Role of CED-4 in the activation of CED-3

Genetic analyses of the nematode Caenorhabditis elegans have identified three core components of the cell-death apparatus1. CED-3 and CED-4 promote, whereas CED-9 inhibits cell death. Recent studies indicate that CED-4 might interact independently with CED-3 and CED-9, forming the crux of a multicomponent death complex2. But except for its role as an adaptor molecule, little is known about CED-4 function. A clue came with the observation that mutation of the phosphate-binding loop (P-loop) of CED-4 disrupts its ability to induce chromatin condensation in yeast3. Further, a P-loop mutant of CED-4 (CED-4K165R) fails to process CED-3 in vivo, both in insect4 and mammalian cells (unpublished). We now confirm that CED-4 induces CED-3 activation and subsequent apoptosis, and that the process requires binding of ATP.