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

文献类型：期刊论文

作者Liu, Ruilong7,8,9; Ren, Xuelian6,9; Park, Yae Eun7,8; Feng, Huixu9; Sheng, Xinlei7,8; Song, Xiaohan6; Aminitabrizi, Roya5; Shah, Hardik5; Li, Lingting4; Zhang, Yu4
刊名CELL METABOLISM
出版日期2025-02-04
卷号37期号:2页码:28
ISSN号1550-4131
DOI10.1016/j.cmet.2024.11.005
通讯作者Huang, He(hhuang@simm.ac.cn) ; Zhao, Yingming(yingming.zhao@uchicago.edu)
英文摘要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.
WOS关键词CELL-CYCLE ; LACTATE ; EXPRESSION ; METABOLISM ; CANCER ; COENZYME ; COMPLEX ; ENZYMES
资助项目University of Chicago ; Nancy and Leonard Florsheim family fund ; National Institutes of Health (Cancer Center Support Grant)[P30CA014599] ; National Institutes of Health (NIH)[GM135504] ; National Institutes of Health (NIH)[AR078555] ; National Institutes of Health (NIH)[CA251677] ; National Institutes of Health (NIH)[R35CA220449] ; National Institutes of Health (NIH)[P50CA196516] ; National Natural Science Foundation of China[22277125] ; National Natural Science Foundation of China[92253306] ; Shanghai Municipal Science and Technology Major Project ; Shanghai Post-doctoral Excellence Program[2021426] ; CAS special research fellow promotion program ; NIH/NCI[R01CA258586] ; Distinguished Scientist Award from the Sontag Foundation[RR190034] ; Distinguished Scientist Award from the Sontag Foundation[RP230344] ; Cancer Prevention and Research Institute of Texas (CPRIT) awards ; Howard Hughes Medical Institute Investigator Program
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
WOS记录号WOS:001437864500001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/316484]  
专题中国科学院上海药物研究所
通讯作者Huang, He; Zhao, Yingming
作者单位1.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA
2.Univ Pittsburgh, Hillman Canc Ctr, Med Ctr, Pittsburgh, PA 15232 USA
3.Univ Pittsburgh, Sch Med, Dept Neurosurg, Pittsburgh, PA 15213 USA
4.Chinese Acad Sci, CAS Ctr Excellence Mol Plant Sci, Shanghai Inst Plant Physiol & Ecol, Key Lab Synthet Biol, Shanghai 200032, Peoples R China
5.Univ Chicago, Comprehens Canc Ctr, Biol Sci Div, Metabol Platform, Chicago, IL 60637 USA
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
7.Univ Chicago, Comprehens Canc Ctr, Chicago, IL 60637 USA
8.Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
10.Univ Texas Southwestern Med Ctr Dallas, Childrens Med Ctr Res Inst, Dallas, TX 75390 USA
推荐引用方式
GB/T 7714		 Liu, Ruilong,Ren, Xuelian,Park, Yae Eun,et al. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis[J]. CELL METABOLISM,2025,37(2):28.
APA Liu, Ruilong.,Ren, Xuelian.,Park, Yae Eun.,Feng, Huixu.,Sheng, Xinlei.,...&Zhao, Yingming.(2025).Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.CELL METABOLISM,37(2),28.
MLA Liu, Ruilong,et al."Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis".CELL METABOLISM 37.2(2025):28.

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来源：上海药物研究所

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