title: New hypotheses derived from the structure of a flaviviral Xrn1-resistant RNA: Conservation, folding, and host adaptation.
abstract: 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.
authors.affiliation: a Department of Biochemistry and Molecular Genetics.|b Howard Hughes Medical Institute; University of Colorado Denver; School of Medicine ; Aurora , CO USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kieft
authors.affiliation: c Department of Pediatrics ; University of Colorado Denver; School of Medicine ; Aurora , CO USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rabe
authors.affiliation: a Department of Biochemistry and Molecular Genetics.
authors.forename: Erich G
authors.initials: EG
authors.lastname: Chapman
mesh_terms: D020413:3' Untranslated Regions; D000220:Adaptation, Biological; D001483:Base Sequence; D019143:Evolution, Molecular; D005095:Exoribonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005416:Flavivirus / Q000235:genetics*; D016679:Genome, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D059370:RNA Folding; D020871:RNA Stability; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D020413:3' Untranslated Regions; D012367:RNA, Viral; D005095:Exoribonucleases
keywords: RNA folding; RNA structure; Xrn1 resistance; flaviviral RNA; sfRNA