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Signalling by proteolysis: death receptors induce apoptosis
1Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy.
International Journal of Clinical & Laboratory Research
|November 5, 1998
Summary
Programmed cell death (apoptosis) is genetically regulated. Death receptors initiate apoptosis by forming a signaling complex that activates the protease FLICE (caspase-8), triggering cell death.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Apoptosis, or programmed cell death, is a crucial genetically regulated process in metazoan development and homeostasis.
- Death receptors, including Fas, TNFR-2, DR3, and TRAIL receptors, mediate apoptosis upon ligand binding or ectopic expression.
Purpose of the Study:
- To elucidate the mechanism of death-inducing signaling complex assembly and protease activation in apoptosis.
- To describe the first instance of a transmembrane receptor directly engaging a protease within a signaling complex to initiate a proteolytic cascade.
Main Methods:
- Investigated the hierarchical assembly of the death-inducing signaling complex following receptor activation.
- Focused on the interaction between death receptors, adapter molecule FADD, and the protease FLICE (caspase-8).
Main Results:
- Receptor activation leads to the binding of the death domain to FADD.
- FADD recruits the zymogen form of FLICE (caspase-8), leading to its self-activation upon approximation.
- This self-activation triggers the apoptotic pathway through a proteolytic signaling cascade.
Conclusions:
- The study describes a novel mechanism where a transmembrane receptor directly engages a protease (FLICE/caspase-8) at the signaling complex.
- This interaction initiates a proteolytic signaling cascade, providing new insights into the regulation of apoptosis.