Caspase-8 serves both apoptotic and nonapoptotic roles.
Knockout of caspase-8, a cysteine protease that participates in the signaling for cell death by receptors of the TNF/nerve growth factor family, is lethal to mice in utero. To explore tissue-specific roles of this enzyme, we established its conditional knockout using the Cre/loxP recombination system. Consistent with its role in cell death induction, deletion of caspase-8 in hepatocytes protected them from Fas-induced caspase activation and death. However, application of the conditional knockout approach to investigate the cause of death of caspase-8 knockout embryos revealed that this enzyme also serves cellular functions that are nonapoptotic. Its deletion in endothelial cells resulted in degeneration of the yolk sac vasculature and embryonal death due to circulatory failure. Caspase-8 deletion in bone-marrow cells resulted in arrest of hemopoietic progenitor functioning, and in cells of the myelomonocytic lineage, its deletion led to arrest of differentiation into macrophages and to cell death. Thus, besides participating in cell death induction by receptors of the TNF/nerve growth factor family, caspase-8, apparently independently of these receptors, also mediates nonapoptotic and perhaps even antiapoptotic activities.
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Tae-Bong
TB
Kang
Tehila
T
Ben-Moshe
Eugene E
EE
Varfolomeev
Yael
Y
Pewzner-Jung
Nir
N
Yogev
Anna
A
Jurewicz
Ari
A
Waisman
Ori
O
Brenner
Rebecca
R
Haffner
Erika
E
Gustafsson
Parameswaran
P
Ramakrishnan
Tsvee
T
Lapidot
David
D
Wallach
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002319:Cardiovascular System / Q000196:embryology / Q000201:enzymology; D053181:Caspase 8; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology; D004727:Endothelium / Q000196:embryology / Q000201:enzymology; D022781:Hepatocytes / Q000201:enzymology / Q000502:physiology; D008099:Liver / Q000196:embryology / Q000201:enzymology / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout
D016173:Macrophage Colony-Stimulating Factor; C505526:Casp8 protein, mouse; D053181:Caspase 8; D020169:Caspases