Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis

Di Zhang; Jinjun Gao; Zhijun Zhu; Qianying Mao; Zhiqiang Xu; Pankaj K. Singh; Cornelius C. Rimayi; Carlos Moreno-Yruela; Shuling Xu; Gongyu Li; Yi Cheng Sin; Yue Chen; Christian A. Olsen; Nathaniel W. Snyder; Lunzhi Dai; Lingjun Li; Yingming Zhao

doi:10.1038/s41589-024-01680-8

Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis

Di Zhang^*, Jinjun Gao, Zhijun Zhu, Qianying Mao, Zhiqiang Xu, Pankaj K. Singh, Cornelius C. Rimayi, Carlos Moreno-Yruela, Shuling Xu, Gongyu Li, Yi Cheng Sin, Yue Chen, Christian A. Olsen, Nathaniel W. Snyder, Lunzhi Dai^*, Lingjun Li^*, Yingming Zhao^*

^*Corresponding author af dette arbejde

Biologiske lægemidler

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

86 Citationer (Scopus)

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Abstract

Lysine l-lactylation (K_l-la) is a novel protein posttranslational modification (PTM) driven by l-lactate. This PTM has three isomers: K_l-la, N-ε-(carboxyethyl)-lysine (K_ce) and d-lactyl-lysine (K_d-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that K_l-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not K_d-la or K_ce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in l-lactylation, correlates positively with K_l_-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights K_l-la as the primary responder to glycolysis and the Warburg effect. (Figure presented.)

Originalsprog	Engelsk
Tidsskrift	Nature Chemical Biology
Vol/bind	21
Sider (fra-til)	91-99
ISSN	1552-4450
DOI	https://doi.org/10.1038/s41589-024-01680-8
Status	Udgivet - 2025

Bibliografisk note

Funding Information:
We thank R. G. Roeder at Rockefeller University and B. Ren at the University of California, San Diego for great discussions and suggestions. We also extend our thanks to F. L. Muller at the University of Texas MD Anderson Cancer Center and J. J. Galligan at the University of Arizona for sharing the reagents. This work was supported by the National Natural Science Foundation of China (grant no. 32270822 to D.Z.), the Peking-Tsinghua Center for Life Science, the State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences of Peking University and the Li Ge Zhao Ning Life Science Junior Research Fellowship to D.Z.; the National Key R&D Program of China (grant no. 2018YFC2000305 to L.D.), the 135 project of West China Hospital (grant nos. ZYYC23013 and ZYJC21005 to L.D.), the National Clinical Research Center for Geriatrics of West China Hospital (no. Z2024JC002 to L.D.); the University of Chicago, Nancy and Leonard Florsheim family fund to Y.Z.; the National Institutes of Health (grant nos. AR078555 and CA251677 to Y.Z., R01GM132261 to N.W.S. and DK071801, AG052324, S10RR029531 and S10OD028473 to L.L.), the National Science Foundation (grant no. CHE-2108223 to L.L.) and by the European Research Council under the European Union\u2019s Horizon 2020 Research and Innovation Program (grant no. CoG-725172 to C.A.O.). We thank the Center for Research Informatics at the University of Chicago for supporting the proteomic data analysis.

Publisher Copyright:
© The Author(s) 2024.

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Citationsformater

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title = "Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis",

abstract = "Lysine l-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by l-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and d-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in l-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect. (Figure presented.)",

author = "Di Zhang and Jinjun Gao and Zhijun Zhu and Qianying Mao and Zhiqiang Xu and Singh, {Pankaj K.} and Rimayi, {Cornelius C.} and Carlos Moreno-Yruela and Shuling Xu and Gongyu Li and Sin, {Yi Cheng} and Yue Chen and Olsen, {Christian A.} and Snyder, {Nathaniel W.} and Lunzhi Dai and Lingjun Li and Yingming Zhao",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2025",

doi = "10.1038/s41589-024-01680-8",

language = "English",

volume = "21",

pages = "91--99",

journal = "Nature Chemical Biology",

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T1 - Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis

AU - Zhang, Di

AU - Gao, Jinjun

AU - Zhu, Zhijun

AU - Mao, Qianying

AU - Xu, Zhiqiang

AU - Singh, Pankaj K.

AU - Rimayi, Cornelius C.

AU - Moreno-Yruela, Carlos

AU - Xu, Shuling

AU - Li, Gongyu

AU - Sin, Yi Cheng

AU - Chen, Yue

AU - Olsen, Christian A.

AU - Snyder, Nathaniel W.

AU - Dai, Lunzhi

AU - Li, Lingjun

AU - Zhao, Yingming

PY - 2025

Y1 - 2025

N2 - Lysine l-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by l-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and d-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in l-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect. (Figure presented.)

AB - Lysine l-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by l-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and d-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in l-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect. (Figure presented.)

U2 - 10.1038/s41589-024-01680-8

DO - 10.1038/s41589-024-01680-8

M3 - Journal article

C2 - 39030363

AN - SCOPUS:85198916871

SN - 1552-4450

VL - 21

SP - 91

EP - 99

JO - Nature Chemical Biology

JF - Nature Chemical Biology

ER -