Survival function of the FADD-CASPASE-8-cFLIP(L) complex.
Caspase-8, the initiator caspase of the death receptor pathway of apoptosis, its adapter molecule, FADD, required for caspase-8 activation, and cFLIPL, a caspase-8-like protein that lacks a catalytic site and blocks caspase-8-mediated apoptosis, are each essential for embryonic development. Animals deficient in any of these genes present with E10.5 embryonic lethality. Recent studies have shown that development in caspase-8-deficient mice is rescued by ablation of RIPK3, a kinase that promotes a form of programmed, necrotic cell death. Here, we show that FADD, RIPK3 double-knockout mice develop normally but that the lethal effects of cFLIP deletion are not rescued by RIPK3 deficiency. Remarkably, in mice lacking FADD, cFLIP, and RIPK3, embryonic development is normal. This can be explained by the convergence of two cell processes: the enzymatic activity of the FADD-caspase-8-cFLIPL complex blocks RIPK3-dependent signaling (including necrosis), whereas cFLIPL blocks RIPK3-independent apoptosis promoted by the FADD-caspase-8 complex.
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
Christopher P
CP
Dillon
Andrew
A
Oberst
Ricardo
R
Weinlich
Laura J
LJ
Janke
Tae-Bong
TB
Kang
Tehila
T
Ben-Moshe
Tak W
TW
Mak
David
D
Wallach
Douglas R
DR
Green
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053181:Caspase 8 / Q000235:genetics / Q000502:physiology*; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis / Q000235:genetics / Q000503:physiopathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8