程序性坏死介绍

Necroptosis2021/5/91DefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.2021/5/92History1988:discoveryofTNFinducednecrosis2005:firstintroductionoftheterm“Necroptosis”2021/5/93MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane2021/5/94BiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)2021/5/95OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome2021/5/96LigandsandReceptorsLigandtospecificreceptorsTNF-αDAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1α,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycan2021/5/97LigandsandReceptorsDeathReceptors(DR)FAS(factorassociatedsuicide,CD95)FASL(CD95L)TNFR1/2(tumornecrosisfactorreceptor)TNFTRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAILPathogenRecognitionReceptors(PRR)TLR(toll-likereceptor)PAMPs&DAMPsNLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPs2021/5/98ComplexⅠTRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）2021/5/99ComplexⅡ(DISC)CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis2021/5/910NecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL2021/5/911“RIP1decideswhetheritdieswhileRIP3decideshowitdies”

2021/5/912ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+2021/5/913ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof

membraneOutletofDAMPSChangethebalanceofiron2021/5/914ExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)2021/5/915ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+2021/5/916Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome2021/5/917Toll-likereceptorpathway2021/5/918UsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitorofcIAPbydegr