程序性坏死介绍

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）ComplexⅡ(DISC)•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！