Kep1 interacts genetically with dredd/caspase-8, and kep1 mutants alter the balance of dredd isoforms.

The Drosophila kep1 gene encodes an RNA binding protein related to the murine QUAKING apoptotic inducer. We have previously shown that kep1 can induce apoptosis when transfected into different cell lines. To better define the role of Kep1 in apoptosis, we generated kep1 null flies. These flies were viable, but females displayed reduced fertility, with approximately half of the eggs laid from kep1- homozygotes failing to hatch. In addition, loss of kep1 suppressed GMR-rpr-mediated apoptosis in the Drosophila eye, and kep1 mutant flies had increased susceptibility to Escherichia coli infection. We found that Kep1 bound dredd RNA in vitro, and that extracts prepared from kep1 mutant ovaries had markedly reduced proteolytic cleavage activity toward the caspase-8 target substrate IETD-7-amino-4-trifluoromethyl coumarin. We observed increased levels of the beta isoform of dredd mRNA in kep1 mutants as compared with wild-type. Taken together, our results suggest that Kep1 regulates apoptosis by influencing the processing of dredd RNA.