Dredd,a Novel Effector of the Apoptosis ActivatorsReaper, Grim,andHidinDrosophila

Abstract

Caspases are widely conserved proteases considered to be essential effectors of apoptosis. We identified a novel Drosophila gene, dredd, which shares extensive homology to all members of the caspase gene family. Cells specified for programmed death in development exhibit a striking accumulation of dredd RNA that requires signaling by the death activators REAPER, GRIM, and HID. Furthermore, directed misexpression of each activator was sufficient to drive ectopic accumulation of dredd RNA. Heterozygosity at the dredd locus suppressed apoptosis in transgenic models of reaper- and grim-induced cell killing, demonstrating that levels of dredd product can modulate signaling triggered by these death activators. Finally, expression of REAPER, GRIM, and HID was found to trigger processing of DREDD protein precursor through a mechanism that is insensitive to, and upstream of, known caspase inhibitors. Taken together, these observations establish mechanistic connections between activators of apoptosis and a new downstream death effector in Drosophila.

Caspase function in programmed cell death

“…12,13 Cell Death Caspases in Drosophila There are seven caspases in Drosophila named DCP-1, DREDD/DCP-2, DRICE, DRONC, DECAY, DAMM and STRICA/DREAM. [14][15][16][17][18][19][20] Similar to mammalian caspases, Drosophila caspases can be divided into initiator and effector caspases based on their prodomains. 21 The caspases DREDD, DRONC and STRICA contain long amino-terminal prodomains, whereas DCP-1, DRICE, DECAY and DAMM have short prodomains (Figure 2).…”

“…DREDD contains two DEDs in its prodomain region, whereas DRONC is the only CARD-containing caspase in flies. 15,17 STRICA, the third fly caspase with a long amino-terminal region contains a Ser/Thrrich prodomain that lacks any CARD or DED-like structures. 20 The significance and function of this unusual prodomain in STRICA is not currently known, and similar prodomains have not been reported in mammals.…”

“…15 This conclusion was based on expression analysis and overexpression studies that showed that the mRNA for dredd accumulates in preapoptotic cells, and that signalling by RPR, HID and GRIM results in processing of DREDD to its active form in transfected Drosophila S2 cells. 15 Additional evidence for a function of DREDD in apoptosis came from the observation that heterozygosity at the dredd locus suppresses cell death induced by the ectopic expression of rpr, grim and hid in transgenic models, indicating that the concentration of DREDD may be a ratelimiting step in apoptosis. 15 However, subsequent genetic data from the analysis of dredd mutants suggest that the primary function of DREDD is in innate immune response by regulating the activation of RELISH, a member of the NF-kB family.…”

“…15 Additional evidence for a function of DREDD in apoptosis came from the observation that heterozygosity at the dredd locus suppresses cell death induced by the ectopic expression of rpr, grim and hid in transgenic models, indicating that the concentration of DREDD may be a ratelimiting step in apoptosis. 15 However, subsequent genetic data from the analysis of dredd mutants suggest that the primary function of DREDD is in innate immune response by regulating the activation of RELISH, a member of the NF-kB family. 22 Flies mutated at the dredd locus fail to induce the synthesis of antimicrobial peptides and are highly susceptible to infection by Gramnegative bacteria.…”

Caspases: an ancient cellular sword of Damocles

“…43,44 Little is known about the substrates or cleavage site specificity of DREDD, although its catalytic cysteine appears in a QACQE pentapeptide motif, suggesting that its specificity may differ from QACRGcontaining caspases. 44 Like caspase-8, DREDD contains a long prodomain with two putative DED domains, a homotypic protein-protein interaction domain also found in some apical mammalian caspases. 43,44 DREDD was therefore proposed to function as an apical caspase in vivo.…”