美国芝加哥大学Yingming Zhao等研究人员合作发现，核GTPSCS作为乳酰-CoA合成酶发挥作用，来促进组蛋白乳酸化和胶质瘤发生。相关论文于2024年12月5日在线发表于国际学术期刊《细胞—代谢》。

研究人员报告了鸟苷三磷酸（GTP）特异性SCS（GTPSCS），作为核内乳酰辅酶A（CoA）合成酶的发现。通过与L-乳酸复合的GTPSCS的晶体结构分析以及随后的突变实验，研究人员阐明了这一机制。GTPSCS转运到细胞核并与p300相互作用，促进组蛋白乳酸化，而不是琥珀酰化。

这个过程依赖于GTPSCS G1亚单位中的核定位信号和G2亚单位残基K73的乙酰化，后者介导与p300的相互作用。GTPSCS/p300的协同作用共同调控组蛋白H3K18la和GDF15的表达，促进胶质瘤的增殖和放射抗性。GTPSCS代表了催化乳酰-CoA合成以进行表观遗传组蛋白乳酸化，并调控胶质瘤中致癌基因表达的首个酶。

据了解，组蛋白赖氨酸乳酸化是一个生理和病理学上相关的表观遗传途径，可以通过与瓦博格效应相关的L-乳酸刺激。然而，细胞如何利用L-乳酸生成乳酰CoA，以及这一过程如何被调控仍不清楚。

附：英文原文

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

Author: Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G. Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A. Cole, Ralph J. DeBerardinis, Samuel K. McBrayer, He Huang, Yingming Zhao

Issue&Volume: 2024-12-05

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.

DOI: 10.1016/j.cmet.2024.11.005

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00451-0