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


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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    • "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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    ABSTRACT: In many cells, mRNAs containing inverted repeated Alu elements (IRAlus) in their 3' untranslated regions (UTRs) are inefficiently exported to the cytoplasm. Such nuclear retention correlates with paraspeckle-associated protein complexes containing p54(nrb). However, nuclear retention of mRNAs containing IRAlus is variable, and how regulation of retention and export is achieved is poorly understood. Here we show one mechanism of such regulation via the arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1). We demonstrate that disruption of CARM1 enhances the nuclear retention of mRNAs containing IRAlus. CARM1 regulates this nuclear retention pathway at two levels: CARM1 methylates the coiled-coil domain of p54(nrb), resulting in reduced binding of p54(nrb) to mRNAs containing IRAlus, and also acts as a transcription regulator to suppress NEAT1 transcription, leading to reduced paraspeckle formation. These actions of CARM1 work together synergistically to regulate the export of transcripts containing IRAlus from paraspeckles under certain cellular stresses, such as poly(I:C) treatment. This work demonstrates how a post-translational modification of an RNA-binding protein affects protein-RNA interaction and also uncovers a mechanism of transcriptional regulation of the long noncoding RNA NEAT1. © 2015 Hu et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 03/2015; 29(6):630-45. DOI:10.1101/gad.257048.114 · 10.80 Impact Factor
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    PLoS ONE 08/2014; 9(8):e104770. DOI:10.1371/journal.pone.0104770 · 3.23 Impact Factor
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    • "Stau1 is a double-stranded RNA-binding protein that is ubiquitously expressed and alternative splicing of its mRNA generates protein isoforms of 55 kDa (Stau155) and 63 kDa (Stau163) (7,8). Stau1 is involved in several post-transcriptional mechanisms that control gene expression including mRNA transport (4,5,9), translation (3,10,11), decay (6,12), nuclear export (13,14) and splicing (14). All these functions are likely very important for cell physiology as compelling data indicate that Stau1 is involved in cell differentiation (12,15–20), dendritic spine morphogenesis (9,21) and long-term synaptic plasticity (21), a cellular mechanism for long term memory. "
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    ABSTRACT: Staufen1 (Stau1) is a ribonucleic acid (RNA)-binding protein involved in the post-transcriptional regulation of gene expression. Recent studies indicate that Stau1-bound messenger RNAs (mRNAs) mainly code for proteins involved in transcription and cell cycle control. Consistently, we report here that Stau1 abundance fluctuates through the cell cycle in HCT116 and U2OS cells: it is high from the S phase to the onset of mitosis and rapidly decreases as cells transit through mitosis. Stau1 down-regulation is mediated by the ubiquitin-proteasome system and the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). Stau1 interacts with the APC/C co-activators Cdh1 and Cdc20 via its first 88 N-terminal amino acids. The importance of controlling Stau155 levels is underscored by the observation that its overexpression affects mitosis entry and impairs proliferation of transformed cells. Microarray analyses identified 275 Stau155-bound mRNAs in prometaphase cells, an early mitotic step that just precedes Stau1 degradation. Interestingly, several of these mRNAs are more abundant in Stau155-containing complexes in cells arrested in prometaphase than in asynchronous cells. Our results point out for the first time to the possibility that Stau1 participates in a mechanism of post-transcriptional regulation of gene expression that is linked to cell cycle progression in cancer cells.
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