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 antibodies causes rapid recruitment of TNFR-associated factor 3 (TRAF3) to the LT beta R cytoplasmic domain. Further, stable overexpression of a TRAF3 mutant that lacks the RING and zinc finger domains inhibits LT beta R-mediated cell death. The inhibition is specific for LT beta R cell 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 mutant 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 component of the LT beta R death signaling complex and indicate that at least two independent signaling pathways are initiated by LT beta R ligation.