程序性坏死介绍课件

Necroptosis程序性坏死介绍DefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.程序性坏死介绍History1988:discoveryofTNFinducednecrosis2005:firstintroductionoftheterm“Necroptosis”程序性坏死介绍MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane程序性坏死介绍BiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)程序性坏死介绍OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome程序性坏死介绍LigandsandReceptorsLigandtospecificreceptorsTNF-αDAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1α,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycan程序性坏死介绍LigandsandReceptorsDeathReceptors(DR)FAS(factorassociatedsuicide,CD95)FASL(CD95L)TNFR1/2(tumornecrosisfactorreceptor)TNFTRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAILPathogenRecognitionReceptors(PRR)TLR(toll-likereceptor)PAMPs&DAMPsNLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPs程序性坏死介绍ComplexⅠTRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）程序性坏死介绍ComplexⅡ(DISC)CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1

RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis程序性坏死介绍NecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL程序性坏死介绍“RIP1decideswhetheritdieswhileRIP3decideshowitdies”

程序性坏死介绍ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+程序性坏死介绍ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof

membraneOutletofDAMPSChangethebalanceofiron程序性坏死介绍ExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)程序性坏死介绍ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+程序性坏死介绍Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome程序性坏死介绍Toll-likereceptorpathway程序性坏死介绍UsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitorofcIAPbydegration