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Published on: March 5, 2018
Serial killers: ordering caspase activation events in apoptosis
E A Slee1, C Adrain, S J Martin
1Division of Molecular & Cell Biology, Smurfit Institute of Genetics, Trinity College, Dublin 2, Ireland.
Abstract:
Caspases participate in the molecular control of apoptosis in several guises; as triggers of the death machinery, as regulatory elements within it, and ultimately as a subset of the effector elements of the machinery itself. The mammalian caspase family is steadily growing and currently contains 14 members. At present, it is unclear whether all of these proteases participate in apoptosis. Thus, current research in this area is focused upon establishing the repertoire and order of caspase activation events that occur during the signalling and demolition phases of cell death. Evidence is accumulating to suggest that proximal caspase activation events are typically initiated by molecules that promote caspase aggregation. As expected, distal caspase activation events are likely to be controlled by caspases activated earlier in the cascade. However, recent data has cast doubt upon the functional demarcation of caspases into signalling (upstream) and effector (downstream) roles based upon their prodomain lengths. In particular, caspase-3 may perform an important role in propagating the caspase cascade, in addition to its role as an effector caspase within the death programme. Here, we discuss the apoptosis-associated caspase cascade and the hierarchy of caspase activation events within it.
Insights
Caspases are key regulators of apoptosis, acting as triggers, regulators, and effectors. Research clarifies the order of caspase activation, revealing complex roles beyond simple upstream or downstream functions.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Caspases are crucial proteases involved in regulating apoptosis (programmed cell death).
- The mammalian caspase family comprises 14 members, but their precise roles in apoptosis remain under investigation.
- Understanding the caspase cascade is essential for deciphering cell death signaling pathways.
Purpose of the Study:
- To elucidate the repertoire and activation order of caspases during apoptosis.
- To investigate the functional roles of different caspases within the apoptotic cascade.
- To re-evaluate the traditional demarcation of caspases into signaling (upstream) and effector (downstream) roles.
Main Methods:
- Review and synthesis of current research on caspase activation and function in apoptosis.
- Analysis of evidence regarding caspase aggregation in initiating proximal activation events.
- Examination of data challenging the prodomain length-based classification of caspases.
Main Results:
- Evidence suggests proximal caspase activation is often initiated by molecules promoting caspase aggregation.
- Distal caspase activation is typically controlled by caspases activated earlier in the cascade.
- Recent findings challenge the strict functional division of caspases based on prodomain length, indicating roles beyond signaling or effector functions.
Conclusions:
- The caspase cascade in apoptosis is complex, involving intricate hierarchies of activation events.
- Caspase-3, in particular, may play a significant role in propagating the caspase cascade, in addition to its effector functions.
- Further research is needed to fully delineate the roles and interactions of all mammalian caspases in apoptosis.
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