Requirement of FADD for tumor necrosis factor-induced activation of acid sphingomyelinase

The generation of mice strains deficient for select members of the signalin g complex of the 55-kDa tumor necrosis factor receptor (TNF-R55) has allowe d the assignment of specific cellular responses to distinct TNF-R55-associa ted proteins. In particular, the TNF-R55-associated protein FADD seems to b e responsible for recruitment and subsequent activation of caspase 8. In th is report we demonstrate the requirement of FADD for TNF-induced activation of endosomal acid sphingomyelinase (A-SMase), In primary embryonic fibrobl asts from FADD-deficient mice the activation of A-SMase by TNF-R55 ligation was almost completely impaired. This effect is specific in that other TNF responses like activation of NF-kappa B or neutral (N-)SMase remained unaff ected. In addition, interleukin-l-induced activation of A-SMase in FADD-def icient cells was unaltered. In FADD(-/-) embryonic fibroblasts reconstitute d by transfection with a FADD cDNA expression construct, the TNF responsive ness of A-SMase was restored. The results of this study suggest that FADD, in addition to its role in triggering a proapoptotic caspase cascade, is re quired for TNF-induced activation of A-SMase.