Apoptosis induced by death receptors
1Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland. pascal.schneider@ib.unil.ch
Abstract:
Death receptors belong to the TNF receptor family and are characterised by an intracellular death domain that serves to recruit adapter proteins such as TRADD and FADD and cysteine proteases such as Caspase-8. Activation of Caspase-8 on the aggregated receptor leads to apoptosis. Triggering of death receptors is mediated through the binding of specific ligands of the TNF family, which are homotrimeric type-2 membrane proteins displaying three receptor binding sites. There are various means of modulating the activation of death receptors. The status of the ligand (membrane-bound vs. soluble) is critical in the activation of Fas and of TRAIL receptors. Cleavage of membrane-bound FasL to a soluble form (sFasL) does not affect its ability to bind to Fas but drastically decreases its cytotoxic activity. Conversely, cross-linking epitope-tagged sFasL with anti-tag antibodies to mimic membrane-bound ligand results in a 1000-fold increase in cytotoxicity. This suggests that more than three Fas molecules need to be aggregated to efficiently signal apoptosis. Death receptors can also be regulated by decoy receptors. The cytotoxic ligand TRAIL interacts with five receptors, only two of which (TRAIL-R1 and -R2) have a death domain. TRAIL-R3 is anchored to the membrane by a glycolipid and acts as a dominant negative inhibitor of TRAIL-mediated apoptosis when overexpressed on TRAIL-sensitive cells. Intracellular proteins interacting with the apoptotic pathway are potential modulators of death receptors. FLIP resembles Caspase-8 in structure but lacks protease activity. It interacts with both FADD and Caspase-8 to inhibits the apoptotic signal of death receptors and, at the same time, can activate other signalling pathways such as that leading to NF-kappa B activation.
Insights
Death receptors initiate apoptosis via ligand binding and aggregation. Modulating ligand status, decoy receptors, and intracellular proteins like FLIP are key to controlling this cell death pathway.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Death receptors, part of the TNF receptor superfamily, possess intracellular death domains crucial for recruiting adapter proteins and initiating apoptosis.
- Ligand binding to death receptors, typically homotrimeric TNF family members, triggers downstream signaling cascades.
- Regulation of death receptor activation is complex, involving ligand form, decoy receptors, and intracellular modulators.
Purpose of the Study:
- To elucidate the mechanisms regulating death receptor-mediated apoptosis.
- To explore the roles of ligand status, decoy receptors, and intracellular proteins in modulating apoptosis signaling.
- To understand how these factors influence cytotoxic activity and downstream pathways like NF-kappa B.
Main Methods:
- Analysis of ligand-receptor interactions, including membrane-bound versus soluble forms (e.g., FasL, TRAIL).
- Investigation of decoy receptor function (e.g., TRAIL-R3) in inhibiting apoptosis.
- Examination of intracellular protein interactions (e.g., FLIP) with apoptotic pathway components.
Main Results:
- Soluble FasL (sFasL) binding to Fas is less cytotoxic than membrane-bound FasL, requiring aggregation of multiple Fas molecules for efficient apoptosis signaling.
- Decoy receptors like TRAIL-R3 can act as dominant-negative inhibitors of TRAIL-mediated apoptosis.
- FLIP, a Caspase-8 homolog, inhibits death receptor-induced apoptosis while potentially activating other pathways like NF-kappa B.
Conclusions:
- Death receptor activation and apoptosis are tightly regulated by multiple mechanisms.
- Ligand aggregation state and decoy receptors are critical for controlling cytotoxic signaling.
- Intracellular proteins offer further regulatory points, influencing both apoptosis and other cellular pathways.
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