程序性坏死介绍.pptx

1、NecroptosisDefinitionNecrosis:a form of cell injury which results in the premature death of cells in living tissue by autolysis.Necroptosis:a programmed form of necrosis,or inflammatory cell death.History1988:discovery of TNF induced necrosis2005:first introduction of the term“Necroptosis”Morphologi

2、cal characterisicsIncreasingly translucent cytoplasmSwelling of organellesMinor ultrastructural modifications of nucleusDisruption of the plasma membraneBiochemistry characteristicsWithout caspase in most casesRandom degradation of DNA(smear)Forming of ROS(reactive oxygen species)OverviewLigand Rece

3、ptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosomeLigands and ReceptorsLigand to specific receptorsTNF-DAMPs:damage-associated molecular patternsIntracellular molecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1,IL-33PAMPs:pathogen-associated molecular patternsViral or bact

4、erial nucleotides LipoproteinsLipopolysaccharide PeptidoglycanLigands and ReceptorsDeath Receptors(DR)FAS(factor associated suicide,CD95)FASL(CD95L)TNFR1/2(tumor necrosis factor receptor)TNFTRAILR1/2(TNF-related apoptosis-inducing ligand receptor)TRAILPathogen Recognition Receptors(PRR)TLR(toll-like

5、 receptor)PAMPs&DAMPsNLR(nucleotide binding and oligomerization domain-like receptor)PAMPsComplex TRADD:adaptor proteinTRAF2:bridge between TRADD and cIAPs RIP1(RIPK1):Lys-63(Prevent cell death,NEMO)cIAPs:E3 ubiquitin ligasesDeath domain(DD)Death effector domain(DED)NCRIPReceptor-interacting serine/

6、threonine-protein kinase“RIP1 decides whether it dies while RIP3 decides how it dies”Death domainConservative kinase domainNCRIP homotypic Interaction motif（RHIM）Complex (DISC)CYLD(cylindromatosis):RIP1-deubiquitylating enzymeInhibitor of cIAPInternalization of the complexFADD:caspase,RIP1/3RIP1 RIP

7、1+RIP3Caspase:inhibit RIP1/3ApoptosisNecrosomeInhibitor of caspaseChemical inhibitor:zVAD-fmk/BocD-fmkvIRA(viral inhibitor of RIP activation)RIP:auto-P and trans-PS161-P on RIP1S199-P on RIP3microfilament-like complexS227-P on RIP3T357-P and S358-P on MLKL“RIP1 decides whether it dies while RIP3 dec

8、ides how it dies”The way cells dieIncrease of ROSBreakdown of lysosomeDecrease of ATP and NAD+ExecutorPoly-MLKLPI AffinityActivation of channelFormation of porePermeabilisation of membrane Outlet of DAMPSChange the balance of ironExecutor Key enzyme of metabolismPYLG:GlycogenlysisGLUL/GLDH:glutamino

9、lysisRise of Calcium iron in plasmcPLA2:formation of ox-AA(LOX)Calpainlysosome membrane permeabilizationExcesive ROS(ROS:Leak before reaching the terminal of respiratory chain)ExecutorRepression of ANTadenine nucleotide translocase Activation of PARP1Catalyze repair of DNA UV mediated DNA damageROSu

10、pregulate of Calcium ironReceptor?Decrease of ATP and NAD+Re-overviewLigand Receptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosomeToll-like receptor pathwayUseful inhibitorsNecrostatin:inhibitor of RIP1SMAC:inhibitor of cIAP by degrationzVAD-fmk/BocD-fmk:Inhibitor of CaspaseWhy choose necroptosisAn extreme way to alert other cellsAn alternative way of apoptosis 谢谢！谢谢！