1、NecroptosisDefinition 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 necrosis 2005: first introduction of the term “Necroptosis”Mo
2、rphological characterisics Increasingly translucent cytoplasm Swelling of organelles Minor ultrastructural modifications of nucleus Disruption of the plasma membraneBiochemistry characteristics Without caspase in most cases Random degradation of DNA (smear) Forming of ROS (reactive oxygen species)Ov
3、erviewLigand Receptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosomeLigands 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 mo
4、lecular patterns Viral or bacterial nucleotides Lipoproteins Lipopolysaccharide PeptidoglycanLigands 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
5、Recognition Receptors(PRR) TLR(toll-like receptor)PAMPs&DAMPs NLR(nucleotide binding and oligomerization domain-like receptor) PAMPsComplex TRADD: adaptor protein TRAF2: bridge between TRADD and cIAPs RIP1(RIPK1):Lys-63 (Prevent cell death, NEMO) cIAPs:E3 ubiquitin ligasesDeath domain (DD)Death effe
6、ctor domain (DED)NCRIP Receptor-interacting serine/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 enzyme Inhibitor of cIAP In
7、ternalization of the complex FADD:caspase, RIP1/3 RIP1 RIP1+RIP3 Caspase:inhibit RIP1/3 ApoptosisNecrosome 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
8、T357-P and S358-P on MLKL“RIP1 decides whether it dies while RIP3 decides how it dies”The way cells die Increase of ROS Breakdown of lysosome Decrease of ATP and NAD+Executor Poly-MLKL PI Affinity Activation of channel Formation of pore Permeabilisation of membrane Outlet of DAMPSChange the balance
9、of ironExecutor Key enzyme of metabolism PYLG:Glycogenlysis GLUL/GLDH:glutaminolysis Rise of Calcium iron in plasm cPLA2:formation of ox-AA(LOX) Calpainlysosome membrane permeabilizationExcesive ROS(ROS: Leak before reaching the terminal of respiratory chain) Executor Repression of ANT adenine nucle
10、otide translocase Activation of PARP1 Catalyze repair of DNA UV mediated DNA damage ROS upregulate of Calcium iron Receptor?Decrease of ATP and NAD+Re-overviewLigand Receptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosomeToll-like receptor pathwayUseful inhibitors Necrostatin:inhibitor of RIP1 SMAC:inhibitor of cIAP by degration zVAD-fmk/BocD-fmk:Inhibitor of CaspaseWhy choose necroptosis An extreme way to alert other cells An alternative way of apoptosis 谢谢！谢谢！
