

  • Cell Res. 2018 Jan;28(1):111-125. doi: 10.1038/cr.2017.149.
He Huang 1,  Zhouqing Luo 2 3,  Shankang Qi 1,  Jing Huang 3,  Peng Xu 3,  Xiuxuan Wang 4,  Li Gao 4,  Fangyi Li 5,  Jian Wang 5,  Wenhui Zhao 6,  Wei Gu 7,  Zhucheng Chen 3,  Lunzhi Dai 4,  Junbiao Dai 2 3,  Yingming Zhao 1
Affiliations

Affiliations

  • 1 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 2 Center for Synthetic Biology Engineering Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
  • 3 MOE Key Laboratory of Bioinformatics and Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Department of General Practice and Lab of PTM, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
  • 5 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 6 Department of Biochemistry and Molecular Biology, Health Science Center and Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University, Beijing 100191, China.
  • 7 Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA.
PMID: 29192674 DOI: 10.1038/cr.2017.149
Abstract

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 (Khib) that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone Khib 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 Khib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major Enzymes to remove Khib. Moreover, we report the first global profiling of Khib proteome in mammalian cells, identifying 6 548 Khib sites on 1 725 substrate proteins. Our study has thus discovered both the "writers" and "erasers" for histone Khib marks, and major Khib 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.

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