Abstract
Although essential in mammals, in flies the importance of mitochondrial outer membrane permeabilization for apoptosis remains highly controversial. Herein, we demonstrate that Drosophila Omi (dOmi), a fly homologue of the serine protease Omi/HtrA2, is a developmentally regulated mitochondrial intermembrane space protein that undergoes processive cleavage, in situ, to generate two distinct inhibitor of apoptosis (IAP) binding motifs. Depending upon the proapoptotic stimulus, mature dOmi is then differentially released into the cytosol, where it binds selectively to the baculovirus IAP repeat 2 (BIR2) domain in Drosophila IAP1 (DIAP1) and displaces the initiator caspase DRONC. This interaction alone, however, is insufficient to promote apoptosis, as dOmi fails to displace the effector caspase DrICE from the BIR1 domain in DIAP1. Rather, dOmi alleviates DIAP1 inhibition of all caspases by proteolytically degrading DIAP1 and induces apoptosis both in cultured cells and in the developing fly eye. In summary, we demonstrate for the first time in flies that mitochondrial permeabilization not only occurs during apoptosis but also results in the release of a bona fide proapoptotic protein.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis*
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Binding Sites
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Caspase Inhibitors
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Caspases / metabolism
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Cell Line
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Conserved Sequence
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Crystallography, X-Ray
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Drosophila Proteins / antagonists & inhibitors*
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Drosophila Proteins / chemistry
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Drosophila Proteins / genetics
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Drosophila melanogaster / cytology*
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Drosophila melanogaster / enzymology*
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Drosophila melanogaster / genetics
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Drosophila melanogaster / growth & development
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Gene Expression Regulation, Developmental
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / chemistry
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Inhibitor of Apoptosis Proteins / genetics
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Mitochondria / enzymology*
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Mitochondria / metabolism
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Mitochondrial Proteins / chemistry
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Models, Molecular
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Molecular Sequence Data
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Protein Structure, Quaternary
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Protein Structure, Tertiary
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Protein Transport
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Sequence Alignment
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Serine Endopeptidases / chemistry
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
Substances
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Caspase Inhibitors
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DIAP1 protein, Drosophila
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Drosophila Proteins
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Inhibitor of Apoptosis Proteins
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Mitochondrial Proteins
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2
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Caspases