Article

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

Department of Biochemistry and Biophysics, School of Medicine and Dentistry.
Genes & development (Impact Factor: 10.8). 07/2013; 27(13):1495-510. DOI: 10.1101/gad.220962.113
Source: PubMed

ABSTRACT

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.

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    • "Thus, 3'UTR shortening can help genes evade the TE/piRNA/ Miwi-based mRNA elimination during spermatogenesis. Previous studies have shown that TEs in 3'UTRs can play regulatory roles for mRNA metabolism626364and some TEs can confer functional pAs to the host gene[65]. APA regulation in spermatogenesis can thus effectively permit evolution of TEs in 3'UTRs without inhibiting the expression of host genes, contributing to exaptation ofWe found that 3'UTR shortening is coupled with upregulation of gene transcription and open state of chromatin , as indicated by RNAPII and H3K4me3 levels, respectively. "
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    • "Furthermore, although our data support the view that the reduced binding capability of methylated p54 nrb to dsRNAs could result from a direct conformational change of p54 nrb methylation at the coiled-coil domain, we cannot exclude the possibility that these methyl sites may recruit other effector proteins to facilitate the release of mRNA-IRAlus from methylated p54 nrb (Yang et al. 2014). Finally, the dsRNA-binding protein STAU1 (Wickham et al. 1999) was recently shown to compete with p54 nrb for the binding of 3 ′ UTR IRAlus, independent of editing (Elbarbary et al. 2013). It will be of interest to examine whether the binding of 3 ′ UTR IRAlus with STAU1 occurs after the release of mRNAs containing IRAlus from methylated p54 nrb . "
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