Myeloma overexpressed 2 (Myeov2) regulates L11 subnuclear localization through Nedd8 modification.
Myeloma overexpressed 2 (Myeov2) regulates L11 subnuclear localization through Nedd8 modification.
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DOI：
10.1371/journal.pone.0065285
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chiba T
中科院分区：
文献类型：
--
作者：
Ebina M;Tsuruta F;Katoh MC;Kigoshi Y;Someya A;Chiba T
核仁是一个动态的结构，控制核糖体RNA的生物合成和感受细胞的压力。核仁中含有大量的蛋白质，包括核糖体蛋白，它们将细胞应激传导到下游信号传导通路，如p53通路。最近，据报道，修饰的泛素样分子，Nedd8，调节核糖体蛋白L11的亚核定位。L11在正常情况下主要定位于核仁内。然而，细胞应激触发了L11的去eddylation和再分布，以及随后的p53激活。虽然Nedd8修饰被认为对L11定位很重要，但L11的neddylation如何调节的机制在很大程度上仍然未知。在这里，我们表明，骨髓瘤过表达2（Myeov2）控制L11定位通过下调Nedd8的修改。Myeov2的表达减少了包括L11在内的蛋白质的neddylation。我们还发现Myeov2与L11结合，并将L11保留在核质中。虽然Myeov2与Nedd8去结合酶COP9信号体相互作用，但L11去结合是由另一种去结合酶Nedp1介导的，独立于Myeov2。最后，p53转录活性被Myeov2表达上调。这些数据表明，Myeov2阻碍L11 neddylation通过它们的相互作用，并限制L11的核质，以调节核仁的完整性。我们的研究结果提供了一个新的致癌应激和p53通路之间的联系，并可能揭示对癌症的保护机制。
Nucleolus is a dynamic structure that controls biogenesis of ribosomal RNA and senses cellular stresses. Nucleolus contains a number of proteins including ribosomal proteins that conduct cellular stresses to downstream signaling such as p53 pathway. Recently, it has been reported that modification by a ubiquitin-like molecule, Nedd8, regulates subnuclear localization of ribosomal protein L11. Most of L11 is normally localized and neddylated in nucleolus. However, cellular stress triggers deneddylation and redistribution of L11, and subsequent activation of p53. Although Nedd8 modification is thought to be important for L11 localization, the mechanism of how neddylation of L11 is regulated remains largely unknown. Here, we show that Myeloma overexpressed 2 (Myeov2) controls L11 localization through down-regulation of Nedd8 modification. Expression of Myeov2 reduced neddylation of proteins including L11. We also found that Myeov2 associates with L11 and withholds L11 in nucleoplasm. Although Myeov2 interacted with a Nedd8 deconjugation enzyme COP9 signalosome, L11 deneddylation was mediated by another deneddylase Nedp1, independently of Myeov2. Finally, p53 transcriptional activity is upregulated by Myeov2 expression. These data demonstrate that Myeov2 hampers L11 neddylation through their interactions and confines L11 to nucleoplasm to modulate nucleolar integrity. Our findings provide a novel link between oncogenic stress and p53 pathway and may shed light on the protective mechanism against cancer.
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