HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells.
HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells.
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DOI：
10.1016/j.bbrc.2005.02.165
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发表时间：
2005-04
影响因子：
3.1
通讯作者：
K. Sekine;Yanyan Hao;Yasuyuki Suzuki;R. Takahashi;T. Tsuruo;M. Naito
中科院分区：
文献类型：
--
作者：
K. Sekine;Yanyan Hao;Yasuyuki Suzuki;R. Takahashi;T. Tsuruo;M. Naito
Apollon/BRUCE是一种巨大的IAP蛋白，其氨基端和羧基端分别具有BIR和UBC结构域。Apollon结合并泛素化SMAC/DIABLO和caspase9，并通过促进这些蛋白的蛋白酶体降解来调节细胞凋亡。Apollon过表达抑制细胞凋亡，而下调则使细胞对细胞凋亡敏感，提示Apollon水平在细胞凋亡调控中起重要作用。我们发现HtrA2/Omi利用丝氨酸蛋白酶活性催化裂解Apollon。相反，Apollon泛素化并促进通过iap结合基序与Apollon结合的HtrA2的蛋白酶体降解。因此，Apollon和HtrA2相互下调。表达具有催化活性而非无活性的HtrA2诱导表达apollon的细胞凋亡。然而，在阿波罗缺失细胞中，表达具有iap结合基序的催化失活HtrA2突变体也会诱导细胞凋亡。这些结果表明，HtrA2通过丝氨酸蛋白酶结构域和iap结合基序两种不同的机制诱导apollon缺失细胞的凋亡。
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.