Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways
Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways
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DOI：
10.1038/sj.cdd.4402079
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发表时间：
2007-04-01
影响因子：
12.4
通讯作者：
Gonen, H.
中科院分区：
文献类型：
--
作者：
Herman-Bachinsky, Y.;Ryoo, H. -D.;Gonen, H.
凋亡蛋白抑制剂（Inhibitors of apoptosis proteins，IAPs）通过抑制促凋亡调节因子的活性来抑制细胞死亡，在正常和恶性肿瘤细胞的凋亡调控中发挥重要作用。许多IAP是泛素连接酶，它们的活性通过泛素化和随后降解其靶标来介导。在这里，我们证实了以前的观察，即DIAP 1（果蝇IAP 1）可以通过两步机制降解：（i）有限的半胱天冬酶介导的切割和（ii）通过泛素N-末端规则途径降解释放的片段。然而，我们证明，这一途径并不是唯一一个参与DIAP 1降解，完整的蛋白质可以独立于先前的半胱天冬酶裂解降解。重要的是，这种降解模式不需要DIAP 1的环指介导的自噬活性，DIAP 1被认为靶向许多环指E3进行自我破坏。我们的初步数据表明，DIAP 2介导DIAP 1降解，这表明在凋亡途径中存在一个新的调节环。研究DIAP 1的autoubiquitinating活性的作用，我们证明，它不涉及形成基于Lys 48的聚泛素链，但可能通过Lys 63连接的链。我们的初步数据表明，autoubiquitination用于减弱DIAP 1对外源底物的连接酶活性。
Inhibitors of apoptosis proteins (IAPs) suppress cell death by inactivating proapoptotic regulators, and therefore play important roles in controlling apoptosis in normal and malignant cells. Many IAPs are ubiquitin ligases, and their activity is mediated via ubiquitination and subsequent degradation of their targets. Here we corroborate a previous observation that DIAP1 (Drosophila IAP1) can be degraded via a two-step mechanism: (i) limited caspase-mediated cleavage and (ii) degradation of the released fragment via the ubiquitin N-end rule pathway. Yet, we demonstrate that this pathway is not the only one involved in DIAP1 degradation, and the intact protein can be degraded independent of prior caspase cleavage. Importantly, this mode of degradation does not require the RING-finger-mediated autoubiquitinating activity of DIAP1, believed to target many RING-finger E3s for self-destruction. Our preliminary data suggest that DIAP2 mediates DIAP1 degradation, suggesting a novel regulatory loop within the apoptotic pathway. Studying the role of the autoubiquitinating activity of DIAP1, we demonstrate that it does not involve formation of Lys48-based polyubiquitin chains, but probably chains linked via Lys63. Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates.