程序性坏死介绍.ppt

Necroptosis,Definition,Necrosis:aformofcellinjurywhichresultsintheprematuredeathofcellsinlivingtissuebyautolysis.Necroptosis:aprogrammedformofnecrosis,orinflammatorycelldeath.,History,1988:discoveryofTNFinducednecrosis2005:firstintroductionoftheterm“Necroptosis”,Morphologicalcharacterisics,IncreasinglytranslucentcytoplasmSwellingoforganellesMinorultrastructuralmodificationsofnucleusDisruptionoftheplasmamembrane,Biochemistrycharacteristics,WithoutcaspaseinmostcasesRandomdegradationofDNA(smear)FormingofROS(reactiveoxygenspecies),Overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,LigandsandReceptors,LigandtospecificreceptorsTNF-DAMPs:damage-associatedmolecularpatternsIntracellularmolecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1,IL-33PAMPs:pathogen-associatedmolecularpatternsViralorbacterialnucleotidesLipoproteinsLipopolysaccharidePeptidoglycan,LigandsandReceptors,DeathReceptors(DR)FAS(factorassociatedsuicide,CD95)FASL(CD95L)TNFR1/2(tumornecrosisfactorreceptor)TNFTRAILR1/2(TNF-relatedapoptosis-inducingligandreceptor)TRAILPathogenRecognitionReceptors(PRR)TLR(toll-likereceptor)PAMPs&DAMPsNLR(nucleotidebindingandoligomerizationdomain-likereceptor)PAMPs,Complex,TRADD:adaptorproteinTRAF2:bridgebetweenTRADDandcIAPsRIP1(RIPK1):Lys-63(Preventcelldeath,NEMO)cIAPs:E3ubiquitinligases,Deathdomain(DD),Deatheffectordomain(DED),N,C,RIP,Receptor-interactingserine/threonine-proteinkinase“RIP1decideswhetheritdieswhileRIP3decideshowitdies”,Deathdomain,Conservativekinasedomain,N,C,RIPhomotypicInteractionmotif（RHIM）,Complex(DISC),CYLD(cylindromatosis):RIP1-deubiquitylatingenzymeInhibitorofcIAPInternalizationofthecomplexFADD:caspase,RIP1/3RIP1RIP1+RIP3Caspase:inhibitRIP1/3Apoptosis,Necrosome,InhibitorofcaspaseChemicalinhibitor:zVAD-fmk/BocD-fmkvIRA(viralinhibitorofRIPactivation)RIP:auto-Pandtrans-PS161-PonRIP1S199-PonRIP3microfilament-likecomplexS227-PonRIP3T357-PandS358-PonMLKL,“RIP1decideswhetheritdieswhileRIP3decideshowitdies”,Thewaycellsdie,IncreaseofROSBreakdownoflysosomeDecreaseofATPandNAD+,Executor,Poly-MLKLPIAffinityActivationofchannelFormationofporePermeabilisationofmembrane,OutletofDAMPSChangethebalanceofiron,Executor,KeyenzymeofmetabolismPYLG:GlycogenlysisGLUL/GLDH:glutaminolysisRiseofCalciumironinplasmcPLA2:formationofox-AA(LOX)Calpain,lysosomemembranepermeabilization,ExcesiveROS,(ROS:Leakbeforereachingtheterminalofrespiratorychain),Executor,RepressionofANTadeninenucleotidetranslocaseActivationofPARP1CatalyzerepairofDNAUVmediatedDNAdamageROSupregulateofCalciumironReceptor?,DecreaseofATPandNAD+,Re-overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,Toll-likereceptorpathway,Usefulinhibitors,Necrostatin:inhibitorofRIP1SMAC: