Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila.
Despite the essential role of mitochondria in a variety of mammalian cell death processes, the involvement of mitochondrial pathway in Drosophila cell death has remained unclear. To address this, we cloned and characterized DmHtrA2, a Drosophila homolog of a mitochondrial serine protease HtrA2/Omi. We show that DmHtrA2 normally resides in mitochondria and is up-regulated by UV-irradiation. Upon receipt of apoptotic stimuli, DmHtrA2 is translocated to extramitochondrial compartment; however, unlike its mammalian counterpart, the extramitochondrial DmHtrA2 does not diffuse throughout the cytosol but stays near the mitochondria. RNAi-mediated knock-down of DmHtrA2 in larvae or adult flies results in a resistance to stress stimuli. DmHtrA2 specifically cleaves Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), a cellular caspase inhibitor, and induces cell death both in vitro and in vivo as potent as other fly cell death proteins. Our observations suggest that DmHtrA2 promotes cell death through a cleavage of DIAP1 in the vicinity of mitochondria, which may represent a prototype of mitochondrial cell death pathway in evolution.
Igaki
Tatsushi
T
Department of Genetics, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06536, USA.
Suzuki
Yasuyuki
Y
Tokushige
Naoko
N
Aonuma
Hiroka
H
Takahashi
Ryosuke
R
Miura
Masayuki
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D000074923:High-Temperature Requirement A Serine Peptidase 2; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2