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Toll-LikeReceptors(TLR)第一页，共二十三页。Toll-LikeReceptorSignaling•TollreceptorinitiallydiscoveredinDrosophilaasimportantreceptorindorso-ventralembryonicpattern–Tollmutantsreferstothefactthatthesemutantscouldnotestablishaproperdorsal-ventralaxis–TollinGermanmeans‘great’,apparentlythiswasoneofthewordsdescribingthescientists’enthusiasmafterobservingthemutantflies•HoffmanandcolleaguesshowedthatToll-mutantfliessusceptibletofungalinfections•MammalianhomologuesdiscoveredanddesignatedasToll-LikeReceptors(TLR)•TLRsrecognizespecificpatternsinpathogenswhicharenotobservedinmammals第二页，共二十三页。第三页，共二十三页。Toll-LikeReceptors第四页，共二十三页。Toll-LikeReceptors第五页，共二十三页。第六页，共二十三页。第七页，共二十三页。•LargemoleculesfoundinoutermembraneofGram-negativebacteria•Comprisedofalipidandsaccharidecomponent•Highlyimmunogenic•RecognizedbyTLR4•Cancausesepticshockandleadtodeath•OftenreferredtoasEndotoxinsinceitisnotsecretedbutisabyproductofbacteriallysis•GreatvariabilityamongdifferentbacterialstrainsLipoPolySaccharides(LPS)第八页，共二十三页。第九页，共二十三页。•TLR3,TLR7andTLR8detectviralnucleicacids•Foundinintracellularmembranessinceviralnucleicacidsareendogenouslygenerated•NotetheTIRdomainsoftheseTLRsfacethecytosolofthecell•PolyI:CisanagonistforTLR3thatmimicsbindingofdsRNAtoTLR3ViralNucleicAcids第十页，共二十三页。CytoplasmictailsofTLRsshowsimilaritiestoIL-1receptor(TIR)CommonadaptortoTLRsisMyD88CrucialprolineresidueinallTLRTIRdomains,exceptTLR3Ifsubstitutedwithhistidine,nosignalingoccursAllTLRslikelyhaveaMyD88pathway(TLR3isanexception)TLR4hasaMyD88independentpathwayaswellCytoplasmicTIRdomainTLRsandTIRDomain第十一页，共二十三页。MyD88knockoutmicehavenoresponsetoLPSMyD88isessentialtoallinflammatorysignalingpathwaysMyD88s,asplicevariantofMyD88downregulatestheinflammatoryresponseMyD88interactswithTIRdomainofTLRandrecruitsIRAK-4,IRAK-1andTRAF-6MyD88Adaptor第十二页，共二十三页。•4IRAKsknown,IRAK1,IRAK-2,IRAK-MandIRAK-4•IRAKareserine/threoninekinases•IRAK-4phosphorylatesIRAK-1•IRAK-MplaysaninhibitoryroleinTLRsignaling•IRAK-4phosphorylatesIRAK-1•TRAF6isamemberoftheTNFreceptorassociatedfactor(TRAF)family•TRAF6interactswithIRAK-1andgetsactivated•ReleaseofTRAF6/IRAK-1ensuesIRAKandTRAF6第十三页，共二十三页。•TRAF6/IRAK-1complexassociateswith3proteins–TAK1(TGF-Bactivatedkinase)–TAB1(TAK1bindingproteins)–TAB2(TAK1bindingproteins)•Largecomplexassociateswithmembrane•EventuallyIRAK-1staysinmembranewhileTRAF6/TAK1/TAB1/TAB2movetocytosol•E2LigasessuchasUbc13andUev1AjoinfurtherenlargingcomplexIRAKandTRAF6Release第十四页，共二十三页。TAK-1Activation•Theenlargedcomplexthatincludes–TRAF6,TAK1,TAB1,TAB2,Ubc13,Uev1AactivateTAK1•ActivatedTAK1phosphorylatesIKKcomplex•ActivatedTAK1canalsophosphorylateMAPKinases•IKKcomplexconsistsofIKK,and/NEMO•IBphosphorylationresultsinNF-Btranslocationtonucleus第十五页，共二十三页。第十六页，共二十三页。第十七页，共二十三页。第十八页，共二十三页。第十九页，共二十三页。第二十页，共二十三页。MyD88IndependentPathwayMyD88KnockoutmicedonotproduceinflammatorycytokinessuchasTNF-HoweverwithTLR4stimulationNF-BandJNKdelayedactivityoccursThisstronglysuggeststheexistenceof2pathwaysinTLRsignalingaMyD88dependentpathway(early)aMyD88independentpathway(late)TLR3stimulationalsoexchibitsaMyD88independentpathwayTLR4第二十一页，共二十三页。•Figuresobtainedfrom:•TakedaandAkira,2004•Wikipedia•Kuby,6theditionAcknowledgements第二十二页，共二十三页。内容总结Toll-LikeReceptors(TLR)。Toll-LikeReceptors(TLR)。Toll-LikeReceptorSignaling。IRAK-4phosphorylatesIRAK-1。Acknowledgements第二十三页，共二十三页。