The mammalian orthologue of ecdysoneless (ECD) protein is required for embryogenesis, cell cycle progression, and mitigation of endoplasmic reticulum 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 an 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 publicly available BC mRNA The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data sets. In both data sets, ECD mRNA overexpression correlated with short patient survival, specifically ErbB2+ BC. In the METABRIC data set, ECD overexpression also correlated with poor patient survival in triple-negative breast cancer (TNBC). Furthermore, 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 novel mechanistic insight into the physiological and pathological functions of ECD.

中文翻译：

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哺乳动物 Ecdysoneless 蛋白与 RNA 解旋酶 DDX39A 相互作用以调节核 mRNA 输出。

无蜕皮激素 (ECD) 蛋白的哺乳动物直向同源物是胚胎发生、细胞周期进程和缓解内质网应激所必需的。在这里，我们确定了 mRNA 输出复合物的关键成分作为 ECD 的结合伙伴，并表征了 ECD 与关键 mRNA 输出相关的 DEAD BOX 蛋白解旋酶 DDX39A 的功能相互作用。我们发现 ECD 通过与 DDX39A 的相互作用参与 RNA 输出。ECD 敲低 (KD) 会阻止 mRNA 从细胞核输出到细胞质，后者通过表达全长 ECD 而不是与 DDX39A 相互作用有缺陷的 ECD 突变体来拯救。我们之前已经表明 ECD 蛋白在 ErbB2+ 乳腺癌 (BC) 中过度表达。在这项研究中，我们将分析扩展到两个公开可用的 BC mRNA 癌症基因组图谱 (TCGA) 和乳腺癌国际联盟的分子分类 (METABRIC) 数据集。在这两个数据集中，ECD mRNA 过度表达与患者生存期短相关，特别是 ErbB2+ BC。在 METABRIC 数据集中，ECD 过度表达还与三阴性乳腺癌 (TNBC) 患者的不良生存率相关。此外，ErbB2+ BC 细胞中的 ECD KD 由于其核输出受阻导致 ErbB2 mRNA 水平降低，并且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新的机制见解。在 METABRIC 数据集中，ECD 过度表达还与三阴性乳腺癌 (TNBC) 患者的不良生存率相关。此外，ErbB2+ BC 细胞中的 ECD KD 由于其核输出受阻导致 ErbB2 mRNA 水平降低，并且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新的机制见解。在 METABRIC 数据集中，ECD 过度表达还与三阴性乳腺癌 (TNBC) 患者的不良生存率相关。此外，ErbB2+ BC 细胞中的 ECD KD 由于其核输出受阻导致 ErbB2 mRNA 水平降低，并且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新的机制见解。