Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins
Smac/Diablo antagonizes ubiquitin ligase activity of inhibitor of apoptosis proteins
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DOI：
10.1074/jbc.m313859200
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发表时间：
2004-06-25
影响因子：
4.8
通讯作者：
Martin, SJ
中科院分区：
文献类型：
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作者：
Creagh, EM;Murphy, BM;Martin, SJ
凋亡抑制蛋白(IAPs)通过与活性的caspase结合并拮抗其功能来阻断细胞的凋亡。IAP功能可被Smac/Diablo中和，Smac/Diablo是一种IAP结合蛋白，在细胞凋亡过程中从线粒体释放出来。由于环状结构域的存在，某些IAP除了能够与caspase相互作用外，还表现出泛素蛋白异肽连接酶的活性。然而，目前尚不清楚人IAP的泛素蛋白异肽连接酶活性是否参与了其凋亡抑制活性，或者这种IAP特性是否可以通过与Smac/DIABLO的结合来调节。在这里，我们证明了XIAP的泛素连接酶活性，以及较小程度的c-IAP-1和c-IAP2，通过与Smac/Diablo结合而受到有效抑制。我们还表明，XIAP环域的突变使该IAP成为一种不那么有效的凋亡抑制因子，表明XIAP的泛素连接酶活性参与了其抗凋亡功能。这些数据表明，Smac/Diablo通过同时拮抗caspase-IAP相互作用和抑制IAP泛素连接酶活性而促进细胞凋亡。
Inhibitor of apoptosis proteins (IAPs) can block apoptosis through binding to active caspases and antagonizing their function. IAP function can be neutralized by Smac/Diablo, an IAP-binding protein that is released from mitochondria during apoptosis. In addition to their ability to interact with caspases, certain IAPs also display ubiquitin-protein isopeptide ligase activity because of the presence of a RING domain. However, it is not known whether the ubiquitin-protein isopeptide ligase activities of human IAPs contribute to their apoptosis inhibitory activity or whether this IAP property can be modulated through association with Smac/Diablo. Here we demonstrate that the ubiquitin ligase activities of XIAP, and to a lesser extent c-IAP-1 and c-IAP2, are potently repressed through binding to Smac/Diablo. We also show that mutation of the XIAP RING domain rendered this IAP a less effective inhibitor of apoptosis, suggesting that the ubiquitin ligase activity of XIAP contributes to its anti-apoptotic function. These data suggest that Smac/Diablo potentiates apoptosis by simultaneously antagonizing caspase-IAP interactions and repressing IAP ubiquitin ligase activities.