程序性坏死介绍-PPT

单击此处编辑母版标题样式,编辑母版文本样式,第二级,第三级,第四级,第五级,Necroptosis,1,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.,2,History,1988:discovery of TNF induced necrosis,2005:first introduction of the term“Necroptosis”,3,Morphological characterisics,Increasingly translucent cytoplasm,Swelling of organelles,Minor ultrastructural modifications of nucleus,Disruption of the plasma membrane,4,Biochemistry characteristics,Without caspase in most cases,Random degradation of DNA,(,smear,),Forming of ROS(reactive oxygen species),5,Overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,6,Ligands and Receptors,Ligand to specific receptors,TNF-,DAMPs:damage-associated,molecular,patterns,Intracellular molecules:HMGB1,ATP,F-actin,Hsp,Alarmins:IL-1,IL-33,PAMPs:,pathogen-associated molecular,patterns,Viral or bacterial nucleotides,Lipoproteins,Lipopolysaccharide,Peptidoglycan,7,Ligands and Receptors,Death Receptors(DR),FAS(factor associated suicide,CD95),FASL(CD95L),TNFR1/2(tumor necrosis factor receptor),TNF,TRAILR1/2(TNF-related,apoptosis-inducing ligand receptor,),TRAIL,Pathogen Recognition Receptors(PRR),TLR(toll-like receptor),PAMPs&DAMPs,NLR(nucleotide binding and oligomerization domain-like receptor),PAMPs,8,大家有疑问的，可以询问和交流,可以互相讨论下，但要小声点,9,Complex,TRADD:adaptor protein,TRAF2: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,Receptor-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,）,10,Complex (DISC),CYLD(cylindromatosis):RIP1-deubiquitylating,enzyme,Inhibitor of cIAP,Internalization of the complex,FADD:caspase,RIP1/3,RIP1,RIP1+,RIP3,Caspase:inhibit RIP1/3,Apoptosis,11,Necrosome,Inhibitor of caspase,Chemical inhibitor:zVAD-fmk/BocD-fmk,vIRA(viral inhibitor of RIP activation),RIP:auto-P and trans-P,S161-P on RIP1,S199-P on RIP3,microfilament-like complex,S227-P on RIP3,T357-P and S358-P on MLKL,12,“,RIP1 decides whether it dies while RIP3 decides how it dies,”,13,The way cells die,Increase of ROS,Breakdown of lysosome,Decrease of ATP and NAD,+,14,Executor,Poly-MLKL,PI Affinity,Activation of channel,Formation of pore,Permeabilisation of,membrane,Outlet of DAMPS,Change the balance of iron,15,Executor,Key enzyme of metabolism,PYLG:Glycogenlysis,GLUL/GLDH:glutaminolysis,Rise of Calcium iron in plasm,cPLA2:formation of ox-AA(LOX),Calpain,lysosome membrane permeabilization,Excesive ROS,(ROS:Leak before reaching the terminal of respiratory chain),16,Executor,Repression of ANT,adenine,nucleotide translocase,Activation of PARP1,Catalyze repair of DNA,UV mediated DNA damage,ROS,upregulate of Calcium iron,Receptor?,Decrease of ATP and NAD,+,17,Re-overview,Ligand,Receptor,Complex,Complex,Necrosome,Executor,Apoptosis,Survival,Necroptosis,Pro-necrosome,18,Toll-like receptor pathway,19,Useful inhibitors,Necrostatin:inhibitor of RIP1,SMAC:inhibitor of cIAP by degration,zVAD-fmk/BocD-fmk:Inhibitor of Caspase,20,Why choose necroptosis,An extreme way to alert other cells,An alternative way of apoptosis,21,