title: A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability.
abstract: All arthropod-borne flaviviruses generate a short noncoding RNA (sfRNA) from the viral 3' untranslated region during infection due to stalling of the cellular 5'-to-3' exonuclease XRN1. We show here that formation of sfRNA also inhibits XRN1 activity. Cells infected with Dengue or Kunjin viruses accumulate uncapped mRNAs, decay intermediates normally targeted by XRN1. XRN1 repression also resulted in the increased overall stability of cellular mRNAs in flavivirus-infected cells. Importantly, a mutant Kunjin virus that cannot form sfRNA but replicates to normal levels failed to affect host mRNA stability or XRN1 activity. Expression of sfRNA in the absence of viral infection demonstrated that sfRNA formation was directly responsible for the stabilization of cellular mRNAs. Finally, numerous cellular mRNAs were differentially expressed in an sfRNA-dependent fashion in a Kunjin virus infection. We conclude that flaviviruses incapacitate XRN1 during infection and dysregulate host mRNA stability as a result of sfRNA formation.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Moon
authors.forename: John R
authors.initials: JR
authors.lastname: Anderson
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Wilusz
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Khromykh
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wilusz
mesh_terms: D020413:3' Untranslated Regions; D000330:Aedes / Q000166:cytology / Q000821:virology*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003716:Dengue Virus / Q000235:genetics* / Q000502:physiology; D005095:Exoribonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D006207:Half-Life; D054884:Host-Pathogen Interactions; D006801:Humans; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism; D022661:RNA, Untranslated / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D012367:RNA, Viral / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D059467:Transcriptome; D014902:West Nile virus / Q000235:genetics / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D019476:Insect Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D022661:RNA, Untranslated; D012367:RNA, Viral; D029701:Saccharomyces cerevisiae Proteins; D005095:Exoribonucleases; C068398:XRN1 protein, S cerevisiae; C470512:XRN1 protein, human