Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease

Madhavi Challa, Srinivas Malladi, Brett J. Pellock, Douglas Dresnek, Shankar Varadarajan, Y. Whitney Yin, Kristin White, Shawn B. Bratton

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3144-3156
Number of pages13
JournalEMBO Journal
Volume26
Issue number13
DOIs
StatePublished - Jul 11 2007

Keywords

  • Apoptosis
  • DIAP1
  • DRONC
  • Drosophila
  • dOmi

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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