BackgroundRegulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood.ResultsHere, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5′UTR of target mRNAs directly upstream of the AUG start codon.ConclusionsOur data support a model whereby purine motifs towards the 3′ end of the 5′UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

中文翻译：

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eIF4A2 在 Ccr4 启动时驱动翻译抑制，而不是通过 5'UTR 中富含嘌呤的基序


背景 mRNA 生命周期的调节对于基因表达控制和细胞命运的决定至关重要。 miRNA 代表了一种关键的 mRNA 调节机制，但尽管经过了数十年的研究，它们的作用模式仍然没有被完全了解。结果在这里，我们表明 eIF4A2 是通过 Ccr4-Not 复合物发挥作用的抑制性 miRNA 途径的主要效应器。我们证明，虽然 DDX6 与 Ccr4-Not 相互作用，但其在机制中的作用并不那么明显。通过与 Ccr4-Not 复合物的相互作用，eIF4A2 在翻译起始时抑制 mRNA。我们证明天然 eIF4A2 与化学抑制的 eIF4A1 具有相似的 RNA 选择性。 eIF4A2 通过结合富含嘌呤的基序来发挥其抑制作用，这些基序富集在 AUG 起始密码子直接上游的靶 mRNA 的 5'UTR 中。结论我们的数据支持一个模型，其中朝向 5'UTR 3' 末端的嘌呤基序相关联随着 eIF4A2 结合增加核糖体占用率和可能的 uORF 激活。