程序性坏死介绍.ppt

1、Necroptosis,Definition,Necrosis:aformofcellinjurywhichresultsinthepremature,deathofcellsinlivingtissuebyautolysis.,Necroptosis:aprogrammedformofnecrosis,orinflammatory,celldeath.,History,?,1988:discoveryofTNFinducednecrosis,?,2005:firstintroductionoftheterm“Necroptosis”,Morphologicalcharacterisics,I

2、ncreasinglytranslucentcytoplasm,Swellingoforganelles,Minorultrastructuralmodificationsofnucleus,Disruptionoftheplasmamembrane,Biochemistrycharacteristics,Withoutcaspaseinmostcases,RandomdegradationofDNA(smear),FormingofROS(reactiveoxygenspecies),Overview,Ligand,Receptor,Complex,Complex,Necrosome,Exe

3、cutor,Apoptosis,Survival,Necroptosis,Pro-necrosome,LigandsandReceptors,Ligandtospecificreceptors,TNF-,DAMPs:damage-associatedmolecularpatterns,Intracellularmolecules:HMGB1,ATP,F-actin,Hsp,Alarmins:IL-,1,IL,-33,PAMPs:pathogen-associatedmolecularpatterns,Viralorbacterialnucleotides,Lipoproteins,Lipopo

4、lysaccharide,Peptidoglycan,LigandsandReceptors,DeathReceptors(DR),FAS(factorassociatedsuicide,CD95),?,FASL(CD95L),TNFR1/2,(tumornecrosisfactorreceptor),?,TNF,TRAILR1/2(TNF-relatedapoptosis-inducing,ligandreceptor),?,TRAIL,PathogenRecognitionReceptors(PRR),TLR(toll-likereceptor),?,PAMPs&DAMPs,NLR(nuc

5、leotidebindingandoligomerization,domain-likereceptor),?,PAMPs,Complex,TRADD:adaptorprotein,TRAF2:bridgebetweenTRADDandcIAPs,RIP1(RIPK1),:Lys-63(Preventcelldeath,NEMO),cIAPs,:E3ubiquitinligases,Deathdomain,(DD),Deatheffectordomain,(DED),N,C,RIP,?,Receptor-interactingserine/threonine-protein,kinase,?,

6、“,RIP1decideswhetheritdieswhileRIP3,decideshowitdies,”,Deathdomain,Conservativekinasedomain,N,C,RIPhomotypic,Interactionmotif,（,RHIM,）,Complex,(DISC),CYLD(cylindromatosis):RIP1-deubiquitylatingenzyme,InhibitorofcIAP,Internalizationofthecomplex,FADD:caspase,RIP1/3,RIP1,?,RIP1+RIP3,Caspase:inhibitRIP1

7、/3,Apoptosis,Necrosome,Inhibitorofcaspase,Chemicalinhibitor:zVAD-fmk/BocD-fmk,vIRA(viralinhibitorofRIPactivation),RIP:auto-Pandtrans-P,S161-PonRIP1,S199-PonRIP3,microfilament-likecomplex,S227-PonRIP3,T357-PandS358-PonMLKL,“,RIP1decideswhetheritdieswhileRIP3decides,howitdies,”,Thewaycellsdie,Increase

8、ofROS,Breakdownoflysosome,DecreaseofATPandNAD,+,Executor,Poly-MLKL,PIAffinity,Activationofchannel,Formationofpore,Permeabilisationof,membrane,OutletofDAMPS,Changethebalanceofiron,Executor,Keyenzymeofmetabolism,PYLG:Glycogenlysis,GLUL/GLDH:glutaminolysis,RiseofCalciumironinplasm,cPLA2:formationofox-A

9、A(LOX),Calpain,lysosomemembranepermeabilization,ExcesiveROS,(ROS:Leakbeforereachingtheterminalofrespiratorychain),Executor,RepressionofANT,adeninenucleotidetranslocase,ActivationofPARP1,CatalyzerepairofDNA,UVmediatedDNAdamage,ROS,upregulateofCalciumiron,Receptor?,DecreaseofATPandNAD,+,Re-overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,Toll-likereceptorpathway,Usefulinhibitors,Necrostatin:inhibitorofRIP1,SM