Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis PMID: 39642882

ADC Targets in Oncology

2026-04-10

Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis

Cell Metab. 2025 Feb 4;37(2):377-394.e9. doi: 10.1016/j.cmet.2024.11.005.

Ruilong Liu ¹ , Xuelian Ren ² , Yae Eun Park ³ , Huixu Feng ⁴ , Xinlei Sheng ³ , Xiaohan Song ⁵ , Roya AminiTabrizi ⁶ , Hardik Shah ⁶ , Lingting Li ⁷ , Yu Zhang ⁷ , Kalil G Abdullah ⁸ , Sarah Dubois-Coyne ⁹ , Hening Lin ¹⁰ , Philip A Cole ⁹ , Ralph J DeBerardinis ¹¹ , Samuel K McBrayer ¹² , He Huang ¹³ , Yingming Zhao ¹⁴

Affiliations

1. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA; Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
3. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA; Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
4. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
6. Biological Science Division, Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
7. Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
8. Department of Neurosurgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Hillman Comprehensive Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
9. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
10. Howard Hughes Medical Institute, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
11. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
12. Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
13. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: [email protected].
14. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA; Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA. Electronic address: [email protected].

Abstract

Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.

Keywords

GDF15; histone marks; hypoxia; lactyl-CoA; lactyl-CoA synthetase; lactylation; p300; succinyl-CoA synthetase; the Warburg effect; tumorigenesis.