Abstract
The mammalian Staufen proteins (Stau1 and Stau2) mediate degradation of mRNA containing complex secondary structures in their 3’-untranslated region (UTR) through a pathway known as Staufen-mediated mRNA decay (SMD). This pathway also involves the RNA helicase UPF1, which is best known for its role in the nonsense-mediated mRNA decay (NMD) pathway. Here we present a biochemical reconstitution of the recruitment and activation of UPF1 in context of the SMD pathway. We demonstrate the involvement of UPF2, a core NMD factor and a known activator of UPF1, in SMD. UPF2 acts as an adaptor between Stau1 and UPF1, stimulates the catalytic activity of UPF1 and plays a central role in the formation of an SMD-competent mRNP. Our study elucidates the molecular mechanisms of SMD and points towards extensive cross-talk between UPF1-mediated mRNA decay pathways in cells.
Highlights
The mammalian Staufen proteins (Stau[1] and Stau2) mediate degradation of messenger RNA (mRNA) containing complex secondary structures in their 3’-untranslated region (UTR) through a pathway known as Staufen-mediated mRNA decay (SMD)
We deduce that the interaction between Stau[1] and up-frameshift 1 (UPF1) is not strong enough to elicit the large conformational change in UPF1 that is necessary for stimulation of its catalytic activity[17]
This includes the Ski[2] and Mtr[4] helicases that are associated with the cytoplasmic and nuclear exosomes, Dhh[1] (DDX6/RCK in humans) that mediates mRNA decapping, and a number of helicases such as DHX34, MOV10, and UPF1 that are involved in the nonsense-mediated mRNA decay (NMD) pathway[39,40,41,42]
Summary
The mammalian Staufen proteins (Stau[1] and Stau2) mediate degradation of mRNA containing complex secondary structures in their 3’-untranslated region (UTR) through a pathway known as Staufen-mediated mRNA decay (SMD). While Staufen is known to be a key mRNA transport and localization factor in Drosophila[6,7], binding of the mammalian Staufen paralogs, Stau[1] and Stau[2], to inter- and intra-molecular RNA duplexes within the 3′-UTR triggers degradation of the target mRNA8,9. This degradation process, referred to as Staufen-mediated mRNA decay (SMD), relies on efficient translation, and recruitment of the RNA helicase up-frameshift 1 (UPF1) to the Staufen-binding sites (SBS) of the target mRNA10,11
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