A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation.
A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)-mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor-kappaB (NF-kappaB). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell-mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders.
Daniel
Soizic
S
Department of Surgery and Medicine, 99 Brookline Ave, Boston MA 02215, USA.
Arvelo
Maria B
MB
Patel
Virendra I
VI
Longo
Christopher R
CR
Shrikhande
Gautam
G
Shukri
Tala
T
Mahiou
Jerome
J
Sun
David W
DW
Mottley
Christina
C
Grey
Shane T
ST
Ferran
Christiane
C
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000276:immunology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D053200:Fas-Associated Death Domain Protein; D015870:Gene Expression; D006358:Hot Temperature; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D003165:Complement System Proteins; D003513:Cycloheximide; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases