The mouse cell surface protein TOSO regulates Fas/Fas ligand-induced apoptosis through its binding to Fas-associated death domain.

Mouse TOSO, the homologue of human TOSO gene, was cloned and characterized in the present study. Using immunofluorescence confocal microscopy we localized TOSO to the cytoplasmic membrane of expressing cells. Using stably transfected mouse TOSO (mTOSO)-expressing Jurkat cells, we show that TOSO protects cells from Fas/Fas ligand- and tumor necrosis factor-induced apoptosis but not from TNF-related apoptosis-inducing ligand-induced apoptosis. The Fas-induced activation of caspase-8 was significantly inhibited by the expression of mTOSO. Using deletion mutants and glutathione S-transferase pull-down approaches, we have shown that mTOSO regulates apoptosis by directly binding to Fas-associated death domain through its C-terminal domain, suggesting the disruption of death-inducing signaling complex formation as mechanism of action. Furthermore, we have expressed mTOSO in transgenic mice and show that mTOSO overexpressing primary T lymphocytes are resistant to Fas/Fas ligand-induced apoptosis.