Necroptosis程序性壞死介紹專家講座第1頁DefinitionNecrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.程序性壞死介紹專家講座第2頁History1988:discoveryofTNFinducednecrosis:firstintroductionoftheterm“Necroptosis”程序性壞死介紹專家講座第3頁MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane程序性壞死介紹專家講座第4頁BiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies)程序性壞死介紹專家講座第5頁OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

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

RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis程序性壞死介紹專家講座第10頁NecrosomeInhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL程序性壞死介紹專家講座第11頁“RIP1decideswhetheritdieswhileRIP3decideshowitdies”

程序性壞死介紹專家講座第12頁ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+程序性壞死介紹專家講座第13頁ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationof

membraneOutletofDAMPSChangethebalanceofiron程序性壞死介紹專家講座第14頁ExecutorKeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)程序性壞死介紹專家講座第15頁ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?DecreaseofATPandNAD+程序性壞死介紹專家講座第16頁Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutor

Apoptosis

Survival

NecroptosisPro-necrosome程序性壞死介紹專家講座第17頁Toll-likereceptorpathway程序性壞死介紹專家講座第18頁UsefulinhibitorsNecrostatin:inhibitorofRIP1SMAC:inhibitorofc