Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase
Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase
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DOI：
10.1016/j.molcel.2004.05.018
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发表时间：
2004-06-18
期刊：
影响因子：
16
通讯作者：
Jentsch, S
中科院分区：
文献类型：
--
作者：
Bartke, T;Pohl, C;Jentsch, S
凋亡细胞的死亡和存活是由促凋亡蛋白和抗凋亡蛋白控制的。由于这些蛋白质相互作用，细胞命运由促凋亡蛋白与抗凋亡蛋白的相对活性决定。在这里，我们报告，布鲁斯，一个保守的528 kDa的外周膜蛋白的trans-Golgi网络，保护细胞免受凋亡和功能作为一种抑制剂的凋亡（IAP）。通过使用野生型和突变体形式，我们表明，布鲁斯抑制半胱天冬酶的活性和凋亡依赖于其BIR结构域。在细胞凋亡诱导后，布鲁斯被三种机制拮抗：第一，通过与Smac结合;第二，通过蛋白酶HtrA 2;第三，通过半胱天冬酶介导的切割。除了其IAP活性外，布鲁斯还具有作为嵌合E2/E3泛素连接酶的独特性质，其中Smac是底物。我们的工作表明，由于它的两个活动和它的本地化，布鲁斯可能作为一个专门的调节细胞死亡途径。
Apoptotic cell death and survival is controlled by pro- and antiapoptotic proteins. Because these proteins act on each other, cell fate is dictated by the relative activity of pro- versus antiapoptotic proteins. Here we report that BRUCE, a conserved 528 kDa peripheral membrane protein of the trans-Golgi network, protects cells against apoptosis and functions as an inhibitor of apoptosis (IAP). By using wild-type and mutant forms we show that BRUCE inhibits caspase activity and apoptosis depending on its BIR domain. Upon apoptosis induction, BRUCE is antagonized by three mechanisms: first, through binding to Smac; second by the protease HtrA2; and third, by caspase-mediate cleavage. In addition to its IAP activity BRUCE has the distinctive property of functioning as a chimeric E2/E3 ubiquitin ligase with Smac being a substrate. Our work suggests that, owing to its two activities and its localization, BRUCE may function as a specialized regulator of cell death pathways.