Caspase functions in cell death and disease

Abstract

Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.

Figure 1.

Domain structure of human caspases.

Figure 2.

Extrinsic and intrinsic pathways of apoptosis. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/TRADD), to recruitment, dimerization, and activation of caspase-8. Active caspase-8 then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP, and caspase-9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases.

Figure 3.

Signaling and composition of inflammasomes. Activation of inflammatory caspases such as caspase-1 is achieved through inflammasome formation. A multitude of cellular stimuli are recognized by a family of pattern-recognition receptors, engagement of which leads to the binding of the adapter protein ASC and the recruitment and activation of the inactive inflammatory procaspase, typically procaspase-1. Activated caspase-1 in turn cleaves pro-IL-1β, pro-IL-18, and pro-IL-33, which facilitates the secretion of these proinflammatory cytokines leading to inflammation.