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Published on: March 24, 2023
Caspase-8: regulating life and death
Bart Tummers1, Douglas R Green1
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Abstract:
Roles for cell death in development, homeostasis, and the control of infections and cancer have long been recognized. Although excessive cell damage results in passive necrosis, cells can be triggered to engage molecular programs that result in cell death. Such triggers include cellular stress, oncogenic signals that engage tumor suppressor mechanisms, pathogen insults, and immune mechanisms. The best-known forms of programmed cell death are apoptosis and a recently recognized regulated necrosis termed necroptosis. Of the two best understood pathways of apoptosis, the extrinsic and intrinsic (mitochondrial) pathways, the former is induced by the ligation of death receptors, a subset of the TNF receptor (TNFR) superfamily. Ligation of these death receptors can also induce necroptosis. The extrinsic apoptosis and necroptosis pathways regulate each other and their balance determines whether cells live. Integral in the regulation and initiation of death receptor-mediated activation of programmed cell death is the aspartate-specific cysteine protease (caspase)-8. This review describes the role of caspase-8 in the initiation of extrinsic apoptosis execution and the mechanism by which caspase-8 inhibits necroptosis. The importance of caspase-8 in the development and homeostasis and the way that dysfunctional caspase-8 may contribute to the development of malignancies in mice and humans are also explored.
Insights
Caspase-8 initiates extrinsic apoptosis and prevents necroptosis, crucial for cell death regulation. Dysfunctional caspase-8 contributes to malignancies, highlighting its role in development and homeostasis.
Area of Science:
- Cellular Biology
- Molecular Mechanisms of Cell Death
Background:
- Programmed cell death, including apoptosis and necroptosis, is vital for development, homeostasis, and disease control.
- Extrinsic apoptosis is triggered by death receptor ligation, while necroptosis is a regulated form of necrosis.
- Caspase-8 is a key protease regulating both extrinsic apoptosis and necroptosis pathways.
Purpose of the Study:
- To review the role of caspase-8 in initiating extrinsic apoptosis.
- To elucidate the mechanism by which caspase-8 inhibits necroptosis.
- To explore caspase-8's importance in development, homeostasis, and its link to malignancies.
Main Methods:
- Literature review of programmed cell death pathways.
- Analysis of molecular mechanisms involving caspase-8, death receptors, and TNF receptor superfamily.
- Examination of studies on caspase-8 dysfunction in mouse and human cancers.
Main Results:
- Caspase-8 activation is central to extrinsic apoptosis execution.
- Caspase-8 actively suppresses necroptosis, maintaining a balance between cell survival and death.
- Impaired caspase-8 function is implicated in the development of various cancers.
Conclusions:
- Caspase-8 acts as a critical switch, directing cells towards apoptosis or preventing necroptosis.
- The balance regulated by caspase-8 is essential for normal development and tissue homeostasis.
- Targeting caspase-8 pathways may offer therapeutic strategies for cancer treatment.
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