Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Genes Dev. 2013 May 1;27(9):1046-58. doi: 10.1101/gad.215681.113. Epub 2013 Apr 25.
The assembly and disassembly of ribonucleoproteins (RNPs) are dynamic processes that control every step of RNA metabolism, including mRNA stability. However, our knowledge of how RNP remodeling is achieved is largely limited to RNA helicase functions. Here, we report a previously unknown mechanism that implicates the ATPase p97, a protein-remodeling machine, in the dynamic regulation of mRNP disassembly. We found that p97 and its cofactor, UBXD8, destabilize p21, MKP-1, and SIRT1, three established mRNA targets of the RNA-binding protein HuR, by promoting release of HuR from mRNA. Importantly, ubiquitination of HuR with a short K29 chain serves as the signal for release. When cells are subjected to stress conditions, the steady-state levels of HuR ubiquitination change, suggesting a new mechanism through which HuR mediates the stress response. Our studies reveal a new paradigm in RNA biology: nondegradative ubiquitin signaling-dependent disassembly of mRNP promoted by the p97-UBXD8 complex to control mRNA stability.
核糖核蛋白（RNP）的组装和拆卸是动态过程，可控制 RNA 代谢的每一步，包括 mRNA 的稳定性。然而，我们对于 RNP 重塑如何实现的了解在很大程度上仅限于 RNA 解旋酶的功能。在这里，我们报告了一种先前未知的机制，该机制表明 ATP 酶 p97（一种蛋白质重塑机器）参与了 mRNP 拆卸的动态调节。我们发现，p97 及其辅助因子 UBXD8 通过促进 HuR 从 mRNA 上释放，破坏 p21、MKP-1 和 SIRT1，这三种蛋白都是 RNA 结合蛋白 HuR 的 mRNA 靶标。重要的是，HuR 的 K29 短链泛素化可作为释放的信号。当细胞受到应激条件时，HuR 泛素化的稳态水平发生变化，这表明 HuR 介导应激反应的新机制。我们的研究揭示了 RNA 生物学的一个新范例：由 p97-UBXD8 复合物介导的非降解性泛素信号依赖性 mRNP 拆卸可控制 mRNA 的稳定性。
