Myeloma Overexpressed 2 (Myeov2) Regulates L11 Subnuclear Localization through Nedd8 Modification

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.

核仁（Nucleolus）是一种动态结构，可调控核糖体RNA（ribosomal RNA）的生物发生并感知细胞应激。核仁包含多种蛋白质，其中可将细胞应激信号传导至下游通路（如p53通路）的核糖体蛋白便是其中一类。近期有研究报道，泛素样分子（ubiquitin-like molecule）Nedd8的修饰可调控核糖体蛋白L11的亚核定位。正常生理状态下，绝大多数L11定位于核仁并发生Nedd8修饰。然而，细胞应激会触发L11的去Nedd化并使其发生重新分布，进而激活p53通路。尽管学界普遍认为Nedd8修饰对L11的定位至关重要，但L11的Nedd化修饰的调控机制目前仍知之甚少。本研究证实，骨髓瘤过表达蛋白2（Myeov2）可通过下调Nedd8修饰调控L11的定位。Myeov2的表达可降低包括L11在内的多种蛋白质的Nedd化修饰水平。本研究同时发现，Myeov2可与L11结合，并将L11滞留于核质中。尽管Myeov2可与Nedd8去结合酶COP9信号体（COP9 signalosome）相互作用，但L11的去Nedd化修饰是由另一种去Nedd化酶Nedp1介导的，且该过程不依赖于Myeov2。最终，Myeov2的表达可上调p53的转录活性。上述实验数据表明，Myeov2可通过与L11的相互作用抑制L11的Nedd化修饰，并将L11限制在核质中，从而调控核仁的完整性。本研究的发现为致癌应激与p53通路之间搭建了全新的关联，或可为阐明癌症的保护性防御机制提供新的视角。