程序性坏死介绍
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nucleus • Disruption of the plasma membrane
Biochemistry characteristics
• Without caspase in most cases • Random degradation of DNA (smear) • Forming of ROS (reactive oxygen species)
– Permeabilisation of membrane
Executor
• Key enzyme of metabolism
– PYLG:Glycogenlysis
– GLUL/GLDH:glutaminolysis
• Rise of Calcium iron in plasm
– TRAILR1/2(TNF-related apoptosis-inducing ligand receptor) TRAIL
• Pathogen Recognition Receptors(PRR)
– TLR(toll-like receptor)PAMPs&DAMPs – NLR(nucleotide binding and oligomerization
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
Overview
Ligand
Receptor
Survival
Complex Ⅰ Complex Ⅱ Necrosome
Pro-necrosome Apoptosis
Necroptosis
Executor
Ligands and Receptors
• Ligand to specific receptors
– Viral or bacterial nucleotides
Ligands and Receptors
• Death Receptors(DR)
– FAS(factor associated suicide,CD95) FASL(CD95L)
– TNFR1/2(tumor necrosis factor receptor) TNF
• Increase of ROS • Breakdown of lysosome • Decrease of ATP and NAD+
Executor
• Poly-MLKL
– PI Affinity
– Activation of channel – Formation of pore
Outlet of DAMPS Change the balance of iron
– TNF-α
• DAMPs:damage-associated molecular patterns
– Intracellular molecules: HMGB1, ATP, F-actin, Hsp
– Alarmins: IL-1α, IL-33
• PAMPs:pathogen-associated molecular patterns
• microfilament-like complex • S227-P on RIP3 • T357-P and S358-P on MLKL
“RIP1 decides whether it dies while RIP3 decides how it dies”
The way cells die
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
• RIP1(RIPK1):Lys（-6R3HIM(P）revent cell death,
•N“dEecMRidIOPes1)hdoewciditesdiwesh”ether it dies while RIP3
• cIAPs:E3 ubiquitin ligases
Complex Ⅱ (DISC)
Necroptosis
来自百度文库
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.
• CYLD(cylindromatosis):RIP1deubiquitylating enzyme
• Inhibitor of cIAP • Internalization of the complex • FADD:caspase, RIP1/3 • RIP1 RIP1+RIP3 • Caspase:inhibit RIP1/3 • Apoptosis
RIP Complex Ⅰ
• TRADD: adaptor protein
• Receptor-interacting serine/threonine-protein
N kinase
C
N Death effector domain
Death domain
C
(DED)
(DD)
• TRCdooAmnsaFeinrv2a:tivbe kriniadsege beRItnIwtPerhaeocemtionontymTpiocRtif ADDDeaathnddomcaIinAPs
Biochemistry characteristics
• Without caspase in most cases • Random degradation of DNA (smear) • Forming of ROS (reactive oxygen species)
– Permeabilisation of membrane
Executor
• Key enzyme of metabolism
– PYLG:Glycogenlysis
– GLUL/GLDH:glutaminolysis
• Rise of Calcium iron in plasm
– TRAILR1/2(TNF-related apoptosis-inducing ligand receptor) TRAIL
• Pathogen Recognition Receptors(PRR)
– TLR(toll-like receptor)PAMPs&DAMPs – NLR(nucleotide binding and oligomerization
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
Overview
Ligand
Receptor
Survival
Complex Ⅰ Complex Ⅱ Necrosome
Pro-necrosome Apoptosis
Necroptosis
Executor
Ligands and Receptors
• Ligand to specific receptors
– Viral or bacterial nucleotides
Ligands and Receptors
• Death Receptors(DR)
– FAS(factor associated suicide,CD95) FASL(CD95L)
– TNFR1/2(tumor necrosis factor receptor) TNF
• Increase of ROS • Breakdown of lysosome • Decrease of ATP and NAD+
Executor
• Poly-MLKL
– PI Affinity
– Activation of channel – Formation of pore
Outlet of DAMPS Change the balance of iron
– TNF-α
• DAMPs:damage-associated molecular patterns
– Intracellular molecules: HMGB1, ATP, F-actin, Hsp
– Alarmins: IL-1α, IL-33
• PAMPs:pathogen-associated molecular patterns
• microfilament-like complex • S227-P on RIP3 • T357-P and S358-P on MLKL
“RIP1 decides whether it dies while RIP3 decides how it dies”
The way cells die
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
• RIP1(RIPK1):Lys（-6R3HIM(P）revent cell death,
•N“dEecMRidIOPes1)hdoewciditesdiwesh”ether it dies while RIP3
• cIAPs:E3 ubiquitin ligases
Complex Ⅱ (DISC)
Necroptosis
来自百度文库
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.
• CYLD(cylindromatosis):RIP1deubiquitylating enzyme
• Inhibitor of cIAP • Internalization of the complex • FADD:caspase, RIP1/3 • RIP1 RIP1+RIP3 • Caspase:inhibit RIP1/3 • Apoptosis
RIP Complex Ⅰ
• TRADD: adaptor protein
• Receptor-interacting serine/threonine-protein
N kinase
C
N Death effector domain
Death domain
C
(DED)
(DD)
• TRCdooAmnsaFeinrv2a:tivbe kriniadsege beRItnIwtPerhaeocemtionontymTpiocRtif ADDDeaathnddomcaIinAPs