A folded viral noncoding RNA blocks host cell exoribonucleases through a conformationally dynamic RNA structure

Proc Natl Acad Sci U S A. 2018 Jun 19;115(25):6404-6409. doi: 10.1073/pnas.1802429115. Epub 2018 Jun 4.


Folded RNA elements that block processive 5' → 3' cellular exoribonucleases (xrRNAs) to produce biologically active viral noncoding RNAs have been discovered in flaviviruses, potentially revealing a new mode of RNA maturation. However, whether this RNA structure-dependent mechanism exists elsewhere and, if so, whether a singular RNA fold is required, have been unclear. Here we demonstrate the existence of authentic RNA structure-dependent xrRNAs in dianthoviruses, plant-infecting viruses unrelated to animal-infecting flaviviruses. These xrRNAs have no sequence similarity to known xrRNAs; thus, we used a combination of biochemistry and virology to characterize their sequence requirements and mechanism of stopping exoribonucleases. By solving the structure of a dianthovirus xrRNA by X-ray crystallography, we reveal a complex fold that is very different from that of the flavivirus xrRNAs. However, both versions of xrRNAs contain a unique topological feature, a pseudoknot that creates a protective ring around the 5' end of the RNA structure; this may be a defining structural feature of xrRNAs. Single-molecule FRET experiments reveal that the dianthovirus xrRNAs undergo conformational changes and can use "codegradational remodeling," exploiting the exoribonucleases' degradation-linked helicase activity to help form their resistant structure; such a mechanism has not previously been reported. Convergent evolution has created RNA structure-dependent exoribonuclease resistance in different contexts, which establishes it as a general RNA maturation mechanism and defines xrRNAs as an authentic functional class of RNAs.

Keywords: RNA dynamics; RNA structure; exoribonuclease resistance; noncoding RNA maturation; single-molecule FRET.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Base Sequence
  • Exoribonucleases / metabolism*
  • Flavivirus / genetics*
  • Host-Pathogen Interactions / genetics*
  • Nucleic Acid Conformation
  • RNA Folding / genetics*
  • RNA Stability / genetics
  • RNA, Viral / genetics*


  • 3' Untranslated Regions
  • RNA, Viral
  • Exoribonucleases

Associated data

  • PDB/6D3P