STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown
STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown
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DOI：
10.1101/gad.220962.113
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发表时间：
2013-07-01
影响因子：
10.5
通讯作者：
Maquat, Lynne E.
中科院分区：
文献类型：
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作者：
Elbarbary, Reyad A.;Li, Wencheng;Maquat, Lynne E.
对于编码在 3' 非翻译区 (UTR) 内含有反向重复 Alu 元件 (IRAlus) 的转录本的许多人类基因，当介导核保留的 IRAlus 通过选择性多聚腺苷酸化去除时，产物 mRNA 会有效地输出到细胞质。在这里，我们报告了一种通过靶向维持其3'UTR IRAlus的mRNA来促进基因表达的新机制：dsRNA结合蛋白Staufen1（STAU1）与3'UTR IRAlus的结合抑制核保留，从而增强含有3'UTR IRAlus的mRNA（IRAlus mRNA）的核输出。此外，我们发现 3'UTR IRAlus 结合的 STAU1 通过阻止蛋白激酶 R (PKR) 结合来增强 3'UTR IRAlus mRNA 翻译，从而避免 PKR 激活、真核翻译起始因子 2 α (eIF2 α) 磷酸化和全局细胞翻译的抑制。因此，STAU1 与 3'UTR IRAlus 的结合与 3'UTR IRAlus 介导的核滞留一起发挥作用，抑制 PKR 与内源性细胞质 dsRNA 结合所触发的细胞翻译的关闭。我们还表明，变化的 STAU1/PKR 比率通过影响编码 microRNA 结合蛋白 LIN28 的 mRNA 的 3' UTR IRAlus 来促进肌生成。
For a number of human genes that encode transcripts containing inverted repeat Alu elements (IRAlus) within their 3' untranslated region (UTR), product mRNA is efficiently exported to the cytoplasm when the IRAlus, which mediate nuclear retention, are removed by alternative polyadenylation. Here we report a new mechanism that promotes gene expression by targeting mRNAs that maintain their 3' UTR IRAlus: Binding of the dsRNA-binding protein Staufen1 (STAU1) to 3' UTR IRAlus inhibits nuclear retention so as to augment the nuclear export of 3' UTR IRAlus-containing mRNAs (IRAlus mRNAs). Moreover, we found that 3' UTR IRAlus-bound STAU1 enhances 3' UTR IRAlus mRNA translation by precluding protein kinase R (PKR) binding, which obviates PKR activation, eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation, and repression of global cell translation. Thus, STAU1 binding to 3' UTR IRAlus functions along with 3' UTR IRAlus-mediated nuclear retention to suppress the shutdown of cellular translation triggered by PKR binding to endogenous cytoplasmic dsRNAs. We also show that a changing STAU1/PKR ratio contributes to myogenesis via effects on the 3' UTR IRAlus of mRNA encoding the microRNA-binding protein LIN28.