Drob-1, a Drosophila member of the Bcl-2/CED-9 family that promotes cell death

The Bcl-2/CED-9 family of proteins, which includes both antiapoptotic and p roapoptotic members, plays key regulating roles in programmed cell death. W e report here the identification and characterization of Drob-1, the first Drosophila member of the Bcl-2/CED-9 family to be isolated. Drob-1 contains four conserved Bcl-2 homology domains (BH1, BH2. BH3, and BH4) and a C-ter minal hydrophobic domain. Ectopic expression of Drob-1 in the developing Dr osophila eye resulted in a rough-eye phenotype. Furthermore, when overexpre ssed in Drosophila S2 cells, Drob-1 induced apoptosis accompanied by elevat ed caspase activity. This Drob-1-induced cell death, however, could not be antagonized by baculovirus p35, a broad-spectrum caspase inhibitor. Drob-1 was localized to the intracytoplasmic membranes, predominantly to the mitoc hondrial membranes, and a mutant Drob-1 lacking the hydrophobic C terminus lost both its mitochondrial localization and its proapoptotic activity. The se results suggest that Drob-1 promotes cell death by inducing both caspase -dependent and -independent pathways at the mitochondria. Our identificatio n of Drob-1 and further genetic analysis should provide increased understan ding of the universal mechanisms by which the Bcl-2/CED-9 family members an d other related proteins regulate apoptosis.