A novel signaling mechanism for soluble CD95 ligand. Synergy with anti-CD95 monoclonal antibodies for apoptosis and NF-kappaB nuclear translocation.
Soluble CD95 (Fas) ligand (sFasL) is known to be deficient in transducing signals upon engagement with membrane Fas. Here we report that sFasL tranduces, in synergy with non-cytotoxic anti-Fas monoclonal antibody (mAb), signals for apoptosis and nuclear translocation of the NF-kappaB (p65/p50) heterodimer. Activation of the specific signaling pathways correlates with target Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein expression. Synergy with anti-Fas mAb was demonstrated with a trimeric unit of sFasL bearing a single binding site for Fas trimer. In contrast, membrane-bound FasL as expressed on cell-derived vesicles was fully competent in transducing Fas-mediated signals for apoptosis and NF-kappaB nuclear translocation. We propose a model in which the trimeric sFasL signaling requires target expression of a high focal density of Fas, which is induced by the signaling-incompetent anti-Fas mAb. Membrane-bound FasL induces powerful Fas-mediated signals because it possesses both Fas-focusing and signal-transducing functions.
Xiao
Sheng
S
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Jodo
Satoshi
S
Sung
Sun-Sang J
SS
Marshak-Rothstein
Ann
A
Ju
Shyr-Te
ST
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology*; D001483:Base Sequence; D017931:DNA Primers; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015345:Oligonucleotide Probes; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017931:DNA Primers; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D019014:fas Receptor