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The mammalian ecdysoneless protein interacts with RNA helicase DDX39A to regulate nuclear mRNA export
Molecular and Cellular Biology ( IF 3.2 ) Pub Date : 2021-05-03
Saleem, I., Mirza, S., Sarkar, A., Raza, M., Mohapatra, B., Mushtaq, I., Kim, J. H., Mishra, N. K., Alsaleem, M. A., Rakha, E. A., Qiu, F., Guda, C., Band, H., Band, V.

The mammalian orthologue of Ecdysoneless (ECD) protein is required for embryogenesis, cell cycle progression, and mitigation of ER stress. Here, we identified key components of the mRNA export complexes as binding partners of ECD and characterized the functional interaction of ECD with key mRNA export-related DEAD BOX protein helicase DDX39A. We find that ECD is involved in RNA export through its interaction with DDX39A. ECD knockdown (KD) blocks mRNA export from the nucleus to the cytoplasm, which is rescued by expression of full length ECD but not ECD mutant that is defective in interaction with DDX39A. We have previously shown that ECD protein is overexpressed in ErbB2+ breast cancers (BC). In this study, we extended the analyses to two publically available BC mRNA TCGA and METABRIC data sets. In both dataset, ECD mRNA overexpression correlated with short patient survival, specifically ErbB2+ BC. In METABRIC dataset ECD overexpression also correlated with poor patient survival in TNBC . Further, ECD KD in ErbB2+BC cells led to a decrease in ErbB2 mRNA level due to a block in its nuclear export, and was associated with impairment of oncogenic traits. These findings provide a novel mechanistic insight into physiological and pathological function of ECD.



中文翻译:

哺乳动物蜕皮激素无蛋白与RNA解旋酶DDX39A相互作用以调节核mRNA的输出

哺乳动物的Ecdysoneless(ECD)直系同源物是胚胎发生,细胞周期进程和缓解ER应激所必需的。在这里,我们确定了mRNA出口复合物的关键成分作为ECD的结合伴侣,并表征了ECD与mRNA出口相关的DEAD BOX蛋白解旋酶DDX39A的功能相互作用。我们发现ECD通过与DDX39A的相互作用而参与RNA的输出。ECD敲低(KD)阻止了mRNA从细胞核到细胞质的输出,这可以通过表达全长ECD来挽救,但不能通过与DDX39A相互作用而受损的ECD突变体来挽救。先前我们已经证明ECD蛋白在ErbB2 +乳腺癌(BC)中过表达。在这项研究中,我们将分析扩展到两个公开可用的BC mRNA TCGA和METABRIC数据集。在两个数据集中,ECD mRNA的过表达与患者的短期生存有关,特别是与ErbB2 + BC有关。在METABRIC数据集中,ECD的过表达也与TNBC患者的生存不良有关。此外,由于其核输出受阻,ErbB2 + BC细胞中的ECD KD导致ErbB2 mRNA水平降低,并与致癌性状受损有关。这些发现为ECD的生理和病理功能提供了一种新颖的机制性见解。

更新日期:2021-05-04
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