Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Elife. 2017 Oct 9;6:e29630. doi: 10.7554/eLife.29630.
Expression of inflammatory genes is determined in part by post-transcriptional regulation of mRNA metabolism but how stimulus- and transcript-dependent nuclear export influence is poorly understood. Here, we report a novel pathway in which LPS/TLR4 engagement promotes nuclear localization of IRAK2 to facilitate nuclear export of a specific subset of inflammation-related mRNAs for translation in murine macrophages. IRAK2 kinase activity is required for LPS-induced RanBP2-mediated IRAK2 sumoylation and subsequent nuclear translocation. Array analysis showed that an SRSF1-binding motif is enriched in mRNAs dependent on IRAK2 for nuclear export. Nuclear IRAK2 phosphorylates SRSF1 to reduce its binding to target mRNAs, which promotes the RNA binding of the nuclear export adaptor ALYREF and nuclear export receptor Nxf1 loading for the export of the mRNAs. In summary, LPS activates a nuclear function of IRAK2 that facilitates the assembly of nuclear export machinery to export selected inflammatory mRNAs to the cytoplasm for translation.
炎症基因的表达部分取决于 mRNA 代谢的转录后调控，但刺激和转录依赖性核输出的影响还知之甚少。在这里，我们报告了一个新的途径，即 LPS/TLR4 结合促进 IRAK2 的核定位，以促进特定炎症相关 mRNA 子集的核输出，用于翻译在小鼠巨噬细胞中。IRAK2 激酶活性是 LPS 诱导的 RanBP2 介导的 IRAK2 泛素化和随后核转位所必需的。基因芯片分析表明，在依赖 IRAK2 进行核输出的 mRNAs 中富含 SRSF1 结合基序。核 IRAK2 磷酸化 SRSF1 以减少其与靶 mRNAs 的结合，从而促进核输出衔接子 ALYREF 和核输出受体 Nxf1 装载的 RNA 结合，以促进 mRNAs 的输出。总之，LPS 激活了 IRAK2 的核功能，有助于组装核输出机制，将选定的炎症 mRNAs 输出到细胞质中进行翻译。
