Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies

Journal of Cell Science, Mar 2000

J. Wang, M.J. Lenardo

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Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies

Jin Wang 0 Michael J. Lenardo ) 0 0 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Building 10, Room 11N311, 10 Center Drive, MSC 1892, Bethesda, MD 20892-18892 , USA SUMMARY Caspases are a group of cysteine proteases critical for apoptosis of eukaryotic cells. Deletion of genes that encode murine caspases suggests that caspases are involved not only in apoptosis but also in cytokine maturation and cell growth and differentiation. Among them, caspase-1 and caspase-11 are primarily involved in the processing of proinflammatory cytokines. Caspase-3 and caspase-9 are essential for apoptosis during brain development. Caspase8 is required for the development of heart muscle, cell proliferation in the hematopoietic lineage and deathreceptor-mediated apoptosis. These studies suggest that caspases function in cell signaling events including apoptosis, cell growth and differentiation. INTRODUCTION Caspases are a family of cysteine proteases that cleave target proteins at specific aspartate residues (Alnemri et al., 1996; Nicholson et al., 1995). In general, three amino acid residues that lie upstream of the aspartate residue in the substrate determine the specificity of recognition by individual caspases (Thornberry et al., 1997). The roles of caspases in apoptosis first became evident when a cell death-related gene, ced-3, which is essential for apoptosis in Caenorhabditis elegans, was found to be homologous to the mammalian caspases (Yuan et al., 1993). It is now clear that caspases are essential effector molecules for carrying out apoptosis in eukaryotic cells (Nicholson and Thornberry, 1997; Salvesen and Dixit, 1997; Thornberry and Lazebnik, 1998; Wang and Lenardo, 1997). At least fourteen members of the caspase family have been described in mammalian cells thus far (Cryns and Yuan, 1998). They exist as zymogens containing a prodomain and a protease domain (Cryns and Yuan, 1998; Thornberry and Lazebnik, 1998). Caspases which have long prodomains are believed to be the upstream initiator caspases. Among them, caspase-8 and caspase-10 contain two tandem repeats of the death effector domains (DEDs) within their prodomains. Homotypic interactions between the DEDs of caspase-8/10 and the DED of an adaptor molecule, FAS-associating protein with a death domain (FADD; also called Mort1), induce the recruitment of these caspases to death receptors and lead to caspase activation (Salvesen and Dixit, 1999). Another group of caspases that have long prodomains includes caspase-1, caspase-2, caspase4 and caspase-9, each of which contains a caspase-recruitment domain (CARD). The CARDs of these caspases interact with CARD-containing adaptor molecules, and these caspases might also undergo similar adaptor-mediated aggregation and self activation (Salvesen and Dixit, 1999). By contrast, caspases with short prodomains, including caspase-3, caspase6 and caspase-7, are believed to be downstream effector caspases that depend on the upstream initiator caspases for activation. The protease domain of caspases contains a large subunit and a small subunit. Activation of caspases possibly involves the following two proteolytic steps (Thornberry and Lazebnik, 1998). First, the C-terminal, smaller subunit of the protease domain is released. Then, the prodomain is removed from the large subunit of the protease. Crystallography studies suggest that active caspases are heterotetramers composed of two large subunits and two small subunits (Rotonda et al., 1996; Walker et al., 1994; Wilson et al., 1994). CASPASE KNOCKOUT MICE Transfection of caspases into cell lines suggests that overexpression of each caspase can induce apoptosis in certain cell lines. However, it is not clear whether apoptosis induced by overexpressed caspases represents the physiological Caspase-2 No gross abnormality Caspase-3 Perinatal lethality No IL-1b and IL-18 processing Caspase-8 Embryonic lethality Fibroblasts resistant to Fas-, Abnormal heart muscle and TNFR1- and DR-3-mediated hemopoeitic cell development apoptosis Caspase-9 Perinatal lethality Abnormal brain development No IL-1b and IL-18 processing functions of these caspases in vivo. The use of tetrapeptides resembling the recognition sites of caspases to block caspase activities shows that caspases are required for most, if not all, types of apoptosis (Nicholson and Thornberry, 1997; Salvesen and Dixit, 1997). However, these caspase inhibitors are not very specific, owing to the overlapping substrate specificities of caspases. Moreover, it is not clear whether complete inhibition of caspases can be achieved by these inhibitors in cells undergoing apoptosis. Deletion of individual caspases from cell lines or animals is therefore necessary for understanding of unique functions of individual caspases. Knockouts of caspases in mice by homologous recombination reveal that caspases play essential roles in development, immune regulation, and apopt (...truncated)


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J. Wang, M.J. Lenardo. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies, Journal of Cell Science, 2000, pp. 753-757, 113/5,