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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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			Action	DRS
	XD185LPScB1_CON_Slot2-8_1_15609.d.zip	Other
	XD185LPScB1_GABA_Slot2-9_1_15611.d.zip	Other
	XD185LPScB1_combined.zip	Other
	XD185LQB1_CON_Slot1-50_1_6293.d.zip	Other
	XD185LQB1_GABA_Slot1-51_1_6298.d.zip	Other

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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

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

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

Succinylation proteome analysis of Cd-exposed Neuro-2a cells

Project description:Cadmium is a neurotoxic compound which induces cognitive alterations similar to those produced by Alzheimer's disease (AD). Autophagic flux impairment is a hallmark in Cd-induced AD-like pathology. However, the underlying mechanism remains obscure. In these study, Neuro-2a cells were exposed to different concentrations of Cd (1, 2, and 4 μM) for 72 h, and C57 mice (8 week) were orally administered Cd for 12 weeks. Chronic Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, thereby contributing to defects in autophagic clearance and subsequently leading to APP accumulation and nerve cell death. Mechanistically, proteomic analysis coupled with Ingenuity Pathway Analysis identified the crucial key target molecule in Cd-impaired autophagic flux. Four-dimensional label-free succinylation quantitative proteomics were performed in Neuro-2a cells with and without 4 μM CdCl2 treatment for 72h. Then, vital molecules and crucial succinylation sites were identified. Moreover, the function and important role of the resulting molecule with crucial succinylation site were determined. These results may thus open an avenue for therapeutic intervention in chronic Cd-induced AD-like pathology.

2024-10-17 | PXD048158 | Pride

Succinylation proteome analysis of seedling leaves of Bd21

Project description:Protein lysine succinylation, an emerging protein post-translational modification widespread among microbiology, animals and plants, represents an important regulator of cellular processes. In our study, we took the first succinylation proteome analysis in the seedling leaves of Bd21 to draw a schematic map. With high accuracy nano LC-MS/MS combined with affinity purification, a total of 605 succinylated peptides in 323 proteins were identified and were implicated in various molecular functions and cellular biological processes. More than half (53.4%) of the proteins only have one lysine succinylated site. These identified proteins are involved in a variety of cellular functions such as amino acids transport/metabolism, post-translational modification, translation/ribosomal structure and lipid metabolism, especially energy and carbohydrate metabolism via GO, conservation analysis, protein interaction network and other bioinformatics analysis. Motif-X analysis of the succinylation sites identified fourteen significantly enriched succinylation motifs (-Ksucc-----K-, -Ksucc------G- etc) for the first time in plants and will provide possible succinylation binding locus for future studies. Secondary structure analysis showed that the succinylation sites occurred predominantly in alpha helix and coil structures which similar with acetylation. 155 (59.2%) of the homologous succinylated proteins were also identified in other three species (E. coli, S. cerevisiae and H. sapiens). 119 (45.4%) succinylated proteins and 115 (19%) sites were also to be acetylated at the same time. Our succinylated protein data set provides a promising starting point for further functional analysis of succinylation in B. distachyon, which could facilitate the elucidation of the entire metabolic network in the model monocot plant.

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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

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

Identification of desuccinylase ScCobB2 and its desuccinylation substrates in Streptomyces coelicolor

Project description:As a recently discovered protein posttranslational modification in eukaryotes, lysine succinylation has attracted increasing interest due to its ability to regulate several critical cellular processes including catabolism, β-oxidation, and ketogenesis. Nevertheless, understanding of the regulation mechanism is still at an early stage due to the lack of identified specific desuccinylases in most microorganisms.Here, in the model soil bacteria Streptomyces coelicolor, we biochemically characterized a sirtuin-like protein ScCobB2 as a divergent desuccinylase. Based on it, we identified a total of 673 unique succinylated sites, of which 470 sites in 317 proteins were quantified by combining tandem mass tag labeling, antibody affinity enrichment, and LC−MS/MS analysis. Furtheranalyses of the quantitative succinylome revealed that at least 114 proteins representing two major pathways, carbon metabolism and protein biosynthesis, are obviously hypersuccinylated in ∆ScCobB2 cells. We experimentally examined the regulatory roles of ScCobB2 on 13 hypersuccinylated proteins, including glyceraldehyde-3-phosphate dehydrogenase, aconitate hydratase, and several ribosomal proteins, the results of which suggested a high confidence in our quantitative data. This work provided the first discovery of a specificdesuccinylase in bacteria, and demonstrated it has pivotal regulatory role in multiple biological processes for S. coelicolor, laid the foundation for future research of succinylation regulation in other microorganisms.

2019-06-11 | PXD014202 | Pride