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.
"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 . "
"Changes in the miRNA profile induced by WNV were rather consistent between cell types and the WNV miRNA signature was not significantly affected by the presence or absence of TLR3. These data further suggest that the majority of WNV-regulated miRNAs at early times post-infection (8 hrs) are not TLR3-dependent, but may depend on signaling through other PRRs such as RIG-I and MDA5 and/or other sensors like PKR (RIG-I, MDA5 and PKR are fully functional in HEK293 cells) , , , , , , , , . "
[Show abstract][Hide abstract] ABSTRACT: The innate immune response to West Nile virus (WNV) infection involves recognition through toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), leading to establishment of an antiviral state. MiRNAs (miRNAs) have been shown to be reliable biomarkers of TLR activation. Here, we sought to evaluate the contribution of TLR3 and miRNAs to the host response to WNV infection. We first analyzed HEK293-NULL and HEK293-TLR3 cells for changes in the innate immune response to infection. The presence of TLR3 did not seem to affect WNV load, infectivity or phosphorylation of IRF3. Analysis of experimentally validated NFκB-responsive genes revealed a WNV-induced signature largely independent of TLR3. Since miRNAs are involved in viral pathogenesis and the innate response to infection, we sought to identify changes in miRNA expression upon infection in the presence or absence of TLR3. MiRNA profiling revealed 70 miRNAs induced following WNV infection in a TLR3-independent manner. Further analysis of predicted gene targets of WNV signature miRNAs revealed genes highly associated with pathways regulating cell death, viral pathogenesis and immune cell trafficking.
PLoS ONE 08/2014; 9(8):e104770. DOI:10.1371/journal.pone.0104770 · 3.23 Impact Factor
"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. "
[Show abstract][Hide abstract] 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.
Nucleic Acids Research 06/2014; 42(12). DOI:10.1093/nar/gku506 · 9.11 Impact Factor
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