FAN, A NOVEL WD-REPEAT PROTEIN, COUPLES THE P55 TNF-RECEPTOR TO NEUTRAL SPHINGOMYELINASE

The initiation of intracellular signaling events through the 55 kDa tu mor necrosis factor-receptor (TNF-R55) appears to depend on protein in termediates that interact with specific cytoplasmic domains of TNF-R55 . By combined use of the yeast interaction trap system and a peptide s canning library, the novel WD-repeat protein FAN has been identified, which specifically binds to a cytoplasmic nine amino acid binding moti f of TNF-R55. This region has been previously recognized as a distinct functional domain that is both required and sufficient for the activa tion of neutral sphingomyelinase (N-SMase). Overexpression of full-len gth FAN enhanced N-SMase activity in TNF-treated cells, while truncate d mutants of FAN produced dominant negative effects. The data suggest that FAN regulates ceramide production by N-SMase, which is a crucial step in TNF signaling.