海军军医大学王品等研究人员合作发现，由甘油醛酶II底物SLG诱导的非酶促赖氨酸d-乳酸化抑制炎症免疫反应。相关论文于2025年1月6日在线发表在《细胞研究》杂志上。

据介绍，免疫代谢在免疫和炎症的调节中至关重要。然而，预防异常激活诱导的免疫病理的机制在很大程度上仍不清楚。

研究人员发现糖解分支通路中的甘油醛酶II（GLO2）在先天免疫激活过程中通过三重螺旋蛋白（TTP）介导的mRNA降解受到NF-κB信号通路的特异性下调。因此，其底物S-D-乳酰谷胱甘肽（SLG）在细胞质中积累，并直接诱导蛋白质的d-乳酸化修饰。这种SLG诱导的非酶促乳酸化在一个邻近的半胱氨酸残基的帮助下大大促进，因为它首先与SLG反应形成一个可逆的S-乳酸化巯基中间体，随后通过SN转移将乳酸基团转移到邻近的赖氨酸上。乳酸化组学分析识别了2255个乳酸化位点，主要集中在活化巨噬细胞的细胞质蛋白中，全局蛋白质结构分析表明，赖氨酸与半胱氨酸残基的接近性决定了其对SLG介导的d-乳酸化的敏感性。

此外，乳酸化优先富集于参与免疫激活和炎症通路的蛋白质中，且RelA的赖氨酸310（K310）处的d-乳酸化减弱了炎症信号传导和NF-κB转录活性，从而恢复了免疫稳态。因此，TTP结合位点突变或体内过表达GLO2阻断了先天免疫细胞中的这一反馈乳酸化，并促进了炎症，而GLO2的基因缺失或药理抑制则在体内外限制了免疫激活并减轻了炎症免疫病理。重要的是，GLO2/SLG/d-乳酸化调控轴的失调与人类炎症表型密切相关。总体而言，这些发现揭示了SLG诱导的非酶促d-乳酸化的免疫代谢反馈回路，并提示GLO2作为应对临床炎症性疾病的有前景靶点。

附：英文原文

Title: Nonenzymatic lysine d-lactylation induced by glyoxalase II substrate SLG dampens inflammatory immune responses

Author: Zhao, Qihang, Wang, Qiang, Yao, Qinghua, Yang, Zhengdong, Li, Wenfang, Cheng, Xiaojie, Wen, Yingling, Chen, Rong, Xu, Junfang, Wang, Xuanying, Qin, Dexiang, Zhu, Shuyang, He, Liujie, Li, Nan, Wu, Yanfeng, Yu, Yizhi, Cao, Xuetao, Wang, Pin

Issue&Volume: 2025-01-06

Abstract: Immunometabolism is critical in the regulation of immunity and inflammation; however, the mechanism of preventing aberrant activation-induced immunopathology remains largely unclear. Here, we report that glyoxalase II (GLO2) in the glycolysis branching pathway is specifically downregulated by NF-κB signaling during innate immune activation via tristetraprolin (TTP)-mediated mRNA decay. As a result, its substrate S-D-lactoylglutathione (SLG) accumulates in the cytosol and directly induces D-lactyllysine modification of proteins. This nonenzymatic lactylation by SLG is greatly facilitated by a nearby cysteine residue, as it initially reacts with SLG to form a reversible S-lactylated thiol intermediate, followed by SN-transfer of the lactyl moiety to a proximal lysine. Lactylome profiling identifies 2255 lactylation sites mostly in cytosolic proteins of activated macrophages, and global protein structure analysis suggests that proximity to a cysteine residue determines the susceptibility of lysine to SLG-mediated D-lactylation. Furthermore, lactylation is preferentially enriched in proteins involved in immune activation and inflammatory pathways, and D-lactylation at lysine 310 (K310) of RelA attenuates inflammatory signaling and NF-κB transcriptional activity to restore immune homeostasis. Accordingly, TTP-binding site mutation or overexpression of GLO2 in vivo blocks this feedback lactylation in innate immune cells and promotes inflammation, whereas genetic deficiency or pharmacological inhibition of GLO2 restricts immune activation and attenuates inflammatory immunopathology both in vitro and in vivo. Importantly, dysregulation of the GLO2/SLG/D-lactylation regulatory axis is closely associated with human inflammatory phenotypes. Overall, our findings uncover an immunometabolic feedback loop of SLG-induced nonenzymatic D-lactylation and implicate GLO2 as a promising target for combating clinical inflammatory disorders.

DOI: 10.1038/s41422-024-01060-w

Source: https://www.nature.com/articles/s41422-024-01060-w