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Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation
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
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
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Journal article
Date
2024-02-01
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Cardiovascular Sciences
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https://doi.org/10.1016/j.molmet.2024.101888
Abstract
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 nonenzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, 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 the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.
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Citation
Marissa N. Trujillo, Erin Q. Jennings, Emely A. Hoffman, Hao Zhang, Aiden M. Phoebe, Grace E. Mastin, Naoya Kitamura, Julie A. Reisz, Emily Megill, Daniel Kantner, Mariola M. Marcinkiewicz, Shannon M. Twardy, Felicidad Lebario, Eli Chapman, Rebecca L. McCullough, Angelo D'Alessandro, Nathaniel W. Snyder, Darren A. Cusanovich, James J. Galligan, Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation, Molecular Metabolism, Volume 81, 2024, 101888, ISSN 2212-8778, https://doi.org/10.1016/j.molmet.2024.101888. (https://www.sciencedirect.com/science/article/pii/S221287782400019X)
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Elsevier
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Molecular Metabolism, Vol. 81
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