Featured Publications
Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection
Zhu S, Bradfield C, Maminska A, Park E, Kim B, Kumar P, Huang S, Kim M, Zhang Y, Bewersdorf J, MacMicking J. Native architecture of a human GBP1 defense complex for cell-autonomous immunity to infection. Science 2024, 383: eabm9903. PMID: 38422126, DOI: 10.1126/science.abm9903.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsCaspase-4Surface of Gram-negative bacteriaGuanosine triphosphate hydrolysisImmunity to infectionInnate immunity to infectionCryo-electron tomographyGram-negative bacteriaImmunity proteinSignaling platformsMembrane insertionHuman cellsNative structureCombat infectionsLipopolysaccharide releaseGasdermin DExtended conformationLiving organismsProteinDefense complexCellsNative architectureGBP1BacteriaInfectionPLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection
Xu D, Jiang W, Wu L, Gaudet R, Park E, Su M, Cheppali S, Cheemarla N, Kumar P, Uchil P, Grover J, Foxman E, Brown C, Stansfeld P, Bewersdorf J, Mothes W, Karatekin E, Wilen C, MacMicking J. PLSCR1 is a cell-autonomous defence factor against SARS-CoV-2 infection. Nature 2023, 619: 819-827. PMID: 37438530, PMCID: PMC10371867, DOI: 10.1038/s41586-023-06322-y.Peer-Reviewed Original ResearchConceptsC-terminal β-barrel domainSpike-mediated fusionCell-autonomous defenseLarge-scale exome sequencingΒ-barrel domainGenome-wide CRISPRSARS-CoV-2 infectionHost cell cytosolScramblase activityPhospholipid scramblaseLive SARS-CoV-2 infectionHuman lung epitheliumPLSCR1SARS-CoV-2 USASingle-molecule switchingSARS-CoV-2 variantsExome sequencingHuman populationRestriction factorsViral RNANew SARS-CoV-2 variantsSARS-CoV-2Robust activityLung epitheliumDefense factorsIncreasing the resilience of plant immunity to a warming climate
Kim JH, Castroverde CDM, Huang S, Li C, Hilleary R, Seroka A, Sohrabi R, Medina-Yerena D, Huot B, Wang J, Nomura K, Marr SK, Wildermuth MC, Chen T, MacMicking JD, He SY. Increasing the resilience of plant immunity to a warming climate. Nature 2022, 607: 339-344. PMID: 35768511, PMCID: PMC9279160, DOI: 10.1038/s41586-022-04902-y.Peer-Reviewed Original ResearchConceptsSalicylic acidTranscription factorsSA productionPlant immune systemEffector-triggered immunityPlant growth temperatureFamily transcription factorsAspects of plantImmune transcription factorsElevated growth temperaturesPlant immunityArabidopsis thalianaBiosynthetic genesBasal immunityPlant growthSA receptorsCBP60Disease triangleWarming climateImpaired recruitmentGrowth temperatureAnimal lifeExtreme weather conditionsSARD1Climate changeA human apolipoprotein L with detergent-like activity kills intracellular pathogens
Gaudet RG, Zhu S, Halder A, Kim BH, Bradfield CJ, Huang S, Xu D, Mamiñska A, Nguyen TN, Lazarou M, Karatekin E, Gupta K, MacMicking JD. A human apolipoprotein L with detergent-like activity kills intracellular pathogens. Science 2021, 373 PMID: 34437126, PMCID: PMC8422858, DOI: 10.1126/science.abf8113.Peer-Reviewed Original ResearchMeSH KeywordsApolipoproteins LBacterial Outer MembraneBacteriolysisCell MembraneCell Membrane PermeabilityCells, CulturedCRISPR-Cas SystemsCytosolDetergentsGene EditingGram-Negative BacteriaGTP-Binding ProteinsHumansImmunity, InnateInterferon-gammaLipoproteinsMicrobial ViabilityO AntigensProtein DomainsSalmonella typhimuriumSolubilityConceptsSingle-particle cryo-electron microscopyCell-autonomous defenseCytosol-invasive bacteriaExpression of hundredsNative mass spectrometryCryo-electron microscopyHuman genesDetergent-like activityHost proteinsLipoprotein nanodiscsMammalian lipidsExtracellular transportImmune cytokine interferonCell typesDetergent-like propertiesApolipoprotein LLife-threatening infectionsPotent bactericidal agentsAnionic membranesProteinCytokine interferonNonimmune cellsMass spectrometryCellsMutagenesisA phase-separated nuclear GBPL circuit controls immunity in plants
Huang S, Zhu S, Kumar P, MacMicking JD. A phase-separated nuclear GBPL circuit controls immunity in plants. Nature 2021, 594: 424-429. PMID: 34040255, PMCID: PMC8478157, DOI: 10.1038/s41586-021-03572-6.Peer-Reviewed Original ResearchMeSH KeywordsArabidopsisCell NucleusChromatinCryoelectron MicroscopyGene Expression Regulation, PlantGTP-Binding ProteinsIntrinsically Disordered ProteinsMediator ComplexMultigene FamilyOrganellesPhase TransitionPlant CellsPlant DiseasesPlant ImmunityPromoter Regions, GeneticRNA Polymerase IITranscription, GeneticConceptsLiquid-liquid phase separationRNA polymerase II machineryMembraneless organellesSitu cryo-electron tomographyDefense gene promotersDiverse cellular activitiesSpecific transcriptional coactivatorsHost gene expressionPhase-separated condensatesCryo-electron tomographyGuanylate-binding proteinsPlant defenseArabidopsis thalianaBiotic stressesAllosteric switchMediator complexTranscriptional responseTranscriptional coactivatorDisease resistanceGene expressionCellular activitiesIndispensable playerBiological importanceOrganellesImmune cuesInterferon-
Casanova J, MacMicking J, Nathan C. Interferon-. Science 2024, 384: eadl2016. PMID: 38635718, DOI: 10.1126/science.adl2016.Peer-Reviewed Original ResearchGuanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms
Wandel MP, Kim BH, Park ES, Boyle KB, Nayak K, Lagrange B, Herod A, Henry T, Zilbauer M, Rohde J, MacMicking JD, Randow F. Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms. Nature Immunology 2020, 21: 880-891. PMID: 32541830, PMCID: PMC7381384, DOI: 10.1038/s41590-020-0697-2.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsCaspase-4 activationCaspase-4Human caspase-4Pyroptotic cell deathGram-negative bacteriaCytosolic bacteriaReplicative nicheEvolutionary evidenceIntracellular bacteriaCell deathMultiple antagonistsNeighboring cellsCaspase-11BacteriaAntibacterial defenseBacterial challengeGasderminShigella flexneriProteinDependent pyroptosisActivationPathwayBacterial lipopolysaccharideGBP2Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease
Tretina K, Park ES, Maminska A, MacMicking JD. Interferon-induced guanylate-binding proteins: Guardians of host defense in health and disease. Journal Of Experimental Medicine 2019, 216: 482-500. PMID: 30755454, PMCID: PMC6400534, DOI: 10.1084/jem.20182031.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsNumerous host cell typesHost cell typesImportant human diseasesCritical rheostatBasic biologyMicrobial pathogensHost defense activitiesHuman diseasesSimilar functionsCell typesHomeostatic settingsGTPasesInnate immunityDefense activitiesHost defenseInflammatory syndromeNeoplastic diseaseClinical approachTissue damageBacterial infectionsCentral orchestratorDiseaseIFNRheostatInterferon-induced guanylate-binding proteins in inflammasome activation and host defense
Kim BH, Chee JD, Bradfield CJ, Park ES, Kumar P, MacMicking JD. Interferon-induced guanylate-binding proteins in inflammasome activation and host defense. Nature Immunology 2016, 17: 481-489. PMID: 27092805, PMCID: PMC4961213, DOI: 10.1038/ni.3440.Peer-Reviewed Original ResearchCellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens
Randow F, MacMicking JD, James LC. Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens. Science 2013, 340: 701-706. PMID: 23661752, PMCID: PMC3863583, DOI: 10.1126/science.1233028.Peer-Reviewed Original ResearchIFN-Inducible GTPases in Host Cell Defense
Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD. IFN-Inducible GTPases in Host Cell Defense. Cell Host & Microbe 2012, 12: 432-444. PMID: 23084913, PMCID: PMC3490204, DOI: 10.1016/j.chom.2012.09.007.Peer-Reviewed Original ResearchConceptsGuanylate binding proteinsIFN-inducible GTPasesHuman genome-wide association studiesProtein complex assemblyGenome-wide association studiesPathogen-containing vacuolesHost cell defenseVesicular trafficTranscriptional profilingComplex assemblyCell defenseCell-intrinsic responsesAssociation studiesGTPasesBinding proteinCell interiorIndividual cellsAltered expressionGTPase MDiverse groupCentral roleAutophagicCytosolSpeciesPlantsInterferon-inducible effector mechanisms in cell-autonomous immunity
MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nature Reviews Immunology 2012, 12: 367-382. PMID: 22531325, PMCID: PMC4150610, DOI: 10.1038/nri3210.Peer-Reviewed Original ResearchConceptsCell-autonomous immunityIndividual host cellsHigher organismsVertebrate cellsEffector proteinsIFN-inducible proteinsAutophagic machineryViral life cycleNew proteinsIntracellular distancesGene programMicrobial replicationCapsid assemblyEssential amino acidsMicrobial pathogensHost cellsIntracellular bacteriaIndividual bacteriaKey PointsAtInnate immune systemAmino acidsInterferon familyVariety of mechanismsProteinPathogen classesGBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals
Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD. GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals. Science 2012, 336: 481-485. PMID: 22461501, DOI: 10.1126/science.1217141.Peer-Reviewed Original ResearchMeSH KeywordsAlum CompoundsAnimalsApoptosis Regulatory ProteinsCARD Signaling Adaptor ProteinsCarrier ProteinsCaspase 1Cell LineCytoskeletal ProteinsGTP-Binding ProteinsHumansInflammasomesInterferon-gammaInterleukin-1betaLipopolysaccharidesListeria monocytogenesListeriosisMacrophagesMiceNLR Family, Pyrin Domain-Containing 3 ProteinProtein MultimerizationRNA InterferenceSalmonella typhimuriumUric AcidConceptsGuanylate binding protein 5IL-1β/ILImpaired host defensePresence of infectionNLRP3 inflammasome activationCaspase-1 cleavageNLRP3 inflammasome responseNLRP3 inflammasome assemblyInflammasome assemblyBinding protein 5Inflammatory responseInflammasome activationImmune systemTissue damageInflammasome responseHost defenseInflammasome complexCaspase-1Sensory complexProtein 5InflammasomePathogenic bacteriaILInterleukinNLRA Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection
Kim BH, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD. A Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection. Science 2011, 332: 717-721. PMID: 21551061, DOI: 10.1126/science.1201711.Peer-Reviewed Original ResearchConceptsProtein gene familyCell-autonomous immunityMammalian host defenseHost defense proteinsGene-deficient animalsGene familyAutophagy effectorsDefense proteinsHuman genomeGuanosine triphosphataseHost genesComplete mouseIntracellular bacteriaPhagocyte oxidaseIntracellular pathogensPotent oxidativeAntimicrobial peptidesTrafficking programsHost defenseGenomeFunction analysisFamilyGBP1GenesGBP7Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47
MacMicking JD, Taylor GA, McKinney JD. Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47. Science 2003, 302: 654-659. PMID: 14576437, DOI: 10.1126/science.1088063.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedComputational BiologyDisease SusceptibilityFemaleGTP PhosphohydrolasesGTP-Binding ProteinsHydrogen-Ion ConcentrationImmunity, InnateInterferon-gammaMacrophage ActivationMacrophagesMacrophages, AlveolarMaleMiceMice, Inbred C57BLMutationMycobacterium tuberculosisNitric Oxide SynthaseNitric Oxide Synthase Type IIOligonucleotide Array Sequence AnalysisPhagosomesReverse Transcriptase Polymerase Chain ReactionSignal TransductionTuberculosisConceptsNitric oxide synthase 2LRG-47Principal effector mechanismDefective bacterial killingImmune controlEffector mechanismsMtb replicationImpaired maturationBacterial killingIntracellular pathogensMycobacterium tuberculosisHost macrophagesInfected host macrophagesSynthase 2TuberculosisIRG-47MtbIFNDiseaseMiceMacrophagesIdentification of nitric oxide synthase as a protective locus against tuberculosis
MacMicking J, North R, LaCourse R, Mudgett J, Shah S, Nathan C. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5243-5248. PMID: 9144222, PMCID: PMC24663, DOI: 10.1073/pnas.94.10.5243.Peer-Reviewed Original ResearchMeSH KeywordsAllelesAnimalsCarrier ProteinsCation Transport ProteinsCrosses, GeneticDisease SusceptibilityExonsFemaleGenotypeGlucocorticoidsHaplotypesHeterozygoteHomozygoteImmunity, InnateImmunosuppression TherapyIsoenzymesLungMaleMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred StrainsMice, KnockoutMycobacterium tuberculosisNitric Oxide SynthasePolymerase Chain ReactionPolymorphism, GeneticTuberculosisConceptsNitric oxide synthaseOxide synthasePrimary Mycobacterium tuberculosis infectionInducible nitric oxide synthaseHigh-dose glucocorticoidsMycobacterium tuberculosis infectionWild-type miceWild-type littermatesHost immune systemChronic tuberculosisTuberculosis infectionImmune systemCritical host genesTuberculosisMycobacterium tuberculosisProtective genesMiceProtective locusNOS2Host genesSuch pathwaysResponse pathwaysSynthaseGlucocorticoidsLungNITRIC OXIDE AND MACROPHAGE FUNCTION
MacMicking J, Xie Q, Nathan C. NITRIC OXIDE AND MACROPHAGE FUNCTION. Annual Review Of Immunology 1997, 15: 323-350. PMID: 9143691, DOI: 10.1146/annurev.immunol.15.1.323.ChaptersConceptsExpression of NOS2Nitric oxide synthaseAdaptive immune systemNormal host cellsRemarkable molecular machinesInflammatory diseasesLymphocyte proliferationNO pathwayOxide synthaseImmune responseMacrophage productsMacrophage functionSuppressive effectImmune systemNOS2Nitric oxideHigh-output isoformTumor cellsMacrophagesCytotoxic actionElevated Ca2Transcriptional inductionFunctional dimerCytotoxic activityMolecular machinesAltered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase
MacMicking J, Nathan C, Hom G, Chartrain N, Fletcher D, Trumbauer M, Stevens K, Xie Q, Sokol K, Hutchinson N, Chen H, Mudget J. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995, 81: 641-650. PMID: 7538909, DOI: 10.1016/0092-8674(95)90085-3.Peer-Reviewed Original ResearchConceptsInducible nitric oxide synthaseINOS-/- miceNitric oxide synthaseOxide synthaseAnesthetized wild-type miceCentral arterial blood pressureArterial blood pressureWild-type miceBacterial endotoxic lipopolysaccharidesBlood pressureLiver damagePropionobacterium acnesEarly deathInfectious agentsTissue damageBacterial infectionsTumor cellsLymphoma cellsLipopolysaccharideAltered responseMiceEndotoxic lipopolysaccharideDeathListeria monocytogenesHypotensionInhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase
Karupiah G, Xie Q, Buller R, Nathan C, Duarte C, MacMicking J. Inhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase. Science 1993, 261: 1445-1448. PMID: 7690156, DOI: 10.1126/science.7690156.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid OxidoreductasesAnimalsArginineCell LineCells, CulturedEctromelia virusEctromelia, InfectiousEnzyme InductionFemaleHumansInterferon-gammaMacrophagesMiceMice, Inbred C57BLNitric OxideNitric Oxide SynthaseOmega-N-MethylarginineSimplexvirusTransfectionVaccinia virusVirus ReplicationConceptsViral replicationIFN-gammaHerpes simplex-1 virusNitric oxideDetectable NO synthesisSubstantial antiviral effectEctromelia virus infectionNitric oxide synthaseInducible NO synthaseIFN-gamma-treated macrophagesOxide synthaseAntiviral effectVirus infectionNO synthaseNO synthesisAntiviral activityInterferonEpithelial cellsMouse macrophagesCell productionMacrophagesCell typesSynthaseInhibitors
2022
Rewiring the logic board of IFN signaling
MacMicking J. Rewiring the logic board of IFN signaling. Science Signaling 2022, 15: eadf0778. PMID: 36512642, DOI: 10.1126/scisignal.adf0778.Peer-Reviewed Original Research