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Published on: March 15, 2019
The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila
1Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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.
Insights
Researchers identified and characterized Drosophila Omi/HtrA2, a mitochondrial protein involved in cell death. They found that Drosophila Inhibitor of Apoptosis Protein 1 (DIAP1) binds and degrades dOmi, protecting cells from its lethal effects.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Mitochondrial proteins like cytochrome c and Omi/HtrA2 are crucial for mammalian cell death pathways.
- The role of mitochondria in cell death in Drosophila remains less understood.
Purpose of the Study:
- To identify and characterize the Drosophila ortholog of human Omi/HtrA2.
- To investigate the interaction between Drosophila Omi/HtrA2 and Drosophila Inhibitor of Apoptosis Protein 1 (DIAP1) in cell death regulation.
Main Methods:
- Identification and characterization of Drosophila Omi/HtrA2.
- Analysis of dOmi import into mitochondria and proteolytic maturation.
- Investigation of DIAP1 binding and ubiquitination of dOmi isoforms.
- Assessment of DIAP1's protective role against dOmi-induced cell death in Drosophila eye discs.
Main Results:
- Drosophila Omi/HtrA2 (dOmi) is imported into mitochondria and processed into dOmi-L and dOmi-S isoforms.
- Both dOmi isoforms bind to DIAP1, leading to DIAP1 cleavage and dOmi degradation.
- DIAP1 also polyubiquitinates dOmi, targeting it for proteasomal degradation.
- DIAP1 expression protects Drosophila eye discs from dOmi-induced cell ablation.
Conclusions:
- Drosophila Omi/HtrA2 is a functional mitochondrial protein involved in cell death.
- DIAP1 counterbalances the lethal effects of dOmi through binding, degradation, and ubiquitination.
- The interaction between IAPs and mitochondrial proteins represents a conserved mechanism to regulate cell death.
