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Vol. 17, Issue 5, 2150-2157, May 2006
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Department of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
Submitted December 7, 2005;
Revised February 6, 2006;
Accepted February 10, 2006
Monitoring Editor: Sandra Schmid
The mechanisms through which Caspase-2 leads to cell death are controversial. Here we show, using a combination of cell-free and cell culture-based approaches, that cleavage of the Bcl-2-family protein Bid is required for the induction of apoptosis by Caspase-2. Caspase-2 promoted cytochrome c release from mitochondria in the presence of cytosol from wild-type, but not Bid-deficient, mouse embryonic fibroblasts (MEFs). Recombinant wild-type Bid, but not a noncleavable mutant (D59E), restored cytochrome c release. Similarly, Bid-null MEFs were relatively resistant to apoptosis triggered by active Caspase-2, and apoptosis was restored in Bid-null cells by the expression of wild-type, but not D59E, Bid. Finally, Bid-null MEFs were substantially more resistant to apoptosis induced by heat shock, which has been shown to be dependent on apical activation of Caspase-2. The data are consistent with a model in which Caspase-2 induces apoptosis via cleavage of Bid at D59 and the subsequent engagement of the mitochondrial (intrinsic) pathway.
The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).
* Present address: Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105.
Address correspondence to: Donald D. Newmeyer (don{at}liai.org).
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