Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease

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Science  02 Dec 2016:
Vol. 354, Issue 6316, pp. 1148-1152
DOI: 10.1126/science.aah3963

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Zika virus is fit to be tied

Zika virus (ZIKV) has been associated with fetal microcephaly and Guillain-Barre syndrome. Other mosquito-born flaviviruses, such as dengue virus, encode noncoding subgenomic flavivirus RNAs (sfRNAs) in their 3′ untranslated region that accumulate during infection and cause pathology. Akiyama et al. now report that ZIKV also produces sfRNAs that resist degradation by host exonucleases in infected cells. The authors solved the structure of one of ZIKV's sfRNAs by x-ray crystallography and found that the multi-pseudoknot structure that it adopts underlies its exonuclease resistance.

Science, this issue p. 1148


The outbreak of Zika virus (ZIKV) and associated fetal microcephaly mandates efforts to understand the molecular processes of infection. Related flaviviruses produce noncoding subgenomic flaviviral RNAs (sfRNAs) that are linked to pathogenicity in fetal mice. These viruses make sfRNAs by co-opting a cellular exonuclease via structured RNAs called xrRNAs. We found that ZIKV-infected monkey and human epithelial cells, mouse neurons, and mosquito cells produce sfRNAs. The RNA structure that is responsible for ZIKV sfRNA production forms a complex fold that is likely found in many pathogenic flaviviruses. Mutations that disrupt the structure affect exonuclease resistance in vitro and sfRNA formation during infection. The complete ZIKV xrRNA structure clarifies the mechanism of exonuclease resistance and identifies features that may modulate function in diverse flaviviruses.

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