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

  • Sci Adv. 2022 Jan 21;8(3):eabi6696. doi: 10.1126/sciadv.abi6696.
Carlos Moreno-Yruela  1 ,  Di Zhang  2 ,  Wei Wei  3 ,  Michael Bæk  1 ,  Wenchao Liu  2 ,  Jinjun Gao  2 ,  Daniela Danková  1 ,  Alexander L Nielsen  1 ,  Julie E Bolding  1 ,  Lu Yang  2 ,  Samuel T Jameson  1 ,  Jiemin Wong  3 ,  Christian A Olsen  1 ,  Yingming Zhao  2
Affiliations
  • 1. Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 3. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
PMID: 35044827 DOI: 10.1126/sciadv.abi6696
Abstract

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.