Insights into the assembly and architecture of a Staufen-mediated mRNA decay (SMD)-competent mRNP

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.

The PABPC5/HCG15/ZNF331 Feedback Loop Regulates Vasculogenic Mimicry of Glioma via STAU1-Mediated mRNA Decay

“…STAU (Staufen) is a key mRNA transport and localization factor in Drosophila. Combination of the Stau paralog Stau1 in mammals with the 3 0 UTR region of intermolecular and intramolecular double-stranded structures triggers degradation of target mRNA; 25 this degradation process is called Staufen-mediated mRNA decay (SMD). SMD is a STAU1 mediated mRNA degradation pathway, which STAU1 combines with STAU1 binding site (SBS) formed when the Alu element of lncRNAs recognizes and pairs with the Alu element of target mRNA 3'UTR during translation, and then recruits the ATP-dependent RNA helicase up-frameshift 1 (UPF1) to bind and promote the degradation of target mRNA.…”

More than causing (epi)genomic instability: emerging physiological implications of transposable element modulation

“…One type of TE-containing lncRNA is involved in mRNA degradation, specifically through the Staufen-mediated mRNA decay (SMD) mechanism [ 120 , 121 ]. STAU (Staufen protein) binds to double-stranded RNA that is formed by imperfect base pairing between an Alu element in the 3’UTR of the target mRNA and another Alu element within a lncRNA (named half-STAU1-binding site RNA, ½-sbsRNA ) to elicit the SMD mechanism by recruiting up-frameshift suppressor 1 (UPF1) and UPF2, the core factors in the mRNA degradation pathway.…”

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

“…Instead, UPF2 binds to a STAU1 dimer, recruits UPF1 to the STAU1 mRNP, and activates UPF1′s catalytic functions by binding to the CH domain, thus releasing the helicase and ATPase domains. Furthermore, SMD is suppressed in vivo upon depletion of UPF2 [ 185 ]. These findings may also help to better understand why NMD and SMD compete with each other in cells [ 184 ].…”

“…STAU1 contacts the MIF4G domain of UPF2 which is also where UPF3 binds to UPF2. However, the binding sites are probably not identical, simultaneous binding of STAU1 and UPF3 may be impossible, thus offering an alternative explanation for the competition of SMD and NMD [ 185 ].…”