Department of Biochemistry and Biophysics, School of Medicine and Dentistry.
Genes Dev. 2013 Jul 1;27(13):1495-510. doi: 10.1101/gad.220962.113.
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 2α (eIF2α) 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.
对于一些人类基因，其编码的转录本在 3'非翻译区（UTR）中含有反向重复 Alu 元件（IRAlus），当通过选择性多聚腺苷酸化去除介导核保留的 IRAlus 时，产物 mRNA 会有效地被输出到细胞质中。在这里，我们报告了一种新的机制，通过靶向保留其 3'UTRIRAlus 的 mRNA 来促进基因表达：双链 RNA 结合蛋白 Staufen1（STAU1）与 3'UTRIRAlus 的结合抑制核保留，从而增强含有 3'UTRIRAlus 的 mRNAs（IRAlus mRNAs）的核输出。此外，我们发现，与 3'UTRIRAlus 结合的 STAU1 通过排除蛋白激酶 R（PKR）结合来增强 3'UTRIRAlus mRNA 的翻译，从而避免 PKR 激活、真核翻译起始因子 2α（eIF2α）磷酸化以及全局细胞翻译的抑制。因此，STAU1 与 3'UTRIRAlus 的结合与 3'UTRIRAlus 介导的核保留一起，抑制了 PKR 与内源性细胞质 dsRNA 结合引发的细胞翻译关闭。我们还表明，STAU1/PKR 比值的变化通过影响编码 microRNA 结合蛋白 LIN28 的 mRNA 的 3'UTRIRAlus 对成肌作用产生影响。
