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Signalling by proteolysis: death receptors induce apoptosis
1Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy.
Abstract:
Apoptosis, or programmed cell death, is a genetically regulated mechanism with a central role in both metazoan development and homeostasis. Death receptors (Fas, TNFR-2, DR3, and TRAIL receptors) induce apoptosis upon ligation to cognate ligands or ectopic expression. The assembly of a death-inducing signalling complex occurs in a hierarchical manner upon receptor activation. The death domain of the receptor binds to the corresponding domain of the adapter molecule FADD, which in turn recruits the zymogen form of the death protease FLICE (MACH/caspase-8). Upon approximation, FLICE "zymogens" attain a sufficient concentration to self-activate and to trigger the apoptotic pathway. For the first time, a transmembrane receptor directly engaging a protease at the signalling complex and subsequently triggering a proteolytic signalling cascade is described.
Insights
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.