Environmental Arginine Controls Multinuclear Giant Cell Metabolism and Formation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA515294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8445080.fastq.gz | Fastqsanger.gz | |||
| SRR8445090.fastq.gz | Fastqsanger.gz | |||
| SRR8445100.fastq.gz | Fastqsanger.gz | |||
| SRR8445081.fastq.gz | Fastqsanger.gz | |||
| SRR8445091.fastq.gz | Fastqsanger.gz |
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Project description:Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. Formation of MGCs is energy intensive to enforce membrane fusion and cytoplasmic expansion. Here we used receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation. We found amino acid (AA) scarcity controls MGC formation and reveal specific requirements for extracellular arginine in RANKL cellular programming. Systemic arginine restriction improved outcome in multiple murine arthritis models and its removal induced preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis were independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampened generation of IL-4 induced polykaryons, another form of MGCs. Strikingly, in the absence of extracellular arginine, both cell types displayed flexibility as their formation could be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
2019-12-06 | GSE125101 | GEO
Project description:Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. Formation of MGCs is energy intensive to enforce membrane fusion and cytoplasmic expansion. Here we used receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation. We found amino acid (AA) scarcity controls MGC formation and reveal specific requirements for extracellular arginine in RANKL cellular programming. Indeed, systemic arginine restriction improved outcome in multiple murine arthritis models, by inducing preosteoclast metabolic quiescence, associated with a dysregulated tricarboxylic acid (TCA) cycle, and diverted metabolic fluxes from central metabolic pathways independent of mTORC1 activity or global transcriptional and translational inhibition. A conserved metabolic mechanism occurred in IL-4 induced MGCs. Strikingly, we demonstrate that restriction of multiple AAs triggered metabolic adaptation and blocked MGC formation and each was rescued by their downstream metabolites. These data establish how environmental nutrients control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodeling.
2019-12-17 | PXD012405 | Pride
Project description:Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.
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Project description:Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in hepatocellular carcinoma (HCC) despite reduced expression of arginine synthesis genes, in murine and patient tumors. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
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Project description:Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in hepatocellular carcinoma (HCC) despite reduced expression of arginine synthesis genes, in murine and patient tumors. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
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Project description:Enterococcus faecalis is a commensal bacterium in the gastrointestinal tract (GIT) of humans and other organisms. Outside of the GIT, E. faecalis can cause infections in root canals, wounds, surgical sites, the urinary tract, and on heart valves. Many of these infections can be polymicrobial, and a variety of toxins and nutritional signals influence interactions between E. faecalis and other microbes. Like other bacteria, E. faecalis metabolizes arginine through the arginine deiminase (ADI) pathway, which converts arginine to ornithine and releases ATP, ammonia, and CO2. E. faecalis arginine metabolism also affects virulence of other pathogens, such as Clostridioides difficile and Escherichia coli, during co-culture. E. faecalis may encounter elevated levels of arginine in the GIT or the oral cavity, where arginine is used as an additive in dental therapeutics to disrupt plaque formation and biofilm growth by oral streptococci. However, little is known about how E. faecalis responds to growth in arginine. To address this gap, we used RNAseq and additional in vitro assays to measure changes in growth, gene expression, and biofilm formation in arginine relative to control conditions. Here, we demonstrate that arginine decreases E. faecalis biofilm production and causes widespread differential expression of genes related to metabolism, nutrient transport, quorum sensing, and polysaccharide synthesis. Growth in arginine also increases aggregation of E. faecalis cultures and promotes decreased susceptibility to the antibiotics ampicillin and ceftriaxone. Together, this shows that E. faecalis undergoes global transcriptional changes during growth in arginine and provides a platform for better understanding of how the presence of arginine in the niches colonized by E. faecalis affects the physiology of this organism in addition to the virulence of surrounding microbes.
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Project description:Transcriptome reveals the regulation on arginine metabolism in M.smegmatis.
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Project description:Most available knowledge on fungal arginine metabolism is derived from studies on Saccharomyces cerevisiae, in which arginine catabolism is initiated by releasing urea via the arginase reaction. Orthologs of the S. cerevisiae genes encoding the first three enzymes in the arginase pathway were cloned from Kluyveromyces lactis and shown to functionally complement the corresponding deletion in S. cerevisiae. Surprisingly, deletion of the single K. lactis arginase gene KlCAR1 did not completely abolish growth on arginine as nitrogen source. Growth rate of mutant strongly increased during serial transfer in shake-flask cultures. A combination of RNAseq-based transcriptome analysis and 13C-15N-based flux analysis was used to elucidate the arginase-independent pathway. Isotopic 13C15N-enrichment in ?-aminobutyrate revealed succinate as the entry point in the TCA cycle of the alternative pathway. Transcript analysis combined with enzyme activity measurements indicated increased expression in the Klcar1? mutant of a guanidinobutyrase (EC.3.5.3.7), an enzyme not previously demonstrated in fungi. Expression of the K. lactis KLLA0F27995g (renamed KlGBU1) encoding guanidinobutyrase enabled S. cerevisiae to use guanidinobutyrate as sole nitrogen source and its deletion in K. lactis almost completely abolish growth on this nitrogen source. Phylogenetic analysis suggests that this enzyme activity is widespread in fungi. The goal of the present study was to characterize arginine catabolism in K. lactis. To this end, CAR1, CAR2 and PRO3 orthologs in K. lactis were identified and functionally analysed by deletion, expression in S. cerevisiae and enzyme activity assays. Since deletion of the arginase gene in K. lactis was found not to completely abolish growth on arginine as a sole nitrogen source, the alternative pathway for arginine catabolism operating in this yeast was studied by a combination of transcriptome analysis, 13C and 15N isotope-based flux analysis and enzyme activity assays in cell extracts. To investigate arginine metabolism in the arginase-negative K. lactis strain, strains GG1632 (Klku80? KlCAR1 reference strain) and IMS0367 (Klcar1? Arg+) were grown in aerobic bioreactor batch cultures on glucose chemically defined medium with arginine as sole nitrogen source. RNA sequencing of samples taken during the exponential phase of growth on glucose-arginine media of the reference strain G1631 and the arginase less strain IMS0367 were compared resulting in the characterization of a new function.
2014-07-16 | E-GEOD-56060 | biostudies-arrayexpress
Project description:In other bacteria, arginine induces the expression of genes involved in arginine catabolism. This study obtained the identification of genes involved in the arginine metabolism of Mycobacterium tuberculosis. Mycobacterium tuberculosis was cultured with arginine or ammonium chloride as sole nitrogen source. In the log phase of growth, RNA was isolated and whole genome expression was determined. The study contains three biological replicates.
2015-04-01 | E-GEOD-67445 | biostudies-arrayexpress