Research ArticleBiochemistry

Intra- and Interdimeric Caspase-8 Self-Cleavage Controls Strength and Timing of CD95-Induced Apoptosis

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Science Signaling  11 Mar 2014:
Vol. 7, Issue 316, pp. ra23
DOI: 10.1126/scisignal.2004738

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Interpreting the Death Signal

Apoptosis is a natural form of cell death that can be initiated by death-inducing ligands, such as CD95L. The process involves the cleavage-mediated activation of proteases called initiator caspases, which in turn cleave and activate effector caspases. Kallenberger et al. performed single-cell analysis of initiator caspase-8 activity to quantify the amounts of its membrane-bound and cytosolic activities, which arise from two distinctly cleaved forms of procaspase-8. Models constructed from those data and population data indicated that a combination of cleavage events between and within dimeric complexes occurred to produce a sustained membrane-bound caspase-8 activity and a transient cytosolic activity. This combination of activation mechanisms enables cells to properly interpret strong and weak death-inducing signals arising from high or low concentrations of CD95L, respectively, such that apoptosis only occurs when the concentration is sufficiently high.

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