Three groups have recently reported the identification of a fly ced-4/Apaf1 homolog6,7 (and reviewed in8). These groups have named the gene dapaf-1, dark and hac-1, respectively; in the on-line Drosophila database the gene is called ark (apaf1-related killer). These studies demonstrated that the mechanisms of apoptosome functions in flies are very likely to be the same as those that occur in worms and mammals.

Several authors have hypothesized, in the last 2 years, the existence of other Apaf1-like genes in vertebrates. Due to the evolutionary conservation of the general mitochondrial apoptotic pathway, with the Bcl-2 family being the homolog of ced-9 and the caspases playing ced-3 role in higher eukaryotes, it seems reasonable to expect a large gene family as the mammalian counterpart of ced-4. Only very recently, some proteins have been identified and related to Apaf1 in terms of function and sequence (Figure 1A). The first attempt to isolate an Apaf1-like protein by Imai and collaborators resulted in the identification of FLICE-associated huge protein (FLASH),9 characterized by a domain similar to the Apaf1 ced-4-like domain (or nucleotide-binding domain, NBD), and a DED-recruiting domain (DRD). The DRD was shown to interact with a death-effector domain in caspase-8 (Casp8). FLASH is therefore necessary for the activation of Casp8 in CD95/Fas-mediated apoptosis.9 Unfortunately, Koonin and colleagues have brought strong and convincing arguments against the structural similarity between APAF1 and FLASH, supporting them by phylogenetic evidences.10

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