Science 354, 1148–1152 (2016)

Credit: BENJAMIN M. AKIYAMA

Recent outbreaks of Zika virus (ZIKV), associated with neuronal disorders and birth defects in humans, have focused research into ZIKV biology as a means to identify targets for therapeutic intervention. Studies in related flaviviruses (such as West Nile virus and Dengue virus) have demonstrated that degradation of viral single-stranded RNA genomes by the human exonuclease Xrn1 generates subgenomic flaviviral RNAs (sfRNAs) in infected cells. Akiyama et al. now demonstrate that sfRNAs are also generated during ZIKV infection in a process involving steric blockage of Xrn1 processing by a structured RNA motif. Northern blotting analysis of ZIKV-infected mosquito, monkey and human cell lines and in vitro Xrn1 digestion assays revealed two major sfRNA fragments that correlated in size with two predicted Xrn1-resistant RNA (xrRNA) elements in the 3′ UTR of ZIKV genomic RNA. X-ray crystallographic analysis of the upstream xrRNA1 element revealed a unique fold that includes a three-way junction, a central pseudoknot and a conserved 14-nucleotide ring motif that lassoes the 5′ terminal strand. While mutations that disrupt base pairing in the ring motif have limited effects on sfRNA production, perturbation of the pseudoknot structure enhances Xrn1 processing and reduces sfRNA abundance in infected cells. Docking studies suggest a tight association of folded xrRNA1 with Xrn1, offering a potential RNA–protein interaction that could be a target for small-molecule or vaccine development.