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A death-domain-containing receptor that mediates apoptosis
1Cell Biology Unit, Glaxo-Wellcome Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, UK.
Abstract:
The cell-killing effects of the cytokines TNF-alpha and FasL are mediated by the distinct cell-surface receptors TNFR1, TNFR2 and Fas (also known as CD95/APO-1), which are all members of a receptor superfamily that is important for regulating cell survival. The cytoplasmic regions of TNFR1 and Fas contain a conserved 'death' domain which is an essential component of the signal pathway that triggers apoptosis and activation of the transcription factor NF-kappaB (refs 5,6). Here we report the isolation of a 54K receptor that is a new member of the TNFR superfamily, using the death domain of TNFR1 in a yeast two-hybrid system. This protein, WSL-1, is most similar to TNFR1 itself, particularly in the death-domain region. The gene wsl-1 is capable of inducing apoptosis when transfected into 3T3 and 293 cells, and can also activate NF-kappaB in 293 cells. Like TNFR1, WSL-1 will homodimerize in yeast. WSL-1 also interacts specifically with the TNFR1-associated molecule TRADD. The tissue distribution is very restricted and significantly different from that of Fas and TNFR1.
Insights
Researchers discovered WSL-1, a new cell-surface receptor in the tumor necrosis factor receptor (TNFR) superfamily. This receptor induces apoptosis and activates NF-kappaB, playing a role in cell survival and death pathways.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL) induce cell death via TNFR1, TNFR2, and Fas receptors.
- These receptors are part of a superfamily regulating cell survival.
- TNFR1 and Fas possess a death domain crucial for apoptosis and NF-kappaB activation.
Purpose of the Study:
- To identify novel members of the TNFR superfamily.
- To characterize the function and interactions of a newly isolated receptor, WSL-1.
Main Methods:
- Yeast two-hybrid system using TNFR1 death domain for screening.
- Gene transfection into 3T3 and 293 cells to assess apoptosis and NF-kappaB activation.
- Analysis of protein homodimerization and interaction with TRADD.
Main Results:
- Isolation of a novel 54K receptor, WSL-1, a TNFR superfamily member.
- WSL-1 induces apoptosis and activates NF-kappaB in transfected cells.
- WSL-1 homodimerizes and interacts with TRADD, similar to TNFR1.
Conclusions:
- WSL-1 is a functional receptor within the TNFR superfamily.
- WSL-1 plays a role in apoptosis and NF-kappaB signaling.
- WSL-1 exhibits distinct tissue distribution compared to Fas and TNFR1.