INHIBITION OF THE CAENORHABDITIS-ELEGANS CELL-DEATH PROTEASE CED-3 BY A CED-3 CLEAVAGE SITE IN BACULOVIRUS P35 PROTEIN

THE baculovirus protein p35 inhibits programmed cell death in such diverse animals as insects, nematodes and mammals(1-5). Here we show that p35 protein is a substrate for and inhibitor of the Caenorhabditis elegans cell-death protease CED-3 (refs 6, 7) and a substrate for four CED-3-like vertebrate cysteine protease activities implicated in apoptosis in mammals(7-14). A p35 mutation that greatly reduced p35 activity in vitro as a CED-3 substrate and inhibitor abolished p35 activity in vivo in protecting against cell death in C. elegans. Introduction of the CED-3 cleavage site in p35 into the cowpox virus protein crmA, which inhibits mammalian apoptosis(14-19) but not programmed cell death in C. elegans, caused crmA to block CED3-mediated cell death. These observations suggest that p35 may prevent programmed cell death in C. elegans and other species by acting as a competitive inhibitor of cysteine proteases.