The cytoplasmic domain of the lymphotoxin-β receptor mediates cell death in HeLa cells

Activation of lymphotoxin-beta receptor (LT-beta R) by conjugation with heterotrimeric lymphotoxin, LT-alpha 1/beta 2, or by cross-linking with anti-LT-beta R antibodies can trigger apoptosis. We have observed that overexpression of either LT-beta R or the cytoplasmic domain of LT-beta R (LT-beta R(CD)) also induces apoptosis, which may be attributed to the tendency of LT-beta R(CD) to self associate. The self-association domain of LT-beta R(CD) was mapped to amino acids 324-377, a region of the protein that is also essential for LT-beta R-induced apoptosis. Furthermore, we have shown that LT-beta R(CD)-induced apoptosis could be inhibited by a TRAF3 dominant negative mutant and by the caspase inhibitors Z-VAD-FMK, DEVD -FMK, and CrmA. The ligand-independent apoptosis induced by LT-beta R(CD) will help us to further dissect LT-beta R signaling pathway.