The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper, grim, and hid

In flies and mammals, critical regulators of cell death function by antagonizing Inhibitor of Apoptosis Proteins (IAPs), which themselves directly block caspase action [1]. The three currently known IAP antagonists in Drosophila map to the H99 genomic interval required for all programmed cell death [2]. Here we describe a fourth member of this genetic group, sickle (ski), which maps just outside of the H99 deletion. At its N terminus, Ski shares residues in common with other IAP antagonists in flies (Rpr, Grim, and Hid) [3-5] and in mammals (Smac/DIABLO and Omi/Htra2) [6-10]. Like other activators of apoptosis mapping in the Reaper region, full-length ski induced apoptosis when overexpressed, and the N terminus of this protein specifically bound to the BIR2 domain of DIAP1. However, unlike the N termini of Grim, Hid [11, 12], and Rpr, the N terminus of Ski did not induce apoptosis. ski transcripts accumulate in cells that are fated to die in some but not all regions of the embryo. Genotoxic stimuli induced skI expression, but skI was not responsive to all signals that trigger premature apoptosis. ski is potentially a fourth IAP antagonist in the "Reaper region" and a new candidate transducer of apoptotic damage signaling in Drosophila.