Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
PLoS One. 2013 Jun 12;8(6):e65285. doi: 10.1371/journal.pone.0065285. Print 2013.
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.
核仁是一个动态的结构，控制着核糖体 RNA 的生物发生，并感知细胞应激。核仁包含许多蛋白质，包括核糖体蛋白，它们将细胞应激传导到下游信号通路，如 p53 通路。最近，据报道，一种泛素样分子 Nedd8 的修饰调节核糖体蛋白 L11 的亚核定位。大多数 L11 正常定位于核仁并被 Nedd8 修饰。然而，细胞应激会触发 L11 的去 Neddylation 和重新分布，并随后激活 p53。尽管 Nedd8 修饰被认为对 L11 的定位很重要，但 L11 的 Neddylation 如何被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) 通过下调 Nedd8 修饰来控制 L11 的定位。Myeov2 的表达降低了包括 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 去共轭酶 COP9 信号osome 相互作用，但 L11 的去 Neddylation是由另一种去 Neddylase Nedp1 介导的，与 Myeov2 无关。最后，Myeov2 表达上调了 p53 的转录活性。这些数据表明，Myeov2 通过相互作用阻碍 L11 的 Neddylation，并将 L11 限制在核质中，从而调节核仁的完整性。我们的发现为致癌应激和 p53 通路之间提供了一个新的联系，并可能为癌症的保护机制提供启示。
