Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein

Abstract

The baculovirus protein p35 inhibits programmed cell death in such diverse animals as insects, nematodes and mammals. 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. 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 but not programmed cell death in C. elegans, caused crmA to block CED-3-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.