共 47 条
Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease
被引:43
作者:
Challa, Madhavi
Malladi, Srinivas
Pellock, Brett J.
Dresnek, Douglas
Varadarajan, Shankar
Yin, Y. Whitney
White, Kristin
Bratton, Shawn B.
机构:
[1] Univ Texas, Coll Pharm, Div Pharmacol & Toxicol, Austin, TX 78712 USA
[2] Univ Texas, Inst Cellular & Mol Biol, Austin, TX USA
[3] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA
[4] Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA
关键词:
apoptosis;
DIAP1;
dOmi;
DRONC;
Drosophila;
D O I:
10.1038/sj.emboj.7601745
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
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.
引用
收藏
页码:3144 / 3156
页数:13
相关论文