分子医学 感染免疫的分子机制与疾病A.ppt

MyD88knockoutmicehavenoresponsetoLPSMyD88isessentialtoallinflammatorysignalingpathwaysMyD88s,asplicevariantofMyD88downregulatestheinflammatoryresponseMyD88interactswithTIRdomainofTLRandrecruitsIRAK-4,IRAK-1andTRAF-6MyD88AdaptorRakoff-Nahoumetal.,RecognitionofcommensalmicroflorabyToll-likereceptorsisrequiredforintestinalhomestasis.Cell118:229-41,2004.4IRAKsknown,IRAK1,IRAK-2,IRAK-MandIRAK-4IRAKareserine/threoninekinasesIRAK-4phosphorylatesIRAK-1IRAK-MplaysaninhibitoryroleinTLRsignalingTRAF6isamemberoftheTNFreceptorassociatedfactor(TRAF)familyTRAF6interactswithIRAK-1andgetsactivatedReleaseofTRAF6/IRAK-1ensuessubsequentsignalingIRAKandTRAF6IL-1RI-associatedproteinkinases(IRAKs)tumornecrosisfactorreceptor-associatedfactor6(TRAF6).TRAF6/IRAK-1complexassociateswith3proteinsTAK1(TGF-Bactivatedkinase)TAB1(TAK1bindingproteins)TAB2(TAK1bindingproteins)LargecomplexassociateswithmembraneEventuallyIRAK-1staysinmembranewhileTRAF6/TAK1/TAB1/TAB2movetocytosolE2LigasessuchasUbc13andUev1AjoinfurtherenlargingcomplexIRAKandTRAF6ReleaseTAK-1ActivationTheenlargedcomplexthatincludesTRAF6,TAK1,TAB1,TAB2,Ubc13,Uev1AactivateTAK1ActivatedTAK1phosphorylatesIKKcomplexActivatedTAK1canalsophosphorylateMAPKinasesIKKcomplexconsistsofIKK?,?and?/NEMOI?BphosphorylationresultsinNF-?BtranslocationtonucleusOverviewofMyD88-dependentpathwayMyD88IndependentPathwayMyD88KnockoutmicedonotproduceinflammatorycytokinessuchasTNF-?HoweverwithTLR4stimulationNF-?BandJNKdelayedactivityoccursThisstronglysuggeststheexistenceof2pathwaysinTLRsignalingaMyD88dependentpathwayaMyD88independentpathwayTLR3stimulationalsoexchibitsaMyD88independentpathwayTLR4OverviewofTLRsignalingInflammationCytokinesChemokinesFluidsProteinsB