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NecroptosisDefinition•Necrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.•Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.History•1988:discoveryofTNFinducednecrosis•2005:firstintroductionoftheterm“Necroptosis”Morphologicalcharacterisics•Increasinglytranslucentcytoplasm•Swellingoforganelles•Minorultrastructuralmodificationsofnucleus•DisruptionoftheplasmamembraneBiochemistrycharacteristics•Withoutcaspaseinmostcases•RandomdegradationofDNA(smear)•FormingofROS(reactiveoxygenspecies)OverviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutorApoptosisSurvivalNecroptosisPro-necrosomeLigandsandReceptors•Ligandtospecificreceptors•TNF-α•DAMPs:damage-associatedmolecularpatterns•Intracellularmolecules:HMGB1,ATP,F-actin,Hsp•Alarmins:IL-1α,IL-33•PAMPs:pathogen-associatedmolecularpatterns•Viralorbacterialnucleotides•Lipoproteins•Lipopolysaccharide•PeptidoglycanLigandsandReceptors•DeathReceptors(DR)•FAS(factorassociatedsuicide,CD95)FASL(CD95L)•TNFR1/2(tumornecrosisfactorreceptor)TNF•TRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAIL•PathogenRecognitionReceptors(PRR)•TLR(toll-likereceptor)PAMPs&DAMPs•NLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPsComplexⅠ•TRADD:adaptorprotein•TRAF2:bridgebetweenTRADDandcIAPs•RIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)•cIAPs:E3ubiquitinligasesDeathdomain(DD)Deatheffectordomain(DED)NCRIP•Receptor-interactingserine/threonine-proteinkinase•“RIP1decideswhetheritdieswhileRIP3decideshowitdies”DeathdomainConservativekinasedomainNCRIPhomotypicInteractionmotif（RHIM）Complex(DISC)Ⅱ•CYLD(cylindromatosis):RIP1-deubiquitylatingenzyme•InhibitorofcIAP•Internalizationofthecomplex•FADD:caspase,RIP1/3•RIP1RIP1+RIP3•Caspase:inhibitRIP1/3•ApoptosisNecrosome•Inhibitorofcaspase•Chemicalinhibitor:zVAD-fmk/BocD-fmk•vIRA(viralinhibitorofRIPactivation)•RIP:auto-Pandtrans-P•S161-PonRIP1•S199-PonRIP3•microfilament-likecomplex•S227-PonRIP3•T357-PandS358-PonMLKL“RIP1decideswhetheritdieswhileRIP3decideshowitdies”Thewaycellsdie•IncreaseofROS•Breakdownoflysosome•DecreaseofATPandNAD+Executor•Poly-MLKL•PIAffinity•Activationofchannel•Formationofpore•PermeabilisationofmembraneOutletofDAMPSChangethebalanceofironExecutor•Keyenzymeofmetabolism•PYLG:Glycogenlysis•GLUL/GLDH:glutaminolysis•RiseofCalciumironinplasm•cPLA2:formationofox-AA(LOX)•CalpainlysosomemembranepermeabilizationExcesiveROS(ROS:Leakbeforereachingtheterminalofrespiratorychain)Executor•RepressionofANT•adeninenucleotidetranslocase•ActivationofPARP1•CatalyzerepairofDNA•UVmediatedDNAdamage•ROS•upregulateofCalciumiron•Receptor?DecreaseofATPandNAD+Re-overviewLigandReceptorComplexⅠComplexⅡNecrosomeExecutorApoptosisSurvivalNecroptosisPro-necrosomeToll-likereceptorpathwayUsefulinhibitors•Necrostatin:inhibitorofRIP1•SMAC:inhibitorofcIAPbydegration•zVAD-fmk/BocD-fmk:InhibitorofCaspaseWhychoosenecroptosis•Anextremewaytoalertothercells•Analternativewayofapoptosis谢谢！