Class I histone deacetylases (HDAC1-3) are histone lysine delactylases

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  • Carlos Moreno-Yruela
  • Di Zhang
  • Wei Wei
  • Michael Bæk
  • Wenchao Liu
  • Jinjun Gao
  • Daniela Danková
  • Alexander L. Nielsen
  • Julie E. Bolding
  • Lu Yang
  • Samuel T. Jameson
  • Jiemin Wong
  • Olsen, Christian Adam
  • Yingming Zhao

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide-dependent histone deacetylases (HDACs) for their ability to cleave ε-N-L-lactyllysine marks. Our screens identified HDAC1-3 and SIRT1-3 as delactylases in vitro. HDAC1-3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway's regulatory elements.

Original languageEnglish
Article numbereabi6696
JournalScience Advances
Volume8
Issue number3
ISSN2375-2548
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding Information:
This work was supported by the Ministry of Science and Technology of China (2017YFA054201; to J.W.), the Danish Council for Independent Research-Natural Sciences (grant no. 6108-00166B; to C.A.O.), the Independent Research Fund Denmark-Technical and Production Sciences (grant no. 0136-00412B; to C.A.O.), the Carlsberg Foundation (2013-01-0333 and CF15-011; to C.A.O.), the European Research Council (ERC-CoG-725172-SIRFUNCT; to C.A.O.), the University of Chicago, Nancy and Leonard Florsheim family fund (to Y.Z.), and the NIH (grants GM135504, AR078555, DK118266, and CA251677; to Y.Z.).

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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