NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP |
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Authors: | Kreuz Sebastian Siegmund Daniela Rumpf Jost-Julian Samel Dierk Leverkus Martin Janssen Ottmar Häcker Georg Dittrich-Breiholz Oliver Kracht Michael Scheurich Peter Wajant Harald |
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Institution: | Institute of Cell Biology and Immunology, University of Stuttgart, Germany. |
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Abstract: | 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. |
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Keywords: | apoptosis Bcl2 CD95 FasL IL8 |
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