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1、Necroptosis,Definition,Necrosis: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.,History,1988:discovery of TNF induced necrosis2005:first introduction of the term“Necroptosis”,Morph
2、ological characterisics,Increasingly translucent cytoplasmSwelling of organellesMinor ultrastructural modifications of nucleusDisruption of the plasma membrane,Biochemistry characteristics,Without caspase in most casesRandom degradation of DNA(smear)Forming of ROS(reactive oxygen species),Overview,L
3、igand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,Ligands and Receptors,Ligand to specific receptorsTNF-DAMPs:damage-associated molecular patternsIntracellular molecules:HMGB1,ATP,F-actin,HspAlarmins:IL-1,IL-33PAMPs:pathogen-associated molecular patternsV
4、iral or bacterial nucleotides LipoproteinsLipopolysaccharide Peptidoglycan,Ligands and Receptors,Death 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
5、)TLR(toll-like receptor)PAMPs&DAMPsNLR(nucleotide binding and oligomerization domain-like receptor)PAMPs,Complex,TRADD:adaptor proteinTRAF2:bridge between TRADD and cIAPs RIP1(RIPK1):Lys-63(Prevent cell death,NEMO)cIAPs:E3 ubiquitin ligases,Death domain(DD),Death effector domain(DED),N,C,RIP,Recepto
6、r-interacting serine/threonine-protein kinase“RIP1 decides whether it dies while RIP3 decides how it dies”,Death domain,Conservative kinase domain,N,C,RIP homotypic Interaction motif（RHIM）,Complex(DISC),CYLD(cylindromatosis):RIP1-deubiquitylating enzymeInhibitor of cIAPInternalization of the complex
7、FADD:caspase,RIP1/3RIP1 RIP1+RIP3Caspase:inhibit RIP1/3Apoptosis,Necrosome,Inhibitor 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
8、whether it dies while RIP3 decides how it dies”,The way cells die,Increase of ROSBreakdown of lysosomeDecrease of ATP and NAD+,Executor,Poly-MLKLPI AffinityActivation of channelFormation of porePermeabilisation of membrane,Outlet of DAMPSChange the balance of iron,Executor,Key enzyme of metabolismPY
9、LG:GlycogenlysisGLUL/GLDH:glutaminolysisRise of Calcium iron in plasmcPLA2:formation of ox-AA(LOX)Calpain,lysosome membrane permeabilization,Excesive ROS,(ROS:Leak before reaching the terminal of respiratory chain),Executor,Repression of ANTadenine nucleotide translocase Activation of PARP1Catalyze
10、repair of DNA UV mediated DNA damageROSupregulate of Calcium ironReceptor?,Decrease of ATP and NAD+,Re-overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,Toll-like receptor pathway,Useful inhibitors,Necrostatin:inhibitor of RIP1SMAC:inhibitor of cIAP by degrationzVAD-fmk/BocD-fmk:Inhibitor of Caspase,Why choose necroptosis,An extreme way to alert other cellsAn alternative way of apoptosis,谢谢！,
