NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP.
J Cell Biol
; 166(3): 369-80, 2004 Aug 02.
Article
em En
| MEDLINE
| ID: mdl-15289496
Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFkappaB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFkappaB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFkappaB was activated by overexpressed FLIPL and FLIPS in a cell type-specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFkappaB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFkappaB target gene IL8. As NFkappaB signaling is inhibited during apoptosis, FasL-induced NFkappaB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFkappaB-related response.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Proteínas
/
Proteínas de Transporte
/
NF-kappa B
/
Receptor fas
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Caspases
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Peptídeos e Proteínas de Sinalização Intracelular
/
Proteínas Adaptadoras de Transdução de Sinal
Limite:
Humans
Idioma:
En
Revista:
J Cell Biol
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Alemanha