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 activated 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 amino-acid, 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 gene. Soluble Apo3L induced apoptosis and nuclear factor kappaB (NF-kappaB) activation in human cell lines. Caspase inhibitors blocked apoptosis induction by Apo3L, as did a dominant-negative mutant of the cell death adaptor protein Fas-associated death domain protein (FADD/MORT1), which is critical for apoptosis induction by TNF [3]. Dominant-negative mutants of several factors that play a key role in NF-kappaB induction by TNF [10] inhibited NF-kappaB activation by Apo3L. Thus, Apo3L has overlapping signaling functions with TNF, but displays a much wider tissue distribution.
Marsters
S A
SA
Department of Molecular Oncology Genentech Inc 1 DNA Way, South San Francisco, California, 94080-4918, USA.
Sheridan
J P
JP
Pitti
R M
RM
Brush
J
J
Goddard
A
A
Ashkenazi
A
A
D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D053219:Receptors, Tumor Necrosis Factor, Member 25; D017386:Sequence Homology, Amino Acid; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D053221:TNF-Related Apoptosis-Inducing Ligand; C506033:TNFRSF25 protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha