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
Source: PubMed


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.

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    • "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. "
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    • "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). "
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    • "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). "
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