程序性坏死介绍.ppt

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 necrosis 2005: first introduction of the term “Necroptosis” Morphological characterisics Increasingly translucent cytoplasm Swelling of organelles Minor ultrastructural modifications of nucleus Disruption of the plasma membrane Biochemistry characteristics Without caspase in most cases Random degradation of DNA (smear) Forming of ROS (reactive oxygen species) Overview Ligand Receptor Complex Ⅰ Complex Ⅱ Necrosome Executor Apoptosis Survival Necroptosis Pro-necrosome Ligands and Receptors Ligand to specific receptors TNF-α DAMPs:damage-associated molecular patterns Intracellular molecules: HMGB1, ATP, F-actin, Hsp Alarmins: IL-1α, IL-33 PAMPs:pathogen-associated molecular patterns Viral or bacterial nucleotides Lipoproteins Lipopolysaccharide Peptidoglycan 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)PAMPsDAMPs NLR(nucleotide binding and oligomerization domain-like receptor) PAMPs Complex Ⅰ 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） Complex Ⅱ (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 Necrosome Inhibitor of caspase Chemical inhibito