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bioRxiv · 10.1101/2025.02.25.640220

Class I histone deacetylases catalyze lysine lactylation

Tsusaka, T.·Najar, M. A.·Sharma, I.·Marcinkiewicz, M. M.·Crispim, C. V. D. S.·Snyder, N. W.·Burslem, G.·Goldberg, E. L.
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Abstract

Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the {varepsilon}-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, via a high-energy intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine {beta}-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDAC-catalyzed lysine lactylation accounts for the majority of Kla formation in cells. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.

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Tsusaka, T., Najar, M. A., Sharma, I., Marcinkiewicz, M. M., Crispim, C. V. D. S., Snyder, N. W., Burslem, G., Goldberg, E. L.. 2025-02-28. Class I histone deacetylases catalyze lysine lactylation. https://doi.org/10.1101/2025.02.25.640220

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