Abstract
Macrophages undergo metabolic changes during activation that are coupled to functional responses. The gram negative bacterial product lipopolysaccharide (LPS) is especially potent at driving metabolic reprogramming, enhancing glycolysis and altering the Krebs cycle. Here we describe a role for the citrate-derived metabolite malonyl-CoA in the effect of LPS in macrophages. Malonylation of a wide variety of proteins occurs in response to LPS. We focused on one of these, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In resting macrophages, GAPDH binds to and suppresses translation of several inflammatory mRNAs, including that encoding TNFα. Upon LPS stimulation, GAPDH undergoes malonylation on lysine 213, leading to its dissociation from TNFα mRNA, promoting translation. We therefore identify for the first time malonylation as a signal, regulating GAPDH mRNA binding to promote inflammation.
Highlights
Macrophages undergo metabolic changes during activation that are coupled to functional responses
We found the ACC1 isoform to be the highest expressed in bone marrowderived macrophages (BMDMs), followed by ACSF3, while no expression of the ACC2 isoform was detected. (Fig. 1b)
While ACC2 appears to be expressed in bone marrow immune stem cell precursors, it is not expressed in most immune cells, with the exception of some B cell populations, CD8+ T cells and FoxP3+ Treg cells (Supplementary Fig. 1b)
Summary
Macrophages undergo metabolic changes during activation that are coupled to functional responses. Macrophages have been a particular focus in this regard These front line cells of innate immunity, inflammation, and tissue repair[11], display different metabolic features depending on their function. We found that malonylation of the glycolytic enzyme GAPDH in particular, has an impact on pro-inflammatory cytokine production, by modulating both its enzymatic activity and RNA-binding capacity. This novel finding reveals a hitherto unknown mechanism in LPS signalling that regulates the expression of central proinflammatory mediators, while further emphasising the importance of metabolic reprogramming in macrophage activation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
