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NecroptosisNecroptosisDefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.DefinitionNecrosis:aformofcHistory1988:discoveryofTNFinducednecrosis2005:firstintroductionoftheterm“Necroptosis”History1988:discoveryofTNFMorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembraneMorphologicalcharacterisicsInBiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)BiochemistrycharacteristicsWiOverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor
Apoptosis
Survival
NecroptosisPro-necrosomeOverviewLigandReceptorCompleLigandsandReceptorsLigandtospecificreceptorsTNF-αDAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1α,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycanLigandsandReceptorsLigandtoLigandsandReceptorsDeathReceptors(DR)FAS(factorassociatedsuicide,CD95)FASL(CD95L)TNFR1/2(tumornecrosisfactorreceptor)TNFTRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAILPathogenRecognitionReceptors(PRR)TLR(toll-likereceptor)PAMPs&DAMPsNLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPsLigandsandReceptorsDeathRecComplexⅠTRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）ComplexⅠTRADD:adaptorproteiComplexⅡ(DISC)CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1
RIP1+RIP3Caspase:inhibitRIP1/3ApoptosisComplexⅡ(DISC)CYLD(cylindromNecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKLNecrosomeInhibitorofcaspase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”
“RIP1decideswhetheritdiesThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+ThewaycellsdieIncreaseofRExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof
membraneOutletofDAMPSChangethebalanceofironExecutorPoly-MLKLOutletofDAMExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)ExecutorKeyenzymeofmetabolExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+ExecutorRepressionofANTDecreRe-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor
Apoptosis
Survival
NecroptosisPro-necrosomeRe-overviewLigandReceptorComToll-likereceptorpathwayToll-likereceptorpathwayUsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitorofcIAPbydegrationzVAD-fm
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