2022
m6A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB–mediated antiapoptotic pathway
Zhang T, Ding C, Chen H, Zhao J, Chen Z, Chen B, Mao K, Hao Y, Roulis M, Xu H, Kluger Y, Zou Q, Ye Y, Zhan M, Flavell RA, Li HB. m6A mRNA modification maintains colonic epithelial cell homeostasis via NF-κB–mediated antiapoptotic pathway. Science Advances 2022, 8: eabl5723. PMID: 35333576, PMCID: PMC8956260, DOI: 10.1126/sciadv.abl5723.Peer-Reviewed Original ResearchConceptsMucosal barrier dysfunctionInflammatory bowel diseaseBarrier dysfunctionColonic epithelial cellsColonic mucosal barrier dysfunctionEpithelial cellsStem cellsNF-κB pathwayPotential therapeutic targetEpithelial cell deathEpithelial cell homeostasisSevere colitisBowel diseaseColonic stem cellsTherapeutic targetMouse colonStem cell apoptosisDysfunctionMajor causeCell apoptosisImportant modulatorPathological processesAntiapoptotic pathwaysSpecific deletionCell homeostasis
2021
m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity
Qin Y, Li B, Arumugam S, Lu Q, Mankash SM, Li J, Sun B, Li J, Flavell RA, Li HB, Ouyang X. m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Reports 2021, 37: 109968. PMID: 34758326, PMCID: PMC8667589, DOI: 10.1016/j.celrep.2021.109968.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseProgression of NAFLDLineage-restricted deletionFatty liver diseaseMultiple mRNA transcriptsMyeloid cell activationDiet-induced developmentMethyladenosine (m<sup>6</sup>A) RNA modificationMRNA metabolismProtein methyltransferaseLiver diseaseRNA modificationsCellular stressMetabolic reprogrammingDDIT4 mRNACell activationObesityDifferential expressionMammalian targetMRNA transcriptsSignificant downregulationCytokine stimulationPathway activityMetabolic phenotypeMRNA levelsPooled CRISPR screening identifies m6A as a positive regulator of macrophage activation
Tong J, Wang X, Liu Y, Ren X, Wang A, Chen Z, Yao J, Mao K, Liu T, Meng FL, Pan W, Zou Q, Liu J, Zhou Y, Xia Q, Flavell RA, Zhu S, Li HB. Pooled CRISPR screening identifies m6A as a positive regulator of macrophage activation. Science Advances 2021, 7: eabd4742. PMID: 33910903, PMCID: PMC8081357, DOI: 10.1126/sciadv.abd4742.Peer-Reviewed Original ResearchConceptsMacrophage activationPotential cancer immunotherapy targetInnate immune cellsFaster tumor growthTNF-α productionInnate immune responseCancer immunotherapy targetCre miceImmune cellsImmunotherapy targetImmune responseLPS stimulationTumor growthBacterial infectionsTop candidate genesDeficient macrophagesMultiple cellular responsesMETTL3 deficiencyActivationUnknown roleMETTL3Negative regulatorBinding proteinCellular responsesRNA binding proteinMAP3K2-regulated intestinal stromal cells define a distinct stem cell niche
Wu N, Sun H, Zhao X, Zhang Y, Tan J, Qi Y, Wang Q, Ng M, Liu Z, He L, Niu X, Chen L, Liu Z, Li HB, Zeng YA, Roulis M, Liu D, Cheng J, Zhou B, Ng LG, Zou D, Ye Y, Flavell RA, Ginhoux F, Su B. MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche. Nature 2021, 592: 606-610. PMID: 33658717, DOI: 10.1038/s41586-021-03283-y.Peer-Reviewed Original ResearchConceptsStem cell nicheR-spondin 1Intestinal stromal cellsCell nicheDistinct stem cell nichesIntestinal stem cell nicheStromal cellsIntestinal stem cellsStromal cell populationsTissue homeostasisReactive oxygen speciesIntestinal stemMolecular mechanismsAcute intestinal damageSpecific functionsPrimary cellular sourceStem cellsColon cryptsOxygen speciesCell populationsIntestinal injuryIntestinal damageNicheCellular sourceCellsThe RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells
Wang Y, He K, Sheng B, Lei X, Tao W, Zhu X, Wei Z, Fu R, Wang A, Bai S, Zhang Z, Hong N, Ye C, Tian Y, Wang J, Li M, Zhang K, Li L, Yang H, Li HB, Flavell RA, Zhu S. The RNA helicase Dhx15 mediates Wnt-induced antimicrobial protein expression in Paneth cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2017432118. PMID: 33483420, PMCID: PMC7848544, DOI: 10.1073/pnas.2017432118.Peer-Reviewed Original ResearchConceptsRNA helicasesEssential biological processesPaneth cellsRNA helicase DHX15Antimicrobial protein expressionCell-specific functionsViral RNA sensorsRNA splicingHelicasesUlcerative colitis patientsCell-specific depletionDHX15Complete knockoutKey regulatorBiological processesIntestinal epithelial cellsLethality of miceVivo roleEnteric bacteriaRNA sensorsDextran sodiumColitis patientsLack of evidenceAntimicrobial responsesIntestinal inflammation
2020
m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Gao Y, Vasic R, Song Y, Teng R, Liu C, Gbyli R, Biancon G, Nelakanti R, Lobben K, Kudo E, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA, Li HB, Tebaldi T, Halene S. m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development. Immunity 2020, 52: 1007-1021.e8. PMID: 32497523, PMCID: PMC7408742, DOI: 10.1016/j.immuni.2020.05.003.Peer-Reviewed Original ResearchConceptsDouble-stranded RNADeleterious innate immune responseMammalian hematopoietic developmentEndogenous double-stranded RNAHematopoietic developmentInnate immune responseAbundant RNA modificationMurine fetal liverPattern recognition receptor pathwaysImmune responseProtein codingDsRNA formationRNA modificationsWriter METTL3Hematopoietic defectsPerinatal lethalityNative stateConditional deletionAberrant innate immune responsesLoss of METTL3Hematopoietic failureReceptor pathwayAberrant immune responsePrevents formationFetal livermRNA destabilization by BTG1 and BTG2 maintains T cell quiescence
Hwang SS, Lim J, Yu Z, Kong P, Sefik E, Xu H, Harman CCD, Kim LK, Lee GR, Li HB, Flavell RA. mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence. Science 2020, 367: 1255-1260. PMID: 32165587, DOI: 10.1126/science.aax0194.Peer-Reviewed Original Research
2019
Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells
Hu Z, Qu G, Yu X, Jiang H, Teng XL, Ding L, Hu Q, Guo X, Zhou Y, Wang F, Li HB, Chen L, Jiang J, Su B, Liu J, Zou Q. Acylglycerol Kinase Maintains Metabolic State and Immune Responses of CD8+ T Cells. Cell Metabolism 2019, 30: 290-302.e5. PMID: 31204281, DOI: 10.1016/j.cmet.2019.05.016.Peer-Reviewed Original ResearchConceptsAcylglycerol kinasePhosphatidylinositol-3-OH kinasePTEN phosphatase activityRecruitment of PTENCell glycolytic metabolismCell antigen receptorPTEN activityPlasma membranePTEN phosphorylationKinase activityRapamycin (mTOR) signalingMammalian targetPhosphatase activityCell glycolysisCell expansionGlycolytic metabolismCell proliferationMetabolic programmingMetabolic stateAntigen receptorKinaseCritical roleGlycolysisCellsFunctional state
2018
Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome
Yu X, Teng XL, Wang F, Zheng Y, Qu G, Zhou Y, Hu Z, Wu Z, Chang Y, Chen L, Li HB, Su B, Lu L, Liu Z, Sun SC, Zou Q. Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. Journal Of Experimental Medicine 2018, 215: 2463-2476. PMID: 30115741, PMCID: PMC6122976, DOI: 10.1084/jem.20180397.Peer-Reviewed Original ResearchConceptsCell metabolismPhosphatase catalytic subunitRapamycin complex 1Component raptorRegulatory T Cell StabilityCatalytic subunitMetabolic programsMechanistic targetPivotal regulatorSignaling mechanismTRAF3IP3Metabolic regulatorMetabolic fitnessCell functionRegulatorLysosomesMetabolismT reg cell functionCell stabilityPP2AcComplexes 1RaptorsSubunitsDeletionStrong antitumor T-cell responsesSENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation
Yu X, Lao Y, Teng XL, Li S, Zhou Y, Wang F, Guo X, Deng S, Chang Y, Wu X, Liu Z, Chen L, Lu LM, Cheng J, Li B, Su B, Jiang J, Li HB, Huang C, Yi J, Zou Q. SENP3 maintains the stability and function of regulatory T cells via BACH2 deSUMOylation. Nature Communications 2018, 9: 3157. PMID: 30089837, PMCID: PMC6082899, DOI: 10.1038/s41467-018-05676-6.Peer-Reviewed Original ResearchMeSH KeywordsActive Transport, Cell NucleusAnimalsAntineoplastic AgentsAutoimmunityBasic-Leucine Zipper Transcription FactorsBone Marrow CellsCD4-Positive T-LymphocytesCell DifferentiationCell Line, TumorCell NucleusCysteine EndopeptidasesFemaleGene DeletionGene Expression ProfilingGene Expression RegulationHEK293 CellsHomeostasisHumansImmune ToleranceLymphocyte ActivationMelanoma, ExperimentalMiceMice, Inbred C57BLMice, KnockoutPeptide HydrolasesReactive Oxygen SpeciesSumoylationT-Lymphocytes, RegulatoryConceptsRegulatory T cellsTreg cellsT cellsReactive oxygen speciesSUMO-specific protease 3T effector cell differentiationAntitumor T-cell responsesTreg cell-specific deletionT cell responsesEffector cell differentiationTreg cell stabilityCell-specific deletionT cell activationImmune toleranceTumor immunosuppressionAutoimmune symptomsImmune homeostasisRegulation of ROSRole of SENP3Cell activationCell responsesGene signatureProtease 3Pivotal regulatorNuclear exportm6A mRNA methylation sustains Treg suppressive functions
Tong J, Cao G, Zhang T, Sefik E, Amezcua Vesely MC, Broughton JP, Zhu S, Li H, Li B, Chen L, Chang HY, Su B, Flavell RA, Li HB. m6A mRNA methylation sustains Treg suppressive functions. Cell Research 2018, 28: 253-256. PMID: 29303144, PMCID: PMC5799823, DOI: 10.1038/cr.2018.7.Peer-Reviewed Original Research
2017
m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways
Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, Bailis W, Cao G, Kroehling L, Chen Y, Wang G, Broughton JP, Chen YG, Kluger Y, Simon MD, Chang HY, Yin Z, Flavell RA. m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 2017, 548: 338-342. PMID: 28792938, PMCID: PMC5729908, DOI: 10.1038/nature23450.Peer-Reviewed Original ResearchMeSH KeywordsAdenosineAdoptive TransferAnimalsCell DifferentiationCell ProliferationColitisDisease Models, AnimalDNA-Binding ProteinsFemaleHomeostasisInterleukin-7MaleMethylationMethyltransferasesMiceRNA StabilityRNA, MessengerSignal TransductionSTAT5 Transcription FactorSuppressor of Cytokine Signaling 1 ProteinSuppressor of Cytokine Signaling 3 ProteinSuppressor of Cytokine Signaling ProteinsT-LymphocytesNlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells
Zhu S, Ding S, Wang P, Wei Z, Pan W, Palm NW, Yang Y, Yu H, Li HB, Wang G, Lei X, de Zoete MR, Zhao J, Zheng Y, Chen H, Zhao Y, Jurado KA, Feng N, Shan L, Kluger Y, Lu J, Abraham C, Fikrig E, Greenberg HB, Flavell RA. Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. Nature 2017, 546: 667-670. PMID: 28636595, PMCID: PMC5787375, DOI: 10.1038/nature22967.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosis Regulatory ProteinsCARD Signaling Adaptor ProteinsCaspase 1DEAD-box RNA HelicasesEpithelial CellsFemaleImmunity, InnateInflammasomesInterleukin-18Intestinal MucosaIntestinesIntracellular Signaling Peptides and ProteinsMaleMiceMice, Inbred C57BLPhosphate-Binding ProteinsPyroptosisReceptors, G-Protein-CoupledRNA, Double-StrandedRotavirusRotavirus Infections
2016
The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury
Hu B, Jin C, Li HB, Tong J, Ouyang X, Cetinbas NM, Zhu S, Strowig T, Lam FC, Zhao C, Henao-Mejia J, Yilmaz O, Fitzgerald KA, Eisenbarth SC, Elinav E, Flavell RA. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 2016, 354: 765-768. PMID: 27846608, PMCID: PMC5640175, DOI: 10.1126/science.aaf7532.Peer-Reviewed Original ResearchConceptsCell deathDNA sensor AIM2New therapeutic targetsCaspase-1-dependent deathIntestinal epithelial cellsBone marrow cellsGastrointestinal syndromeTissue injuryInflammasome activationGastrointestinal tractRadiation-induced cell deathRadiation-induced DNA damageTherapeutic targetAcute exposureBone marrowChemotherapeutic agentsMarrow cellsRadiation exposureAIM2Massive cell deathEpithelial cellsHematopoietic failureDeathMolecular mechanismsDNA damage