STAU1 binding 3′ UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown

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.