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Do inducers of apoptosis trigger caspase-independent cell death?
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Jerry E. Chipuk and Douglas R. Green
Abstract | Apoptotic cell death is mediated by molecular pathways that culminate in the activation of a family of cysteine proteases, known as the caspases, which orchestrate the dismantling and clearance of the dying cell. However, mounting evidence indicates that a cell that has been treated with an apoptotic inducer can also initiate a suicide programme that does not rely on caspase activation. Here, we present recent findings and discuss the physiological relevance of caspase-independent cell death.
Apoptosis is a genetically controlled event with roles in tissue development, home-ostasis and disease. It is defined by a pattern of molecular and morphological changes that result in the packaging and rapid removal of the dying cell. Cells that are committed to the apoptotic programme after developmental cues, stress or infection are removed by phagocytosis to prevent a host immune response1.
Since the discovery that the Caenorhabditis elegans cell-death abnormality-3 (ced-3) gene product, which is required for programmed cell death (PCD, see BOX 1) in nematodes, is homologous to the cysteine protease ICE (interleukin-1 converting enzyme), it has been accepted that the CED-3-related proteases (caspases) are essential for the initiation and execution of apoptosis. However, the absolute requirement for caspase activation in apoptosis is no longer considered dogma. Here,we discuss the morphological and biochemical phenotypes of caspase-independent cell death (CICD), present model systems that allow for CICD to be studied, and describe proposed mechanisms of CICD.
We define CICD as the loss of cell viability that is induced by pro-apoptotic conditions, and which proceeds despite the inhibition or disruption of caspase function (BOX 1).Cell
death that is caused by excessive damage that results in necrosis is excluded, as are alternative types of cell death that proceed without caspase activation (for example, the cell death that is mediated by cytotoxic granzyme A). Nevertheless, it is a fine line between our
Lateral gene transfer and the nature of bacterial innovation
definition of CICD and the cellular destruction that is unrelated to apoptosis, and it is likely that we sometimes cross it here.
Apoptosis: death systems
Our understanding of how a cell undergoes apoptosis centres on the activation of caspases, as illustrated by the most...