Trujillo Marissa N, Jennings Erin Q, Hoffman Emely A, Zhang Hao, Phoebe Aiden M, Mastin Grace E, Kitamura Naoya, Reisz Julie A, Megill Emily, Kantner Daniel, Marcinkiewicz Mariola M, Twardy Shannon M, Lebario Felicidad, Chapman Eli, McCullough Rebecca L, D'Alessandro Angelo, Snyder Nathaniel W, Cusanovich Darren A, Galligan James J
bioRxiv. 2023 Oct 10:2023.10.10.561739. doi: 10.1101/2023.10.10.561739.
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.
慢性全身性炎症是代谢紊乱的一种病理生理表现。炎症信号传导导致糖酵解通量增加以及代谢向有氧糖酵解和乳酸生成转变。乳酸的这种增加与组蛋白上乳酰赖氨酸修饰的生成增加相对应，介导对炎症刺激的转录反应。乳酰化也通过乙二醛酶循环中间体乳酰谷胱甘肽（LGSH）的非酶促硫到氮酰基转移产生。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水解酶乙二醛酶2（GLO2）的情况下，RAW264.7巨噬细胞中LGSH显著升高，而在暴露于脂多糖时表现出增强的炎症反应，这与组蛋白乳酰化的增加相对应。有趣的是，我们的数据表明，在未刺激状态下，与乙酰化相比，乳酰化与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到辅酶A的自发硫到硫酰基转移，产生乳酰辅酶A。这代表了这种代谢物生成的第一个已知机制。总的来说，这些数据表明，促进炎症反应的主要因素是LGSH，而不是细胞内乳酸。
