Dataset Information

Environmental Arginine Controls Multinuclear Giant Cell Metabolism and Formation

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Mario Oroshi

LAB HEAD: Gernot Schabbauer

PROVIDER: PXD012405 | Pride | 2019-12-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20180116_QX0_FeMe_SA_ArgMac_01_MCSF-LArg.raw	Raw
	20180116_QX0_FeMe_SA_ArgMac_01_MCSF-RANKL-LArg-recArg.raw	Raw
	20180116_QX0_FeMe_SA_ArgMac_01_MCSF-RANKL-LArg.raw	Raw
	20180116_QX0_FeMe_SA_ArgMac_01_MCSF-RANKL.raw	Raw
	20180116_QX0_FeMe_SA_ArgMac_01_MCSF.raw	Raw

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Publications

Environmental arginine controls multinuclear giant cell metabolism and formation.

Brunner Julia S JS Vulliard Loan L Hofmann Melanie M Kieler Markus M Lercher Alexander A Vogel Andrea A Russier Marion M Brüggenthies Johanna B JB Kerndl Martina M Saferding Victoria V Niederreiter Birgit B Junza Alexandra A Frauenstein Annika A Scholtysek Carina C Mikami Yohei Y Klavins Kristaps K Krönke Gerhard G Bergthaler Andreas A O'Shea John J JJ Weichhart Thomas T Meissner Felix F Smolen Josef S JS Cheng Paul P Yanes Oscar O Menche Jörg J Murray Peter J PJ Sharif Omar O Blüml Stephan S Schabbauer Gernot G

Nature communications 20200122 1

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 ...[more]

PMID: 31969567

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Project description:One of the most common metabolic defects of cancer cells is the deficiency in arginine synthesis due to suppressed expression of argininosuccinate synthetase 1 (ASS1) which renders cancer cells auxotrophic to external arginine supply. Arginine deprivation has been effectively used as a treatment for leukemias, with several clinical trials on solid tumors underway. We previously showed that in prostate cancer arginine depletion induced mitochondrial dysfunction and excessive ROS production resulting in chromatin autophagy, nuclear DNA leakage, and cellular death, but the detailed mechanism of arginine starvation-induced cell death remains unclear. In this study, we demonstrated that arginine deprivation coordinately suppressed metabolic genes, including those responsible for mitochondrial oxidative phosphorylation (OXPHOS), nucleotide metabolism, and DNA repair. The consequent ROS production and impaired DNA damage response resulted in nuclear DNA leakage and cGAS-STING activation which is accompanied by upregulation of type I interferon response. We also showed that coordinated silencing of OXPHOS and DNA repair genes is caused in part by the depletion of α-ketoglutarate (αKG) and inactivation of histone demethylases. Supplementing cell-permeable dimethyl α-ketoglutarate (DMKG) both reduced repressive histone methylations and partially restored OXPHOS gene expressions, mitochondrial functions, and mitigated nuclear DNA leakage. Using our dietary arginine-restriction model, we demonstrate that arginine starvation slows prostate cancer growth with evidence of enhanced interferon responses and recruitment of immune cells. Our data suggests arginine starvation induces cell killing of ASS1-low cancer cells by metabolic depletion and epigenetic silencing of metabolic genes, leading to DNA damage and leakage. Resulting cGAS-STING activation may further enhance these killing effects. We used microarray to analyze the expression difference between control and arginine-depleted cells to find out what genes involved in the regulation of mitochondrial function and arginine deprivation-induced cell death.