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.