Caspase 8 inhibits programmed necrosis by processing CYLD.
Caspase 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner caspase 3 (ref. 1). However, the dominant function of caspase 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK3 (refs 2-6) during embryogenesis and haematopoiesis(7-9). Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis(10); however, the key substrate processed by caspase 8 to block necrosis has been elusive. A key substrate must meet three criteria: it must be essential for programmed necrosis; it must be cleaved by caspase 8 in situations where caspase 8 is blocking necrosis; and mutation of the caspase 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for caspase 8 inhibition. We now identify CYLD as a substrate for caspase 8 that satisfies these criteria. Following TNF stimulation, caspase 8 cleaves CYLD to generate a survival signal. In contrast, loss of caspase 8 prevented CYLD degradation, resulting in necrotic death. A CYLD substitution mutation at Asp 215 that cannot be cleaved by caspase 8 switches cell survival to necrotic cell death in response to TNF.
Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. marie.a.odonnell@mssm.edu
Marie Anne
MA
O'Donnell
Eva
E
Perez-Jimenez
Andrew
A
Oberst
Aylwin
A
Ng
Ramin
R
Massoumi
Ramnik
R
Xavier
Douglas R
DR
Green
Adrian T
AT
Ting
D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D009336:Necrosis; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; C505530:CASP8 protein, human; D053181:Caspase 8