Caspases. Regulating death since the origin of life.

Programmed cell death (PCD) is the genetically controlled suicide of cells. The tight regulation of this program is essential to ensure that it is only activated in the required cells at the proper moment. Deregulation of apoptosis, the main form of PCD in animals, is associated with diseases such as cancer, autoimmune diseases, and neurodegenerative disorders (Shi, 2002). In plants, deregulation of PCD is often associated with pleiotropic developmental defects and lethality (Lorrain et al., 2003). PCD occurs in all eukaryotic kingdoms, both in unicellular and multicellular organisms, and is involved in many aspects of development as well as in responses to external stimuli. PCD has morphological similarities in animals and plants, and it regulates common processes such as morphogenesis of the embryo, organ abscission, formation of hollow tubular structures (vessels), and defense against pathogens (Woltering et al., 2002). In view of the ubiquitous occurrence of PCD throughout nature and the coincident morphological and functional features in eukaryotes, a question arises: Has PCD developed independently in the different kingdoms or has it evolved from a common ancestral cell death process and thus plants, fungi, and animals may share common regulatory mechanisms? The most convincing evidence for a common origin of PCD is that some of the molecular components of the program are conserved in the different kingdoms. Proteins that activate or inhibit PCD in animals, such as the Bcl2 family of proand antiapoptotic proteins, or the baculovirus antiapoptotic proteins p35 and IAP, have a similar effect on PCD when expressed in plants or yeast (Saccharomyces cerevisiae; Lacomme and Santa Cruz, 1999; Mitsuhara et al., 1999; Sanchez et al., 2000; Lincoln et al., 2002; Danon et al., 2004). Moreover, homologs of genes that control apoptosis in animals, such as Defender against Apoptotic Death-1 and Baxinhibitor-1, are encoded in plant genomes and serve the same function in PCD control (Matsumura et al., 2003; Danon et al., 2004). In contrast, there are no evident homologs in plant or fungal genomes of caspases, arguably the key regulators of PCD in animals. Caspases are a family of Cys proteases with specificity for Asp (hence the name) that function as molecular switches to activate the cell death program in metazoans as diverse as mammals, nematodes, or insects (Shi, 2002). PCD promoting signals induce the selfprocessing of inactive caspase zymogens. This irreversible activation triggers a proteolytic cascade that turns on enzymes involved in killing the cell. Paradoxically, although genome mining has not yielded candidate caspases, caspase inhibitors can block PCD in plants, and most instances of plant PCD are associated with the induction of caspase-like activities (del Pozo and Lam, 1998; Watanabe and Lam, 2004). Are these activities encoded by enzymes phylogenetically unrelated to caspases? Do they regulate PCD in a similar manner to animal caspases? We will address these questions in light of the recent identification of plant enzymes displaying caspase activity and regulating PCD.