lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements

Role for long non-coding RNAs The RNA-binding protein Staufen1 (STAU1) promotes the degradation of double-stranded messenger RNA in the process known as Staufen-mediated decay (SMD). STAU1 binds to transcripts in the 3′ untranslated region (UTR), and although a specific stem-loop binding site had been defined for one SMD target, it was unclear how STAU1 was directed to other SMD targets that lack this structure. Chenguang Gong and Lynne Maquat report that pairing of Alu element sequences in long non-coding RNAs (lncRNAs) and in the 3′ UTR of the SMD target generates a double-stranded RNA structure that STAU1 recognizes. This result highlights a new function for lncRNAs. Staufen 1 (STAU1) protein binds regions of dsRNA in the 3′ UTR of mRNAs and promotes their degradation, a process known as SMD (Staufen-mediated mRNA decay). Although a specific stem-loop binding site had been defined for one SMD target, it was unclear how STAU1 was directed to other SMD targets that lack this structure. This paper reports that pairing of Alu element sequences in long non-coding RNAs (lncRNAs) and in the 3′ UTR of the SMD target generates a dsRNA structure that STAU1 recognizes. This result highlights a new function for lncRNAs. Staufen 1 (STAU1)-mediated messenger RNA decay (SMD) involves the degradation of translationally active mRNAs whose 3′-untranslated regions (3′ UTRs) bind to STAU1, a protein that binds to double-stranded RNA 1 , 2 . Earlier studies defined the STAU1-binding site within ADP-ribosylation factor 1 ( ARF1 ) mRNA as a 19-base-pair stem with a 100-nucleotide apex 2 . However, we were unable to identify comparable structures in the 3′ UTRs of other targets of SMD. Here we show that STAU1-binding sites can be formed by imperfect base-pairing between an Alu element in the 3′ UTR of an SMD target and another Alu element in a cytoplasmic, polyadenylated long non-coding RNA (lncRNA). An individual lncRNA can downregulate a subset of SMD targets, and distinct lncRNAs can downregulate the same SMD target. These are previously unappreciated functions of non-coding RNAs and Alu elements 3 , 4 , 5 . Not all mRNAs that contain an Alu element in the 3′ UTR are targeted for SMD even in the presence of a complementary lncRNA that targets other mRNAs for SMD. Most known trans -acting RNA effectors consist of fewer than 200 nucleotides, and these include small nucleolar RNAs and microRNAs. Our finding that the binding of STAU1 to mRNAs can be transactivated by lncRNAs un