2024
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
Asantewaa G, Tuttle E, Ward N, Kang Y, Kim Y, Kavanagh M, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales T, Taylor K, Alimohammadi F, Duncan R, Sechrist Z, Agostini-Vulaj D, Schafer X, Chang H, Smith Z, O’Connor T, Whelan S, Selfors L, Crowdis J, Gray G, Bronson R, Brenner D, Rufini A, Dirksen R, Hezel A, Huber A, Munger J, Cravatt B, Vasiliou V, Cole C, DeNicola G, Harris I. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nature Communications 2024, 15: 6152. PMID: 39034312, PMCID: PMC11271484, DOI: 10.1038/s41467-024-50454-2.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligase catalytic subunitLipid abundanceLipogenic enzyme expressionAbundance in vivoLipid productionCatalytic subunitRepress Nrf2Transcription factorsNrf2 repressionAdult tissuesSynthesis of GSHEnzyme expressionNon-redundantRedox bufferMouse liverLoss of GSHTriglyceride productionIn vivo modelsAbundanceGlutathione synthesisLiver balanceFat storesOxidative stressLipidDeletionA Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation
Bonetti L, Horkova V, Grusdat M, Longworth J, Guerra L, Kurniawan H, Franchina D, Soriano-Baguet L, Binsfeld C, Verschueren C, Spath S, Ewen A, Koncina E, Gérardy J, Kobayashi T, Dostert C, Farinelle S, Härm J, Fan Y, Chen Y, Harris I, Lang P, Vasiliou V, Waisman A, Letellier E, Becher B, Mittelbronn M, Brenner D. A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation. Cell Metabolism 2024, 36: 1726-1744.e10. PMID: 38986617, DOI: 10.1016/j.cmet.2024.06.010.Peer-Reviewed Original ResearchReactive oxygen speciesMitochondrial functionCatalytic subunit of glutamate cysteine ligaseMitochondrial gene expressionDecreased cellular ATPPhosphorylation of 4E-BP1Disrupt mitochondrial functionReduced phosphorylation of 4E-BP1T cell-specific ablationCell's antioxidant mechanismsCell-specific ablationCatalytic subunitIL-22Cellular signalingIntestinal homeostasisIL-22 productionSignificant reactive oxygen speciesSubunit of glutamate cysteine ligaseGene expressionReduced IL-22 productionReduced phosphorylationCellular ATPGut protectionProtein synthesisGlutamate cysteine ligase
2022
Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells
Franchina DG, Kurniawan H, Grusdat M, Binsfeld C, Guerra L, Bonetti L, Soriano-Baguet L, Ewen A, Kobayashi T, Farinelle S, Minafra AR, Vandamme N, Carpentier A, Borgmann FK, Jäger C, Chen Y, Kleinewietfeld M, Vasiliou V, Mittelbronn M, Hiller K, Lang PA, Brenner D. Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells. Nature Communications 2022, 13: 1789. PMID: 35379825, PMCID: PMC8980022, DOI: 10.1038/s41467-022-29426-x.Peer-Reviewed Original ResearchConceptsElectron transport chainMarginal zone B cellsMitochondrial electron transport chainGlutamate-cysteine ligaseCatalytic subunitRedox controlCell-specific ablationRedox balanceTransport chainMetabolic dependenciesCysteine ligaseProtein synthesisMetabolite succinateMTOR activationGlutathione synthesisATP levelsMetabolic propertiesB cellsMetabolic principlesMetabolic featuresDistinct metabolic propertiesMZBCellsActivationLigase
2017
Glutathione Primes T Cell Metabolism for Inflammation
Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y, Cox M, Binsfeld C, Hao Z, Brüstle A, Itsumi M, Jäger C, Chen Y, Pinkenburg O, Camara B, Ollert M, Bindslev-Jensen C, Vasiliou V, Gorrini C, Lang PA, Lohoff M, Harris IS, Hiller K, Brenner D. Glutathione Primes T Cell Metabolism for Inflammation. Immunity 2017, 46: 675-689. PMID: 28423341, DOI: 10.1016/j.immuni.2017.03.019.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEncephalomyelitis, Autoimmune, ExperimentalEnergy MetabolismGlutamate-Cysteine LigaseGlutamineGlutathioneGlycolysisImmunoblottingInflammationMice, Inbred C57BLMice, KnockoutNFATC Transcription FactorsProto-Oncogene Proteins c-mycReactive Oxygen SpeciesSignal TransductionT-LymphocytesTOR Serine-Threonine KinasesConceptsReactive oxygen speciesMYC transcription factorsConditional gene targetingT cell-specific ablationGlutamate-cysteine ligaseT cell metabolismRapamycin 1Catalytic subunitMetabolic integrationTranscription factorsGene targetingMetabolic reprogrammingBiosynthetic requirementsUnexpected roleExpression of NFATAntiviral defenseCysteine ligaseCell metabolismGSH pathwayMammalian targetGSH productionMurine TGSH deficiencyOxygen speciesCell effector functions
2009
Early onset senescence occurs when fibroblasts lack the glutamate–cysteine ligase modifier subunit
Chen Y, Johansson E, Fan Y, Shertzer HG, Vasiliou V, Nebert DW, Dalton TP. Early onset senescence occurs when fibroblasts lack the glutamate–cysteine ligase modifier subunit. Free Radical Biology And Medicine 2009, 47: 410-418. PMID: 19427898, PMCID: PMC2773044, DOI: 10.1016/j.freeradbiomed.2009.05.003.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAnimalsBeta-GalactosidaseCell Culture TechniquesCell CycleCell Growth ProcessesCellular SenescenceCyclin-Dependent Kinase Inhibitor p21DNA DamageFemaleFetusFibroblastsFree Radical ScavengersGlutamate-Cysteine LigaseGlutathioneMiceMice, Inbred C57BLMice, KnockoutPregnancyProtein SubunitsReactive Oxygen SpeciesTumor Suppressor Protein p53ConceptsGlutamate-cysteine ligasePremature senescenceCellular redox environmentCellular antioxidant glutathionePrimary murine fibroblastsSenescence-associated beta-galactosidase activityCell cycle arrestInduction of p53Beta-galactosidase activityPrevents premature senescenceCatalytic subunitCellular senescenceGrowth arrestGlutamate cysteine ligase modifierModifier subunitP21 proteinPhysiological roleSenescenceDNA damageRedox environmentCycle arrestMurine fibroblastsGSH synthesisN-acetylcysteine increasesPrimary cellsCurcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit
Lavoie S, Chen Y, Dalton TP, Gysin R, Cuénod M, Steullet P, Q. K. Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. Journal Of Neurochemistry 2009, 108: 1410-1422. PMID: 19183254, DOI: 10.1111/j.1471-4159.2009.05908.x.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAnimalsAntioxidantsAstrocytesCell SurvivalCells, CulturedCerebral CortexCurcuminDose-Response Relationship, DrugEmbryo, MammalianEnzyme InhibitorsGene ExpressionGlutamate-Cysteine LigaseGlutathioneHydroquinonesMiceMice, Inbred C57BLMice, KnockoutNeuronsProtein SubunitsQuercetinUp-RegulationConceptsGlutamate-cysteine ligaseGCL activityRate-limiting synthesizing enzymeRedox regulatorCatalytic subunitGSH levelsGene expressionCysteine ligaseGlutamate cysteine ligase modifierModifier subunitCell deathCell typesGSH synthesisEnzymeNeurodegenerative diseasesCultured neuronsGCLMSubunitsMRNA levelsSynthesizing enzymesGSHLower GSHAbility of curcuminExpressionLigase
2007
Interaction between the catalytic and modifier subunits of glutamate-cysteine ligase
Yang Y, Chen Y, Johansson E, Schneider SN, Shertzer HG, Nebert DW, Dalton TP. Interaction between the catalytic and modifier subunits of glutamate-cysteine ligase. Biochemical Pharmacology 2007, 74: 372-381. PMID: 17517378, DOI: 10.1016/j.bcp.2007.02.003.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligaseHeterodimer formationEnzyme structure-function relationshipsTwo-hybrid systemGlutathione biosynthesis pathwayPrimary amino acid sequenceC-terminal regionAmino acid sequenceN-terminal regionStructure-function relationshipsBiosynthesis pathwayRegulatory subunitCatalytic subunitDeletion analysisRate-limiting enzymeTertiary structureModifier subunitAmino acidsPoint mutationsSubunitsGCLCGSH inhibitionLigaseEnzyme activityGCLM
2002
Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(−/−) Knockout Mouse NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE*
Yang Y, Dieter MZ, Chen Y, Shertzer HG, Nebert DW, Dalton TP. Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(−/−) Knockout Mouse NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE*. Journal Of Biological Chemistry 2002, 277: 49446-49452. PMID: 12384496, DOI: 10.1074/jbc.m209372200.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAllelesAnimalsBlotting, NorthernBlotting, SouthernBody WeightCell DeathChromatography, GelCysteineDose-Response Relationship, DrugFibroblastsGenotypeGlutamate-Cysteine LigaseGlutamic AcidGlutathioneHomozygoteHydrogen PeroxideImmunoblottingKidneyKineticsLiverMiceMice, KnockoutModels, GeneticMutagenesis, Site-DirectedOxidative StressOxygenPhenotypePolymerase Chain ReactionProtein Structure, TertiaryTime FactorsTissue DistributionConceptsGlutamate-cysteine ligaseModifier subunitGSH biosynthesis pathwayGlutamate-cysteine ligase modifier subunitOxidative stress responseGCL holoenzymeHigher eukaryotesBiosynthesis pathwayCellular functionsCatalytic subunitNovel model systemRate-limiting enzymeNumerous pathophysiological conditionsNull allelesStress responseOvert phenotypeGCL activityOxidant insultSubunitsFetal fibroblastsChronic GSH depletionInitial characterizationHoloenzymeGSH inhibitionGSH depletion