程序性坏死介绍

Necroptosis2021/6/271DefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.2021/6/272History1988:discoveryofTNFinducednecrosis2005:firstintroductionoftheterm“Necroptosis”2021/6/273MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane2021/6/274BiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)2021/6/275OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome2021/6/276LigandsandReceptorsLigandtospecificreceptorsTNF-αDAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1α,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycan2021/6/277LigandsandReceptorsDeathReceptors(DR)FAS(factorassociatedsuicide,CD95)FASL(CD95L)TNFR1/2(tumornecrosisfactorreceptor)TNFTRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAILPathogenRecognitionReceptors(PRR)TLR(toll-likereceptor)PAMPs&DAMPsNLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPs2021/6/278ComplexⅠTRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）2021/6/279ComplexⅡ(DISC)CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1

RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis2021/6/2710NecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL2021/6/2711“RIP1decideswhetheritdieswhileRIP3decideshowitdies”

2021/6/2712ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+2021/6/2713ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof

membraneOutletofDAMPSChangethebalanceofiron2021/6/2714ExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)2021/6/2715ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+2021/6/2716Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome2021/6/2717Toll-likereceptorpathway2021/6/2718UsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitorofcIAPbydegrat