title: Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Akiyama
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.|Howard Hughes Medical Institute (HHMI), University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.|School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Laurence
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Massey
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Costantino
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Xuping
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.affiliation: Molecular Biology Consortium, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Nix
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Beckham
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA. jeffrey.kieft@ucdenver.edu.|RNA BioScience Initiative, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Kieft
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D009033:Culicidae / Q000821:virology; D004847:Epithelial Cells / Q000821:virology; D005095:Exoribonucleases / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000821:virology; D009690:Nucleic Acid Conformation; D022661:RNA, Untranslated / Q000737:chemistry* / Q000235:genetics; D012367:RNA, Viral / Q000737:chemistry* / Q000235:genetics; D014709:Vero Cells; D000071244:Zika Virus / Q000235:genetics / Q000378:metabolism*; D000071243:Zika Virus Infection / Q000821:virology*
chemical_list: D022661:RNA, Untranslated; D012367:RNA, Viral; D005095:Exoribonucleases