The frantic pace of cell death research definitely doesn't seem to slow down. Recently, four groups have reported a new IAP antagonist, the serine protease Omi/HtrA2. 1±4 This protease is able to process itself generating an amino-terminal reaper motif shared with Drosophila Reaper, Grim, Hid and mammalian Smac/DIABLO. Through this reaper motif, Omi/HtrA2 disrupts IAP-caspase complexes in a manner similar to Smac/DIABLO.

Inhibitors of apoptosis (IAPs) were first identified in baculoviruses as proteins able to protect insect cells from apoptosis. Since then, several mammalian IAP proteins have been identified. Mammalian cIAP1, cIAP2, XIAP, NIAP and Livin/KIAP antagonize cell death by acting as inhibitors of activated caspases whereas BRUCE/Apollon and Survivin seem to have distinct functions in the process of cell division (reviewed in Silke et al. 5). How does a cell that has decided on committing suicide do away with IAPs? In Drosophila this is accomplished through the action of the Reaper family of IAP antagonists (RPs). These proteins (Reaper, Grim and Hid) are thought to bind to IAPs displacing active caspases. Interactions between IAPs and caspases or RPs seem to be mutually exclusive and determine the fate of the cell. The first Reaper mammalian homologue, Smac/DIABLO was identified recently and the structural basis for the interaction with XIAP elegantly determined. The current model infers that RPs interact with IAPs through a conserved amino-terminal sequence±a reaper motif. One should state that throughout this review the only basis for assuming that mammalian proteins like Smac/DIABLO and Omi/HtrA2 are homologues of Drosophila Reaper Grim and Hid is the presence of this amino-terminal reaper motif. This motif is characterized by having the amino acid alanine at the N-terminus (AVPS in Omi/HtrA2 and AVPI in Smac/DIABLO) which is critical for the interaction with IAPs. With three RPs characterized in Drosophila, is Smac/DIABLO the only mammalian RP? Apparently not, since Omi/HtrA2 has entered the stage. Like Smac/DIABLO, Omi/HtrA2 was fished-out from cells overexpressing XIAP. HtrA2 is a serine protease previously reported as being involved in mammalian cellular stress response. 6 Although not significantly toxic, overexpressed Omi/HtrA2 sensitises cells for apoptosis1±4 and, perhaps more significantly, removal