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.

Keywords: apoptosis; caspases; caspase substrates; caspase cascades

Figure 1.

Members of the human caspase family of proteases. All caspases are characterized by an N‐terminal domain followed by a large and small subunit. *Full length caspase‐12 is only expressed in a subset of individuals of African decent. **Caspase‐14 is a relatively uncharacterized member implicated in the differentiation of skin cells.

Figure 2.

Sequential activation of caspases during apoptosis. Initiator caspases such as caspases‐8 and ‐9 are activated by pro‐apoptotic signals. These enzymes in turn activate the executioner enzymes such as caspases‐3 and ‐7. Caspase‐3 is particularly important in propagating the cascade through activation of other executioner enzymes as well through positive feed back onto the initiators. The cytotoxic lymphocyte protease granzyme B (GzmB), although not a caspase, has a proteolytic specificity similar to the caspases and can directly process and activate caspases‐3, ‐7 and ‐8 on delivery into target cells.

Figure 3.

Pathways to caspase activation and cell death. Pro‐apoptotic signals are routed through three major pathways. (a) Extrinsic (death receptors), (b) granzyme B (lytic granules derived from cytotoxic lymphocytes) or (c) intrinsic (release of cytochrome c [Cyt c] from the mitochondrial intermembrane space). All pathways lead to the activation of a protease cascade involving members of the caspase family of proteases.

Figure 4.

Consequences of substrate processing by the executioner caspases during the demolition phase of apoptosis. Six representative caspases substrates are shown, but it is important to note that hundreds of proteins are cleaved by the executioner caspases during the demolition phase of apoptosis.

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Walsh, John G, and Martin, Seamus J(Dec 2009) Caspases, Substrates and Sequential Activation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021567]