CAENORHABDITIS-ELEGANS CED-9 PROTEIN IS A BIFUNCTIONAL CELL-DEATH INHIBITOR

The Caenorhabditis elegans gene ced-9 prevents cells from undergoing p rogrammed cell death and encodes a protein similar to the mammalian ce ll-death inhibitor Bcl-2 (refs 1-7). We show here that the CED-9 prote in is a substrate for the C. elegans cell-death protease CED-3 (refs 8 , 9), which is a member of a family of cysteine proteases first define d by CED-3 and human interleukin-1 beta converting enzyme (ICE)(10-12) . CED-9 can be cleaved by CED-3 at two sites near its amino terminus, and the presence of at least one of these sites is important for compl ete protection by CED-9 against cell death. Cleavage of CED-9 by CED-3 generates a carboxy-terminal product that resembles Bcl-2 in sequence and in function. Bcl-2 and the baculovirus protein p35, which inhibit s cell death in different species through a mechanism that depends on the presence of its cleavage site for the CED-3/ICE family of protease s(9,13-17), inhibit cell death additively in C. elegans, Our results i ndicate that CED-9 prevents programmed cell death in C. elegans throug h two distinct mechanisms: first, CED-9 may, by analogy with p35 (refs 9, 17), directly inhibit the CED-3 protease by an interaction involvi ng the CED-3 cleavage sites in CED-9; second, CED-9 may directly or in directly inhibit CED-3 by means of a protective mechanism similar to t hat used by mammalian Bcl-2.