Caenorhabditis elegans CED-9 protein is a bifunctional cell-death inhibitor.
The Caenorhabditis elegans gene ced-9 prevents cells from undergoing programmed cell death and encodes a protein similar to the mammalian cell-death inhibitor Bcl-2. We show here that the CED-9 protein is a substrate for the C. elegans cell-death protease CED-3, which is a member of a family of cysteine proteases first defined by CED-3 and human interleukin-1beta converting enzyme (ICE). 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 complete 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 inhibits cell death in different species through a mechanism that depends on the presence of its cleavage site for the CED-3/ICE family of proteases, inhibit cell death additively in C. elegans. Our results indicate that CED-9 prevents programmed cell death in C. elegans through two distinct mechanisms: first, CED-9 may, by analogy with p35, directly inhibit the CED-3 protease by an interaction involving the CED-3 cleavage sites in CED-9; second, CED-9 may directly or indirectly inhibit CED-3 by means of a protective mechanism similar to that used by mammalian Bcl-2.
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Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Horvitz
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D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016296:Mutagenesis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2
D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; C087233:Ced-9 protein, C elegans; D015801:Helminth Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans