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PMID:18259196

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Citation

Khan, FS, Fujioka, M, Datta, P, Fernandes-Alnemri, T, Jaynes, JB and Alnemri, ES (2008) The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila. Cell Death Differ. 15:1073-83

Abstract

Mitochondrial proteins such as cytochrome c, Smac/DIABLO and Omi/HtrA2 play important roles in the cell death pathways of mammalian cells. In Drosophila, the role of mitochondria in cell death is less clear. Here, we report the identification and characterization of the Drosophila ortholog of human Omi/HtrA2. We show that Drosophila Omi/HtrA2 is imported into the mitochondria where it undergoes proteolytic maturation to yield two isoforms, dOmi-L and dOmi-S. dOmi-L contains a canonical N-terminal IAP-binding motif (AVVS), whereas dOmi-S contains a distinct N-terminal motif (SKMT). DIAP1 was able to bind to both isoforms via its BIR1 and BIR2 domains. This resulted in cleavage of the linker region of DIAP1 between the BIR1 and BIR2 domains and further degradation of the BIR1 domain by the proteolytic activity of dOmi. The binding of DIAP1 to dOmi also resulted in DIAP1-mediated polyubiquitination of dOmi, suggesting that DIAP1 could target dOmi for proteasomal degradation. Consistent with this, expression of DIAP1 in Drosophila eye discs protected them from dOmi-induced eye ablation, indicating that DIAP1 plays an important role in protecting cells from the potentially lethal effects of dOmi. The ability of IAPs to bind to and ubiquitinate mitochondrial proteins such as dOmi may be a key conserved function to counterbalance the lethal effects of these proteins if accidentally released into the cytosol.

Links

PubMed PMC2683371 Online version:10.1038/cdd.2008.19

Keywords

Amino Acid Motifs; Animals; Apoptosis; Caspases/metabolism; Cytosol/enzymology; Drosophila/cytology; Drosophila/enzymology; Drosophila/growth & development; Drosophila Proteins/antagonists & inhibitors; Drosophila Proteins/chemistry; Drosophila Proteins/metabolism; Eye/cytology; Eye/enzymology; Eye/growth & development; Inhibitor of Apoptosis Proteins/metabolism; Mitochondrial Proteins/analysis; Mitochondrial Proteins/antagonists & inhibitors; Mitochondrial Proteins/chemistry; Mitochondrial Proteins/metabolism; Protein Isoforms/chemistry; Protein Isoforms/metabolism; Serine Endopeptidases/chemistry; Serine Endopeptidases/metabolism; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:DIAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9VFJ3

F

Seeded From UniProt

complete

DROME:DIAP1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:HTRA2

enables

GO:0008233: peptidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:HTRA2

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:HTRA2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q24306

F

Seeded From UniProt

complete

DROME:HTRA2

located_in

GO:0005758: mitochondrial intermembrane space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

DROME:HTRA2

enables

GO:0004252: serine-type endopeptidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:HTRA2

involved_in

GO:0042981: regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:IAP1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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