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Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells
Y Hitoshi1, J Lorens, S I Kitada
1Department of Molecular Pharmacology, Stanford University School of Medicine, California 94305, USA.
Abstract:
Fas is a surface receptor that can transmit signals for apoptosis. Using retroviral cDNA library-based functional cloning we identified a gene, toso, that blocks Fas-mediated apoptosis. Toso expression was confined to lymphoid cells and was enhanced after cell-specific activation processes in T cells. Toso appeared limited to inhibition of apoptosis mediated by members of the TNF receptor family and was capable of inhibiting T cell self-killing induced by TCR activation processes that up-regulate Fas ligand. We mapped the effect of Toso to inhibition of caspase-8 processing, the most upstream caspase activity in Fas-mediated signaling, potentially through activation of cFLIP. Toso therefore serves as a novel regulator of Fas-mediated apoptosis and may act as a regulator of cell fate in T cells and other hematopoietic lineages.
Insights
We discovered a new gene, Toso, that inhibits Fas-mediated apoptosis in lymphoid cells. Toso regulates T cell self-killing by blocking caspase-8 processing, acting as a novel cell fate regulator.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Fas receptor triggers apoptosis, a programmed cell death process crucial for immune regulation.
- Dysregulation of Fas-mediated apoptosis is implicated in various immune disorders and autoimmune diseases.
Purpose of the Study:
- To identify novel regulators of Fas-mediated apoptosis.
- To elucidate the mechanism by which Toso inhibits Fas signaling in lymphoid cells.
Main Methods:
- Retroviral cDNA library-based functional cloning was employed to identify apoptosis-blocking genes.
- Toso expression patterns and its effects on apoptosis were analyzed in T cells.
- The molecular mechanism of Toso's inhibitory action was investigated, focusing on caspase-8 processing and cFLIP.
Main Results:
- A novel gene, Toso, was identified that effectively blocks Fas-mediated apoptosis.
- Toso expression is restricted to lymphoid cells and is upregulated in activated T cells.
- Toso inhibits apoptosis induced by TNF receptor family members and TCR activation, specifically by preventing caspase-8 processing, potentially via cFLIP activation.
Conclusions:
- Toso is a novel inhibitor of Fas-mediated apoptosis in lymphoid cells.
- Toso acts as a critical regulator of cell fate, particularly in T cells and other hematopoietic lineages.
- Understanding Toso's role may offer new therapeutic strategies for immune-related diseases.