1. Howard Hughes Medical Institute, Department of Biology, 68-425, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Abstract

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 activi-ties 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 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.