HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells.
Apollon/BRUCE is a giant IAP protein that has BIR and UBC domains in its amino- and carboxy-terminals, respectively. Apollon binds and ubiquitylates SMAC/DIABLO and caspase9, and regulates apoptosis by facilitating proteasomal degradation of these proteins. Apollon overexpression inhibits apoptosis, while its downregulation sensitizes cells to apoptosis, suggesting that Apollon level is important for apoptosis regulation. Here we show that HtrA2/Omi catalytically cleaves Apollon with its serine protease activity. Conversely, Apollon ubiquitylates and facilitates proteasomal degradation of HtrA2 that binds to Apollon through IAP-binding motif. Thus, Apollon and HtrA2 mutually downregulate each other. Expression of catalytically active, but not inactive, HtrA2 induced apoptosis in Apollon-expressing cells. In Apollon-deficient cells, however, expression of catalytically inactive HtrA2 mutant with IAP-binding motif also induced apoptosis. These results indicate that HtrA2 induces apoptosis in two different mechanisms, one with serine protease domain and the other with IAP-binding motif, in Apollon-deficient cells.
Sekine
Keiko
K
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Hao
Yanyan
Y
Suzuki
Yasuyuki
Y
Takahashi
Ryosuke
R
Tsuruo
Takashi
T
Naito
Mikihiko
M
D002384:Catalysis; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006868:Hydrolysis; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000378:metabolism*; D010957:Plasmids; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
C401541:BIRC6 protein, human; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D025801:Ubiquitin; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2