Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER.
Drosophila BRUCE inhibits apoptosis through non-lysine ubiquitination of the IAP-antagonist REAPER.
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DOI：
10.1038/cdd.2011.116
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发表时间：
2012-03
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
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在动物体内，活性的半胱氨酸天冬氨酸酶通过细胞凋亡来清除多余或有害的细胞。在果蝇中，活细胞通过凋亡抑制蛋白(IAP)家族成员dIAP1来阻止caspase的失控激活，而IAP拮抗剂如Reaper、HID和Grim的表达在凋亡之前。该途径的强大遗传修饰物包括编码E2泛素结合酶结构域的另一个IAP家族基因dBruce。虽然dBruce突变体的遗传效应已经被很好地记录下来，但其编码蛋白的分子靶点仍然难以捉摸。在这里，我们报告了dBruce通过一种非传统的机制将死神作为泛素化的目标。具体地说，我们证明了dBruce与收割者在物理上相互作用，这取决于收割者的IAP结合(IBM)和GH3基序。始终如一地，收割者的水平在dBruce−/−背景下升高。出乎意料的是，我们发现dBruce也影响没有任何内部赖氨酸残基的Reaper突变形式的水平，这些残基通常作为传统的泛素受体位点。此外，我们能够生化地检测到赖氨酸缺乏的Reaper蛋白上的泛素结合，并且dBruce的敲除显著降低了这种泛素化的程度。我们的结果表明，dBruce通过促进IAP拮抗剂在非常规受体部位的泛素化来抑制细胞凋亡。
Active caspases execute apoptosis to eliminate superfluous or harmful cells in animals. In Drosophila, living cells prevent uncontrolled caspase activation through an Inhibitor of Apoptosis Protein (IAP) family member, dIAP1, and apoptosis is preceded by the expression of IAP-antagonists, such as Reaper, Hid and Grim. Strong genetic modifiers of this pathway include another IAP family gene encoding an E2 ubiquitin conjugating enzyme domain, dBruce. While the genetic effects of dBruce mutants are well documented, molecular targets of its encoded protein have remained elusive. Here, we report that dBruce targets Reaper for ubiquitination through an unconventional mechanism. Specifically, we show that dBruce physically interacts with Reaper, dependent upon Reaper’s IAP-Binding (IBM) and GH3 motifs. Consistently, Reaper levels were elevated in a dBruce −/− background. Unexpectedly, we found that dBruce also affects the levels of a mutant form of Reaper without any internal lysine residues, which normally serve as conventional ubiquitin acceptor sites. Furthermore, we were able to biochemically detect ubiquitin conjugation on lysine-deficient Reaper proteins, and knockdown of dBruce significantly reduced the extent of this ubiquitination. Our results indicate that dBruce inhibits apoptosis by promoting IAP-antagonist ubiquitination on unconventional acceptor sites.
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