程序性坏死介绍专家讲座

Necroptosis第1页DefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.第2页History1988:discoveryofTNFinducednecrosis2023:firstintroductionoftheterm“Necroptosis”第3页MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane第4页BiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)第5页OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome第6页LigandsandReceptorsLigandtospecificreceptorsTNF-αDAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1α,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycan第7页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第8页ComplexⅠTRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）第9页ComplexⅡ(DISC)CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1

RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis第10页NecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL第11页“RIP1decideswhetheritdieswhileRIP3decideshowitdies”

第12页ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+第13页ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof

membraneOutletofDAMPSChangethebalanceofiron第14页ExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)第15页ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+第16页Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome第17页Toll-likereceptorpathway第18页UsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitoro