Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 17, Issue 5, Pages 2150-2157Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E05-12-1107
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Funding
- NIAID NIH HHS [AI47891, R01 AI047891] Funding Source: Medline
- NIGMS NIH HHS [GM50284, R01 GM062289, GM62289, R01 GM050284] Funding Source: Medline
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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.
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