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 oractivation 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 inflam-matory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled. Caspases are a family of genes important formaintaining homeostasis through regulat-ing cell death and inflammation. Here we will attempt to summarize what we currently know about how caspases normally work, and what happens when members of this diverse gene family fail to work correctly. Caspases are endoproteases that hydrolyze peptide bonds in a reaction that depends on catalytic cysteine residues in the caspase active site and occurs only after certain aspartic acid residues in the substrate. Although caspase-me-diated processing can result in substrate in-activation, it may also generate active signaling molecules that participate in ordered processes such as apoptosis and inflammation. Accord-ingly, caspases have been broadly classified by their known roles in apoptosis (caspase-3,-6,-7,-8, and-9 in mammals), and in inflamma-tion (caspase-1,-4,-5,-12 in humans and cas-pase-1,-11, and-12 in mice) (Fig. 1). The func-tions of caspase-2,-10, and-14 are less easily categorized. Caspases involved in apoptosis have been subclassified by their mechanism of action and are either initiator caspases (caspase-8 and-9) or executioner caspases (caspase-3,-6