URH49 exports mRNA by remodeling complex formation and mediating the NXF1-dependent pathway
URH49 exports mRNA by remodeling complex formation and mediating the NXF1-dependent pathway
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DOI：
10.1016/j.bbagrm.2020.194480
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发表时间：
2020-02-01
影响因子：
4.7
通讯作者：
Masuda, Seiji
中科院分区：
文献类型：
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作者：
Fujita, Ken-ichi;Yamazaki, Tomohiro;Masuda, Seiji
TREX复合物整合来自核mRNA加工事件的信息，以确保mRNA及时输出到细胞质。在人类中，UAP 56及其parasitic URH 49分别形成不同的复合物，TREX复合物和AREX复合物，其在全基因组范围内协同调节特定一组mRNA种类的表达。UAP 56和URH 49之间复合物形成的差异被认为在靶mRNA的调节中起关键作用。到目前为止，对潜在的机制仍然知之甚少。在这里，我们描述了TREX复合物和AREX复合物的形成。在ATP耗尽的条件下，UAP 56形成含有THO亚复合物但不含APOREF和CIP 29的Apo-TREX复合物。URH 49形成含有CIP 29但不含CIPREF和THO亚复合物的Apo-AREX复合物。然而，随着ATP的加入，Apo-TREX复合物和Apo-AREX复合物都被重塑为含有THO亚复合物、APOREF和CIP 29的高度相似的ATP-TREX复合物。URH 49的敲低导致其靶mRNA的减少和胞质分裂失败。类似地，在CIP 29敲低细胞中观察到胞质分裂异常，表明CIP 29属于URH 49调节的mRNA输出途径。最后，我们证实了URH 49依赖性途径中mRNA的输出是通过NXF 1实现的，这也在UAP 56依赖性途径中观察到。我们的研究提出了一种mRNA输出模型，即mRNA选择性依赖于Apo形式的TREX/AREX复合物，该复合物在ATP负载后被重塑为高度相似的ATP形式复合物，并整合到NXF 1中。
The TREX complex integrates information from nuclear mRNA processing events to ensure the timely export of mRNA to the cytoplasm. In humans, UAP56 and its paralog URH49 form distinct complexes, the TREX complex and the AREX complex, respectively, which cooperatively regulate the expression of a specific set of mRNA species on a genome wide scale. The difference in the complex formation between UAP56 and URH49 are thought to play a critical role in the regulation of target mRNAs. To date, the underlying mechanism remains poorly understood. Here we characterize the formation of the TREX complex and the AREX complex. In the ATP depleted condition, UAP56 formed an Apo-TREX complex containing the THO subcomplex but not ALYREF and CIP29. URH49 formed an Apo-AREX complex containing CIP29 but not ALYREF and the THO subcomplex. However, with the addition of ATP, both the Apo-TREX complex and the Apo-AREX complex were remodeled to highly similar ATP-TREX complex containing the THO subcomplex, ALYREF and CIP29. The knockdown of URH49 caused a reduction in its target mRNAs and a cytokinesis failure. Similarly, cytokinesis abnormality was observed in CIP29 knockdown cells, suggesting that CIP29 belongs to the URH49 regulated mRNA export pathway. Lastly, we confirmed that the export of mRNA in URH49-dependent pathway is achieved by NXF1, which is also observed in UAP56-dependent pathway. Our studies propose an mRNA export model that the mRNA selectivity depends on the Apo-form TREX/AREX complex, which is remodeled to the highly similar ATPform complex upon ATP loading, and integrated to NXF1.