NF kappa B activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP

作者：Kreuz S; Siegmund D; Rumpf JJ; Samel D; Leverkus M; Janssen O; Hacker G; Dittrich Breiholz O; Kracht M; Scheurich P; Wajant H^*

来源：The Journal of Cell Biology, 2004, 166(3): 369-380.

DOI：10.1083/jcb.200401036

• apoptosis
• Bcl2
• CD95
• FasL
• IL8

F as (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.

• 出版日期2004-8-2
• 单位河北医科大学