LYMPHOTOXIN-BETA RECEPTOR SIGNALING COMPLEX - ROLE OF TUMOR-NECROSIS-FACTOR RECEPTOR-ASSOCIATED FACTOR 3 RECRUITMENT IN CELL-DEATH AND ACTIVATION OF NUCLEAR FACTOR KAPPA-B

The binding of heterotrimeric lymphotoxin, LT alpha(1) beta(2), to the LT beta receptor (LT beta R), a member of the turner necrosis factor receptor (TNFR) superfamily, induces nuclear factor kappa B (NF-kappa B) activation and cell death in HT29 adenocarcinoma cells. We now show that treatment with LT alpha(1) beta(2) or agonistic LT beta R antibo dies causes rapid recruitment of TNFR-associated factor 3 (TRAF3) to t he LT beta R cytoplasmic domain. Further, stable overexpression of a T RAF3 mutant that lacks the RING and zinc finger domains inhibits LT be ta R-mediated cell death. The inhibition is specific for LT beta R cel l death signaling, since NF-kappa B activation by LT alpha(1) beta(2) and Fas-mediated apoptosis are not inhibited in the same cells. The mu tant and endogenous TRAF3s are both recruited at equimolar amounts to the LT beta R, suggesting that the mutant disrupts the function of the signaling complex. These results implicate TRAF3 as a critical compon ent of the LT beta R death signaling complex and indicate that at leas t two independent signaling pathways are initiated by LT beta R ligati on.