Caspases, Substrates and Sequential Activation

Abstract

Superfluous, aged or damaged cells are eliminated from tissues via a controlled cell death process, called apoptosis. Apoptosis is coordinated by a group of cysteine aspartic acid‐specific proteases (caspases) that become specifically activated within cells destined to die. Some of these proteases act as initiators, their role being to interface with signalling events and initiate the proteolytic cascade, whereas others act as executioner enzymes and carry out the internal dismantling of the cell that results in death. During the terminal phase of apoptosis the executioner caspases (caspases‐3 and ‐7) simultaneously cleave hundreds of protein substrates to terminate cell viability and produce the characteristic apoptotic phenotype. This large‐scale proteolysis also dismembers the cell into discrete fragments that are recognized and removed by scavenging phagocytes. Recent evidence also suggests that the actions of executioner caspases may disable molecules that are capable of initiating or exacerbating immune responses if released into the extracellular space. Key Concepts: Pro‐apoptotic stimuli lead to the activation of caspases. Caspase activation takes the form of a cascade of sequential activation events. Caspases mediate the structural changes characteristic of apoptotic cell death by processing key protein substrates. Caspase‐dependent demolition of the apoptotic cell facilitates its safe removal by surveying phagocytes.