（医学课件）程序性坏死介绍

1、Necroptosis1 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 “Necroptosi

2、s”3 Morphological characterisics Increasingly translucent cytoplasm Swelling of organelles Minor ultrastructural modifications of nucleus Disruption of the plasma membrane4 Biochemistry characteristics Without caspase in most cases Random degradation of DNA (smear) Forming of ROS (reactive oxygen sp

3、ecies)5 OverviewLigand Receptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosome6 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-a

4、ssociated molecular patterns Viral or bacterial nucleotides Lipoproteins Lipopolysaccharide Peptidoglycan7 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) T

5、RAIL Pathogen Recognition Receptors(PRR) TLR(toll-like receptor)PAMPs&DAMPs NLR(nucleotide binding and oligomerization domain-like receptor) PAMPs8 Complex TRADD: adaptor protein TRAF2: bridge between TRADD and cIAPs RIP1(RIPK1):Lys-63 (Prevent cell death, NEMO) cIAPs:E3 ubiquitin ligasesDeath domai

6、n (DD)Death effector 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）9 Complex (DISC) CYLD(cylindromatosis):RIP1-deubiquitylating enzyme In

7、hibitor of cIAP Internalization of the complex FADD:caspase, RIP1/3 RIP1 RIP1+RIP3 Caspase:inhibit RIP1/3 Apoptosis10 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 co

8、mplex S227-P on RIP3 T357-P and S358-P on MLKL11 “RIP1 decides whether it dies while RIP3 decides how it dies”12 The way cells die Increase of ROS Breakdown of lysosome Decrease of ATP and NAD+13 Executor Poly-MLKL PI Affinity Activation of channel Formation of pore Permeabilisation of membrane Outl

9、et of DAMPSChange the balance of iron14 Executor 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) 15 Exec

10、utor 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+16 Re-overviewLigand Receptor Complex Complex Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosome17 Toll-like receptor pathway18 Useful inhibitors Necrostatin:inhibitor of RIP1 SMAC:inhibitor of