IDENTIFICATION OF A LIGAND FOR THE DEATH-DOMAIN-CONTAINING RECEPTOR APO3

The tumor necrosis factor (TNF) cytokine family regulates development and function of the immune system [1], TNF is expressed primarily by a ctivated lymphocytes and macrophages and induces gene transcription or apoptosis in target cells [2,3], We have identified a novel relative of TNF that binds to the recently discovered, death-domain-containing receptor called Apo3 [4] (also known as DR3, WSL-1, TRAMP or LARD [5-9 ]). The Apo3 ligand (Apo3L) is a 249 aminoacid, type II transmembrane protein. The extracellular sequence of Apo3L shows highest identity to that of TNF. We detected Apo3L mRNA in many human tissues and mapped its encoding gene to chromosome 17p13, near the p53 tumor-suppressor g ene. Soluble Apo3L induced apoptosis and nuclear factor kappa B (NF-ka ppa B) activation in human cell lines. Caspase inhibitors blocked apop tosis induction by Apo3L, as did a dominant-negative mutant of the cel l death adaptor protein Pas-associated death domain protein (FADD/MORT 1), which is critical for apoptosis induction by TNF [3], Dominant-neg ative mutants of several factors that play a key role in NF-kappa B in duction by TNF [10] inhibited NF-kappa B activation by Apo3L. Thus, Ap o3L has overlapping signaling functions with TNF, but displays a much wider tissue distribution. (C) Current Biology Ltd ISSN 0960-9822.