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GABA regulates IL-1β production in macrophages

ABSTRACT: Neurotransmitters have been well-documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrated that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-FAD-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of Bcl2l11 and Dusp2, lowering the formation of NLRP3-ASC-Caspase-1 complex. Meanwhile, GABA-succinate axis lowers succinylation of mitochondrial proteins to promote mitochondrial oxidative phosphorylation (OXPHOS). We also found that GABA alleviates the LPS-induced sepsis as well as high-fat diet-induced obesity in mice. Our study proves that GABA is potential in lessening the pro-inflammatory macrophage responses associating with metabolic reprogramming and protein succinylation, thus providing a strategy for treating macrophage-related inflammatory diseases.

INSTRUMENT(S): autoflex

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Jian Fu

LAB HEAD: Jian Fu

PROVIDER: PXD037901 | Pride | 2022-11-29

REPOSITORIES: Pride

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GABA regulates IL-1β production in macrophages

Project description:Neurotransmitters have been well-documented to determine immune cell fates; however, whether and how γ-amino butyric acid (GABA) shapes the function of innate immune cells is still obscure. Here, we demonstrated that GABA orchestrates macrophage maturation and inflammation. GABA treatment during macrophage maturation inhibits interleukin (IL)-1β production from inflammatory macrophages. Mechanistically, GABA enhances succinate-FAD-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of Bcl2l11 and Dusp2, lowering the formation of NLRP3-ASC-Caspase-1 complex. Meanwhile, GABA-succinate axis lowers succinylation of mitochondrial proteins to promote mitochondrial oxidative phosphorylation (OXPHOS). We also found that GABA alleviates the LPS-induced sepsis as well as high-fat diet-induced obesity in mice. Our study proves that GABA is potential in lessening the pro-inflammatory macrophage responses associating with metabolic reprogramming and protein succinylation, thus providing a strategy for treating macrophage-related inflammatory diseases.

2023-01-31 | MTBLS6337 | MetaboLights

Tomato (Solanum lycopersicum) lysine succinylation LC-MS/MS

Project description:Post-translational modification of proteins through lysine succinylation plays important regulatory roles in living cells. Lysine succinylation was recently identified as a novel post-translational modification in several organisms, including Escherichia coli, yeast, Toxoplasma gondii, and HeLa cells, as well as mouse liver. Interestingly, few sites of lysine succinylation were detected in plants. In this study, we identified 347 sites of lysine succinylation in 202 proteins of tomato by using high-resolution mass spectrometry.

2018-10-24 | PXD002380 | Pride

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1β-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.

2016-07-01 | GSE82043 | GEO

Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation

Project description:Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation mechanism accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the downstream pro-inflammatory IL-1Î²-HIF1a axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions via its effect on succinate dehydrogenase, by inhibiting conversion of succinate to fumarate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1-/- mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, changes in mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages. Experiment 1: mature WT BMDM were treated for 12h with 0.25 mM dimethyl itaconate (DI) or vehicle (Unst) and then stimulated with LPS (E. coli 0111:B4; 100 ng/ml, 4h) (DI+LPS; LPS); Experiment 2: mature Irg1-/- BMDM were stimulated with LPS (E. coli 0111:B4; 100 ng/ml) and murine recombinant IFNg (50 ng/ml) for 24h.

2016-07-01 | E-GEOD-82043 | biostudies-arrayexpress

Succinylation in pseudorabies virus infection

Project description:We examined the global succinylation during PRV infection through a 4D label free quantitative proteomics method, which is the conventional separation of the three dimensions of mass-to-charge ratio, retention time, and ion intensity with the inclusion of the ion separation as a fourth dimension. We analyzed the function of some key enzymes that underwent succinylation and determine whether viral proteins undergo succinylation.

2023-03-02 | PXD040521 | Pride

Transcription profiling of Rhizobium leguminosarum bv viciae strain 3841 grown on AMS minimal media with succinate and ammonia compared to succinate GABA

Project description:Rhizobium leguminosarun bv viciae strain 3841 was grown on AMS minimal medium with sucinate and ammonia and compared to a culture grown on succinate GABA

2008-11-10 | E-MEXP-1894 | biostudies-arrayexpress

Succinylome analysis reveals the involvement of lysine succinylation in extreme resistance of Deinococcus radiodurans

Project description:Increasing evidences showing that succinylation of lysine residue mainly regulates enzymes involved in the carbon metabolism pathway, both in prokaryotic and eukaryotic cells. Deinococcus radiodurans is one of the most radioresistant organisms on earth, which is famous for its robust resistance. A major goal in the current study of protein succinylation is to explore its function in D. radiodurans. We used high-resolution liquid chromatography-mass spectrometry (LC-MS/MS) for qualitative proteomics to perform a global succinylation analysis of D. radiodurans and identified 492 succinylation sites on 270 proteins. These identified proteins are involved in a variety of biological process and pathways.

2021-04-26 | PXD012149 | Pride

A Qualitative Proteome-wide Lysine Succinylation Profiling of Tea Revealed Its Involvement in Primary Metabolism

Project description:Background: Lysine succinylation of proteins has potential impacts on protein structure and function, which occurred on post-translation level. However, the information about the lysine succinylation of proteins in tea plants is limited. In the present study, the significant signal of succinylation in tea plants was found by western blot. Subsequently, we performed qualitative analyses to globally identify lysine succinylation substrates by using high accuracy nano LC-MS/MS combined with affinity purification. Results: As a result, a total of 142 lysine succinylation sites were identified in 86 proteins. The identified succinylated proteins are involved in various biological processes and a large proportion of the succinylation sites are present on proteins in the primary metabolism pathway, including glyoxylate and dicarboxylate metabolism, the tricarboxylic acid (TCA) cycle and glycine, serine and threonine metabolism. Moreover, 10 new succinylated sites on histones were detected in tea plants either. Conclusions: These results suggested that succinylated proteins in tea plants might play critical regulatory roles in biological processes, especially in the primary metabolism. This study not only globally analysed the functional annotation of lysine succinylation in tea plants, but also provided valuable information for further investigating the functions of lysine succinylation in tea plants.

2022-02-23 | PXD011717 | Pride

Proteome-wide lysine succinylome profiling and comprehensive analysis of protein lysine co-modification in developing rice seeds

Project description:Lysine succinylation has been recognized as a post-translational modification (PTM) in recent years. It is plausible that succinylation may have a vaster functional impact than acetylation due to bulkier structural changes and greater charge differences on the modified lysine residue. Currently, however, the quantity of identified succinylated proteins and their corresponding functions in cereal plants remain largely unknown. In this study, 854 lysine succinylation sites on 347 proteins have been identified by a thorough investigation in developing rice seeds. Six motifs were revealed as preferred amino-acid sequence arrangements for succinylation sites, and a noteworthy motif preference was discovered in proteins associated with different biological processes, molecular functions, pathways, and domains. Remarkably, heavy succinylation was detected on major seed storage proteins, in conjunction with key enzymes involved in central carbon metabolism and starch biosynthetic pathways for rice seed development. Conserved succinylated proteins were identified amongst varying organisms. Rice proteins with co-modifications of succinylation, acetylation, malonylation, crotonylation, and 2-hydroxyisobutyrylation were identified through a comprehensive comparison analysis. A striking number of highly conserved succinyl-proteins and multi-modified proteins were shown to be involved in vital metabolic events. Our study delivers a platform for expansive investigation of molecular networks administrating cereal seed development via PTMs.

2019-09-09 | PXD013664 | Pride

Succinylome and acetylome analyses of Staphylococcus aureusSuccinylome and acetylome analyses of Staphylococcus aureus

Project description:In this study, we detected the first lysine succinylome and acetylome in a vancomycin-intermediate S. aureus (VISA) strain, XN108.Furthermore,Comparative analysis of the protein succinylation and acetylation between XN108-ΔcobB and XN108-WT strain was conducted on the basis of quantitative detection of both protein expression and protein modification

2022-11-09 | PXD030190 | Pride

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