The exon junction complex (EJC) is an essential constituent and regulator of spliced messenger ribonucleoprotein particles (mRNPs) in metazoans. As a core component of the EJC, CASC3 was described to be pivotal for EJC-dependent nuclear and cytoplasmic processes. However, recent evidence suggests that CASC3 functions differently from other EJC core proteins. Here, we have established human CASC3 knockout cell lines to elucidate the cellular role of CASC3. In the knockout cells, overall EJC composition and EJC-dependent splicing are unchanged. A transcriptome-wide analysis reveals that hundreds of mRNA isoforms targeted by nonsense-mediated decay (NMD) are upregulated. Mechanistically, recruiting CASC3 to reporter mRNAs by direct tethering or via binding to the EJC stimulates mRNA decay and endonucleolytic cleavage at the termination codon. Building on existing EJC-NMD models, we propose that CASC3 equips the EJC with the persisting ability to communicate with the NMD machinery in the cytoplasm. Collectively, our results characterize CASC3 as a peripheral EJC protein that tailors the transcriptome by promoting the degradation of EJC-dependent NMD substrates.

中文翻译：

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CASC3促进外显子连接复合物在转录组范围内激活无意义介导的衰变。

外显子连接复合体（EJC）是后生动物中剪接的信使核糖核蛋白颗粒（mRNPs）的重要组成部分和调节剂。作为EJC的核心组件，CASC3被描述为依赖EJC的核和细胞质过程的关键。但是，最近的证据表明，CASC3的功能不同于其他EJC核心蛋白。在这里，我们建立了人类CASC3敲除细胞系，以阐明CASC3的细胞作用。在敲除单元中，总体EJC组成和EJC依赖的剪接均未改变。转录组范围的分析显示，无义介导的衰变（NMD）靶向的数百个mRNA亚型被上调。从机理上讲，通过直接束缚或通过与EJC结合将CASC3募集到报告mRNA上可刺激mRNA衰减和终止密码子处的核酸内切酶。我们建议在现有EJC-NMD模型的基础上，CASC3使EJC具有与细胞质中NMD机制进行通讯的持久能力。总的来说，我们的结果将CASC3表征为一种外周EJC蛋白，该蛋白通过促进EJC依赖性NMD底物的降解来定制转录组。