Drosophila grim induces apoptosis in mammalian cells

Genetic studies have shown that grim is a central genetic switch of program med cell death in Drosophila; however, homologous genes have not been descr ibed in other species, nor has its mechanism of action been defined. We sho w here that grim expression induces apoptosis in mouse fibroblasts. Cell de ath induced by grim in mammalian cells involves membrane blebbing, cytoplas mic loss and nuclear DNA fragmentation. Grim-induced apoptosis is blocked b y both natural and synthetic caspase inhibitors. We found that grim itself shows caspase-dependent proteolytic processing of its C-terminus in vitro, Grim-induced death is antagonized by bcl-2 in a dose-dependent manner, and neither Fas signalling nor p53 are required for grim pro-apoptotic activity . Grim protein localizes both in the cytosol and in the mitochondria of mou se fibroblasts, the latter location becoming predominant as apoptosis progr esses. These results show that Drosophila grim induces death in mammalian c ells by specifically acting on mitochondrial apoptotic pathways executed by endogenous caspases, These findings advance our knowledge of the mechanism by which grim induces apoptosis and show the conservation through evolutio n of this crucial programmed cell death pathway.