The evolutionary conservation of programmed cell death (PCD) in animals has meant that genetic studies in worms can illuminate PCD in higher organisms. Genetic analysis in the nematode worm C. elegans has provided a conceptual framework involving, at is heart, three genes: two of these, ced-3
, are both required for PCD in the worm, whereas another, ced-9
, inhibits the action of ced-3
in surviving cells. Mammalian homologues have been identified for ced-3
, which encodes a caspase, and for ced-9
, which is related to the cell-death suppressor bcl-2
, but, until now, no vertebrate homologue had been found for ced-4
. Unfortunately, the sequence of CED-4 gave few clues to how this protein works. Earlier this year, several groups reported physical interactions between CED-9, CED-4 and CED-3 proteins, with CED-4 as a linker in a protein complex. The finding of an indirect interaction between the Bcl-2-related protein Bcl-X(L) and some human caspases, through an unknown intermediate protein, suggested that the same physical interaction might occur in mammalian cells via a CED-4 homologue. Indeed, the remarkable evolutionary conservation between CED-3 and caspases, and between CED-9 and Bcl-2-related proteins, suggests that there must be CED-4 homologues in vertebrates. Zou et al. have now identified a human CED-4 homologue, and findings from this group, along with those of others, provide important clues to how CED-4 and its relatives might work.