程序性坏死介绍.pptx

程序性坏死介绍.pptx

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NecroptosisDefinitionNecrosis:

aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:

aprogrammedformofnecrosis,orinflammatorycelldeath.History1988:

discoveryofTNFinducednecrosis2005:

firstintroductionoftheterm“Necroptosis”MorphologicalcharacterisicsIncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembraneBiochemistrycharacteristicsWithoutcaspaseinmostcasesRandomdegradationofDNA（smear）FormingofROS（reactiveoxygenspecies）OverviewLigandReceptorComplexComplexNecrosomeExecutorApoptosisSurvivalNecroptosisPro-necrosomeLigandsandReceptorsLigandtospecificreceptorsTNF-DAMPs:

damage-associatedmolecularpatternsIntracellularmolecules:

HMGB1,ATP,F-actin,HspAlarmins:

IL-1,IL-33PAMPs:

pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycanLigandsandReceptorsDeathReceptors（DR）FAS（factorassociatedsuicide,CD95）FASL（CD95L）TNFR1/2（tumornecrosisfactorreceptor）TNFTRAILR1/2（TNF-relatedapoptosis-inducingligandreceptor）TRAILPathogenRecognitionReceptors（PRR）TLR（toll-likereceptor）PAMPs&DAMPsNLR（nucleotidebindingandoligomerizationdomain-likereceptor）PAMPsComplexTRADD:

adaptorproteinTRAF2:

bridgebetweenTRADDandcIAPsRIP1（RIPK1）:

Lys-63（Preventcelldeath,NEMO）cIAPs:

E3ubiquitinligasesDeathdomain（DD）Deatheffectordomain（DED）NCRIPReceptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）Complex（DISC）CYLD（cylindromatosis）:

RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:

caspase,RIP1/3RIP1RIP1+RIP3Caspase:

inhibitRIP1/3ApoptosisNecrosomeInhibitorofcaspaseChemicalinhibitor:

zVAD-fmk/BocD-fmkvIRA（viralinhibitorofRIPactivation）RIP:

auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL“RIP1decideswhetheritdieswhileRIP3decideshowitdies”ThewaycellsdieIncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+ExecutorPoly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationofmembraneOutletofDAMPSChangethebalanceofironExecutorKeyenzymeofmetabolismPYLG:

GlycogenlysisGLUL/GLDH:

glutaminolysisRiseofCalciumironinplasmcPLA2:

formationofox-AA（LOX）CalpainlysosomemembranepermeabilizationExcesiveROS（ROS:

Leakbeforereachingtheterminalofrespiratorychain）ExecutorRepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?

DecreaseofATPandNAD+Re-overviewLigandReceptorComplexComplexNecrosomeExecutorApoptosisSurvivalNecroptosisPro-necrosomeToll-likereceptorpathwayUsefulinhibitorsNecrostatin:

inhibitorofRIP1SMAC:

inhibitorofcIAPbydegrationzVAD-fmk/BocD-fmk:

InhibitorofCaspaseWhychoosenecroptosisAnextremewaytoalertothercellsAnalternativewayofapoptosis谢谢！

谢谢！