New hypotheses derived from the structure of a flaviviral Xrn1-resistant RNA: Conservation, folding, and host adaptation

RNA Biol. 2015;12(11):1169-77. doi: 10.1080/15476286.2015.1094599. Epub 2015 Sep 23.


Arthropod-borne flaviviruses (FVs) are a growing world-wide health threat whose incidence and range are increasing. The pathogenicity and cytopathicity of these single-stranded RNA viruses are influenced by viral subgenomic non-protein-coding RNAs (sfRNAs) that the viruses produce to high levels during infection. To generate sfRNAs the virus co-opts the action of the abundant cellular exonuclease Xrn1, which is part of the cell's normal RNA turnover machinery. This exploitation of the cellular machinery is enabled by discrete, highly structured, Xrn1-resistant RNA elements (xrRNAs) in the 3'UTR that interact with Xrn1 to halt processive 5' to 3' decay of the viral genomic RNA. We recently solved the crystal structure of a functional xrRNA, revealing a novel fold that provides a mechanistic model for Xrn1 resistance. Continued analysis and interpretation of the structure reveals that the tertiary contacts that knit the xrRNA fold together are shared by a wide variety of arthropod-borne FVs, conferring robust Xrn1 resistance in all tested. However, there is some variability in the structures that correlates with unexplained patterns in the viral 3' UTRs. Finally, examination of these structures and their behavior in the context of viral infection leads to a new hypothesis linking RNA tertiary structure, overall 3' UTR architecture, sfRNA production, and host adaptation.

Keywords: RNA folding; RNA structure; Xrn1 resistance; flaviviral RNA; sfRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • 3' Untranslated Regions
  • Adaptation, Biological
  • Base Sequence
  • Evolution, Molecular
  • Exoribonucleases / chemistry
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism*
  • Flavivirus / genetics*
  • Genome, Viral
  • Host-Pathogen Interactions* / genetics
  • Models, Biological
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • RNA Folding
  • RNA Stability
  • RNA, Viral / chemistry*
  • RNA, Viral / genetics*
  • Sequence Alignment


  • 3' Untranslated Regions
  • RNA, Viral
  • Exoribonucleases