Zhang Xu, Chen Xiaoli, Liu Qiuying, Zhang Shaojie, Hu Wenqian
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
Department of Computer Science, University of Central Florida, Orlando, United States.
Elife. 2017 Jun 21;6:e27786. doi: 10.7554/eLife.27786.
Gene expression is precisely regulated during the inflammatory response to control infection and limit the detrimental effects of inflammation. Here, we profiled global mRNA translation dynamics in the mouse primary macrophage-mediated inflammatory response and identified hundreds of differentially translated mRNAs. These mRNAs' 3'UTRs have enriched binding motifs for several RNA-binding proteins, which implies extensive translational regulatory networks. We characterized one such protein, Zfp36, as a translation repressor. Using primary macrophages from a Zfp36-V5 epitope tagged knock-in mouse generated by CRISPR/Cas9-mediated genome editing, we found that the endogenous Zfp36 directly interacts with the cytoplasmic poly(A)-binding protein. Importantly, this interaction is required for the translational repression of Zfp36's target mRNAs in resolving inflammation. Altogether, these results uncovered critical roles of translational regulations in controlling appropriate gene expression during the inflammatory response and revealed a new biologically relevant molecular mechanism of translational repression via modulating the cytoplasmic poly(A)-binding protein.
在炎症反应过程中，基因表达受到精确调控，以控制感染并限制炎症的有害影响。在此，我们分析了小鼠原代巨噬细胞介导的炎症反应中的全局mRNA翻译动态，并鉴定出数百种差异翻译的mRNA。这些mRNA的3'UTR富含几种RNA结合蛋白的结合基序，这意味着存在广泛的翻译调控网络。我们将一种这样的蛋白质Zfp36鉴定为翻译抑制因子。利用通过CRISPR/Cas9介导的基因组编辑产生的Zfp36-V5表位标签敲入小鼠的原代巨噬细胞，我们发现内源性Zfp36直接与细胞质聚腺苷酸结合蛋白相互作用。重要的是，这种相互作用是Zfp36的靶mRNA在炎症消退过程中发生翻译抑制所必需的。总之，这些结果揭示了翻译调控在炎症反应过程中控制适当基因表达的关键作用，并揭示了一种通过调节细胞质聚腺苷酸结合蛋白进行翻译抑制的新的生物学相关分子机制。
