TY - JOUR
T1 - Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation
AU - Trujillo, Marissa N.
AU - Jennings, Erin Q.
AU - Hoffman, Emely A.
AU - Zhang, Hao
AU - Phoebe, Aiden M.
AU - Mastin, Grace E.
AU - Kitamura, Naoya
AU - Reisz, Julie A.
AU - Megill, Emily
AU - Kantner, Daniel
AU - Marcinkiewicz, Mariola M.
AU - Twardy, Shannon M.
AU - Lebario, Felicidad
AU - Chapman, Eli
AU - McCullough, Rebecca L.
AU - D'Alessandro, Angelo
AU - Snyder, Nathaniel W.
AU - Cusanovich, Darren A.
AU - Galligan, James J.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/3
Y1 - 2024/3
N2 - 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 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.
AB - 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 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.
KW - Glyoxalase
KW - Inflammation
KW - Lactate
KW - Metabolism
KW - Post-translational modification
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U2 - 10.1016/j.molmet.2024.101888
DO - 10.1016/j.molmet.2024.101888
M3 - Article
C2 - 38307385
AN - SCOPUS:85184590484
SN - 2212-8778
VL - 81
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101888
ER -