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The Structural Basis of Pathogenic Subgenomic Flavivirus RNA (sfRNA) Production

Science  18 Apr 2014:
Vol. 344, Issue 6181, pp. 307-310
DOI: 10.1126/science.1250897

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Resisting the Chop

Dengue, West Nile, and Yellow Fever viruses are all flaviviruses that have single-stranded RNA genomes and form specific, short flaviviral RNAs (sfRNAs) during infection that cause viral pathogenicity. These sfRNAs are produced by the incomplete degradation of viral RNA by the host-cell exonuclease Xrn1. What stops the host enzyme from completely chopping up the viral RNA? Chapman et al. (p. 307) reveal a pseudoknot in the structure of the Xrn1-resistant segment of a sfRNA from Murray Valley Encephalitis Virus, which, perhaps, the host Xrn1 exonuclease cannot untangle.

Abstract

Flaviviruses are emerging human pathogens and worldwide health threats. During infection, pathogenic subgenomic flaviviral RNAs (sfRNAs) are produced by resisting degradation by the 5′→3′ host cell exonuclease Xrn1 through an unknown RNA structure-based mechanism. Here, we present the crystal structure of a complete Xrn1-resistant flaviviral RNA, which contains interwoven pseudoknots within a compact structure that depends on highly conserved nucleotides. The RNA’s three-dimensional topology creates a ringlike conformation, with the 5′ end of the resistant structure passing through the ring from one side of the fold to the other. Disruption of this structure prevents formation of sfRNA during flaviviral infection. Thus, sfRNA formation results from an RNA fold that interacts directly with Xrn1, presenting the enzyme with a structure that confounds its helicase activity.

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