Bam-dependent deubiquitinase complex can disrupt germ-line stem cell maintenance by targeting cyclin A
Bam-dependent deubiquitinase complex can disrupt germ-line stem cell maintenance by targeting cyclin A
复制标题
Bam 依赖性去泛素酶复合物可以通过靶向细胞周期蛋白 A 来破坏生殖系干细胞的维持
DOI：
10.1073/pnas.1619188114
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发表时间：
2017-06-13
影响因子：
11.1
通讯作者：
Chen, Dahua
中科院分区：
文献类型：
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作者：
Ji, Shanming;Li, Chaoyi;Chen, Dahua
研究表明，Bam蛋白在果蝇卵巢早期生殖细胞分化中起着关键作用。尽管在过去的20年里，Bam的调控和遗传功能已经得到了广泛的研究，但Bam的生物化学性质仍然难以捉摸。在这里，我们表明，BAM作为一个泛素相关蛋白的功能，并调节CycA的稳定性。我们的研究揭示了Bam作为泛素相关蛋白发挥作用的机制，并与Otu合作去泛素化和稳定CycA，从而平衡GSC的自我更新和分化。果蝇生殖系干细胞（GSCs）是研究干细胞调控机制的理想模型。大理石袋（BAM）已被证明是必要的和足够的，以促进GSC和成囊细胞分化。尽管对其调控和遗传功能进行了广泛的研究，但Bam蛋白的生物化学性质一直未知。在这里，我们报告说，BAM是一种泛素相关蛋白，并控制细胞周期蛋白A（CycA）的营业额。从机制上讲，我们发现Bam与Otu结合形成去泛素化酶复合物，通过去泛素化稳定CycA，从而提供了一种机制来解释Bam在GSC中的异位表达如何促进分化。总的来说，我们的研究结果不仅确定了Bam的生化功能，这有助于GSC的命运决定，但也强调了适当表达的细胞周期蛋白介导的泛素化和去泛素化途径在平衡干细胞自我更新和分化的关键作用。
Significance Previous studies have demonstrated that Bam protein plays a critical role promoting early germ-line cell differentiation in the Drosophila ovary. Although its regulation and genetic functions have been extensively investigated over the last 20 years, the biochemical nature of Bam has still remained elusive. Here, we show that Bam functions as an ubiquitin-associated protein and regulates the stability of CycA. Our study uncovers a mechanism by which Bam functions as an ubiquitin-associated protein, and cooperates with Otu to deubiquitinate and stabilize CycA, thereby balancing GSC self-renewal and differentiation. Drosophila germ-line stem cells (GSCs) provide an excellent model to study the regulatory mechanisms of stem cells in vivo. Bag of marbles (bam) has been demonstrated to be necessary and sufficient to promote GSC and cystoblast differentiation. Despite extensive investigation of its regulation and genetic functions, the biochemical nature of the Bam protein has been unknown. Here, we report that Bam is an ubiquitin-associated protein and controls the turnover of cyclin A (CycA). Mechanistically, we found that Bam associated with Otu to form a deubiquitinase complex that stabilized CycA by deubiquitination, thus providing a mechanism to explain how ectopic expression of Bam in GSCs promotes differentiation. Collectively, our findings not only identify a biochemical function of Bam, which contributes to GSC fate determination, but also emphasizes the critical role of proper expression of cyclin proteins mediated by both ubiquitination and deubiquitination pathways in balancing stem cell self-renewal and differentiation.