Staufen2, like Staufen1, functions in SMD by binding to itself and its paralog and promoting UPF1 helicase but not ATPase activity
Department of Biochemistry and Biophysics, School of Medicine and Dentistry, and Center for RNA Biology, University of Rochester, Rochester, NY 14642. Proceedings of the National Academy of Sciences
(Impact Factor: 9.67).
12/2012; 110(2). DOI: 10.1073/pnas.1213508110
Staufen (STAU)1-mediated mRNA decay (SMD) is a posttranscriptional regulatory mechanism in mammals that degrades mRNAs harboring a STAU1-binding site (SBS) in their 3'-untranslated regions (3' UTRs). We show that SMD involves not only STAU1 but also its paralog STAU2. STAU2, like STAU1, is a double-stranded RNA-binding protein that interacts directly with the ATP-dependent RNA helicase up-frameshift 1 (UPF1) to reduce the half-life of SMD targets that form an SBS by either intramolecular or intermolecular base-pairing. Compared with STAU1, STAU2 binds ∼10-fold more UPF1 and ∼two- to fivefold more of those SBS-containing mRNAs that were tested, and it comparably promotes UPF1 helicase activity, which is critical for SMD. STAU1- or STAU2-mediated augmentation of UPF1 helicase activity is not accompanied by enhanced ATP hydrolysis but does depend on ATP binding and a basal level of UPF1 ATPase activity. Studies of STAU2 demonstrate it changes the conformation of RNA-bound UPF1. These findings, and evidence for STAU1-STAU1, STAU2-STAU2, and STAU1-STAU2 formation in vitro and in cells, are consistent with results from tethering assays: the decrease in mRNA abundance brought about by tethering siRNA-resistant STAU2 or STAU1 to an mRNA 3' UTR is inhibited by downregulating the abundance of cellular STAU2, STAU1, or UPF1. It follows that the efficiency of SMD in different cell types reflects the cumulative abundance of STAU1 and STAU2. We propose that STAU paralogs contribute to SMD by "greasing the wheels" of RNA-bound UPF1 so as to enhance its unwinding capacity per molecule of ATP hydrolyzed.
Available from: Osamu Takeuchi
- "Whereas all three UPF members are required for NMD, UPF2 and UPF3x are also dispensable for SMD and replication-dependent histone mRNA decay (Kaygun and Marzluff, 2005; Kim et al., 2005). Nevertheless, Staufen 1 and 2 are sensors for recognizing dsRNA sequences (Park et al., 2013), but do not have RNase activity. "
[Show abstract] [Hide abstract]
ABSTRACT: Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.
Copyright © 2015 Elsevier Inc. All rights reserved.
Available from: Wildriss Viranaicken
- "All these functions were mapped to regions located outside the N-terminus of Stau1. Nevertheless, although Stau1 dimerization was shown to mainly involve dsRBD3 and dsRBD5 (55,56), a weak contribution of dsRBD2 was also reported (55). In addition, the N-terminus of Stau1 was shown to promote Pr55Gag–Pr55Gag interaction in the course of HIV-1 assembly (41). "
[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.
Available from: Chul Geun Kim
- "SMD is a representative post-transcriptional regulation mechanism sharing many similarities with nonsense-mediated mRNA decay (NMD), including a common factor, upframeshift factor 1 (UPF1) [(22) for review]. Briefly, STAU and UPF1 bind to the SBS, at which UPF1 helicase activity but not ATPase activity is necessary (23). Mammalian STAU has two paralogs, STAU1 and STAU2, both of which bind UPF1 with different binding activities and form homodimers and heterodimers with each other before ultimately mediating SMD (23). "
[Show abstract] [Hide abstract]
ABSTRACT: Requiem (REQ/DPF2) was originally identified as an apoptosis-inducing protein in mouse myeloid cells and belongs to the novel
Krüppel-type zinc finger d4-protein family of proteins, which includes neuro-d4 (DPF1) and cer-d4 (DPF3). Interestingly, when
a portion of the REQ messenger ribonucleic acid (mRNA) 3′ untranslated region (3′UTR), referred to as G8, was overexpressed
in K562 cells, β-globin expression was induced, suggesting that the 3′UTR of REQ mRNA plays a physiological role. Here, we
present evidence that the REQ mRNA 3′UTR, along with its trans-acting factor, Staufen1 (STAU1), is able to reduce the level of REQ mRNA via STAU1-mediated mRNA decay (SMD). By screening
a complementary deoxyribonucleic acid (cDNA) expression library with an RNA–ligand binding assay, we identified STAU1 as an
interactor of the REQ mRNA 3′UTR. Specifically, we provide evidence that STAU1 binds to putative 30-nucleotide stem–loop-structured
RNA sequences within the G8 region, which we term the protein binding site core; this binding triggers the degradation of
REQ mRNA and thus regulates translation. Furthermore, we demonstrate that siRNA-mediated silencing of either STAU1 or UPF1
increases the abundance of cellular REQ mRNA and, consequently, the REQ protein, indicating that REQ mRNA is a target of SMD.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.