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.

中文翻译：

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细胞核 GTPSCS 作为乳酰辅酶 A 合成酶发挥作用，促进组蛋白乳酸化和神经胶质瘤生成


组蛋白赖氨酸乳酸化是一种生理和病理相关的表观遗传途径，可由 Warburg 效应相关的 L-乳酸刺激。然而，细胞利用 L-乳酸产生乳酰辅酶 A （CoA） 的机制以及这一过程如何调节仍然未知。在这里，我们报告了三磷酸鸟苷 （GTP） 特异性 SCS （GTPSCS） 作为细胞核中乳酰辅酶 A 合成酶的鉴定。通过与 L-乳酸复合物中 GTPSCS 的晶体结构阐明其机制，然后进行诱变实验。GTPSCS 转位到细胞核中并与 p300 相互作用以提高组蛋白乳酸化，但不提高琥珀酰化。这个过程依赖于 GTPSCS G1 亚基中的核定位信号和 G2 亚基残基 K73 的乙酰化，后者介导与 p300 的相互作用。GTPSCS/p300 合作协同调节组蛋白 H3K18la 和 GDF15 表达，促进胶质瘤增殖和放射耐药。GTPSCS 是催化表观遗传组蛋白乳酰化的乳酰辅酶 A 合成和调节神经胶质瘤中致癌基因表达的首种酶。