Lactoylglutathione promotes inflammatory signaling in macrophages.
Lactoylglutathione promotes inflammatory signaling in macrophages.
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乳酰谷胱甘肽促进巨噬细胞中的炎症信号传导。
DOI：
10.1101/2023.10.10.561739
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
McCullou
中科院分区：
文献类型：
--
作者：
Trujillo,MarissaN;Jennings,ErinQ;Hoffman,EmelyA;Zhang,Hao;Phoebe,AidenM;Mastin,GraceE;Kitamura,Naoya;Reisz,JulieA;Megill,Emily;Kantner,Daniel;Marcinkiewicz,MariolaM;Twardy,ShannonM;Lebario,Felicidad;Chapman,Eli;McCullou
慢性全身性炎症是代谢紊乱的病理生理学表现。炎症信号传导导致糖酵解通量升高和代谢向有氧糖酵解和乳酸产生转变。乳酸盐的增加与组蛋白上乳酰赖氨酸修饰的产生增加相对应，从而介导对炎症刺激的转录反应。乳酰化也是通过谷胱甘肽酶循环中间体乳酰谷胱甘肽（LGSH）的非酶促S-至-N酰基转移产生的。在这里，我们报告了LGSH在炎症信号传导中的调节作用。在缺乏主要的LGSH水解酶--谷胱甘肽酶2（GLO 2）的情况下，RAW 264.7巨噬细胞显示出LGSH的显著升高，同时当暴露于脂多糖时显示出增强的炎症反应，对应于组蛋白乳糖化的升高。有趣的是，我们的数据表明，在未刺激状态下，乳酰化与比乙酰化更紧密的染色质相关，然而，在刺激后，与乳酰化相关的基因组区域变得明显更容易接近。最后，我们证明了乳酸从LGSH到CoA的自发S-到-S酰基转移，产生乳酰辅酶A。这代表了该代谢物产生的第一个已知机制。总的来说，这些数据表明，LGSH，而不是细胞内乳酸，是促进炎症反应的主要因素。
Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH, while demonstrating a potentiated inflammatory response when exposed to lipopolysaccharides, corresponding with a rise in histone lactoylation. Interestingly, our data demonstrate that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state, however, upon stimulation, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is a primary contributing factor facilitating the inflammatory response.