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Caspases: cellular demolition experts
1Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Abstract:
Apoptosis is co-ordinated by a family of cysteine proteases, the caspases, that dismantle the cell by targeting a panoply of proteins for limited proteolysis. The mammalian caspase family contains 14 members, a subset of which participates in apoptosis, with the remainder likely to be involved in the processing of pro-inflammatory cytokines. Apical caspase activation events are typically initiated by adaptor molecules that promote caspase aggregation and facilitate caspase autoactivation. In contrast, distal caspase activation events are controlled by caspases activated earlier in the cascade. Many cellular stresses provoke apoptosis by damaging mitochondria which results in the release of factors [such as cytochrome c and SMAC (second mitochondrial-derived activator of caspase)/Diablo] that trigger caspase activation and cell death. Here, we discuss the hierarchical nature of the caspase cascade that is triggered upon the release of mitochondrial cytochrome c into the cytoplasm, and the role of specific caspases within this cascade in targeting proteins for degradation. Finally, feedback amplification loops and important control points within the caspase cascade will be discussed.
Insights
The caspase cascade, orchestrated by cysteine proteases, dismantles cells during apoptosis. Mitochondrial damage triggers this cascade, involving cytochrome c release and specific caspase roles in protein degradation and inflammatory responses.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Apoptosis is a regulated cell death process crucial for development and tissue homeostasis.
- Caspases, a family of cysteine proteases, are key executioners of apoptosis.
- Mitochondrial integrity is vital, as its damage can initiate apoptotic pathways.
Purpose of the Study:
- To elucidate the hierarchical activation of the caspase cascade.
- To describe the role of mitochondrial factors in initiating apoptosis.
- To discuss regulatory mechanisms within the caspase cascade.
Main Methods:
- Review and discussion of existing literature on caspase activation and function.
- Analysis of the molecular events following mitochondrial damage.
- Examination of feedback loops and control points in apoptotic signaling.
Main Results:
- Caspase activation follows a hierarchical cascade, initiated by apical caspases and propagated by downstream effectors.
- Mitochondrial release of factors like cytochrome c and SMAC/Diablo is a critical trigger for caspase activation.
- Specific caspases target a wide range of cellular proteins for degradation, dismantling the cell.
Conclusions:
- The caspase cascade is a tightly regulated process essential for apoptosis.
- Mitochondrial pathways play a central role in initiating programmed cell death.
- Understanding caspase regulation offers insights into diseases involving aberrant cell death.