N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection.

Journal Article

The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A-modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A methyltransferases or an m6A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determined that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Altogether, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes.

Full Text

Duke Authors

Cited Authors

  • Gokhale, NS; McIntyre, ABR; McFadden, MJ; Roder, AE; Kennedy, EM; Gandara, JA; Hopcraft, SE; Quicke, KM; Vazquez, C; Willer, J; Ilkayeva, OR; Law, BA; Holley, CL; Garcia-Blanco, MA; Evans, MJ; Suthar, MS; Bradrick, SS; Mason, CE; Horner, SM

Published Date

  • November 2016

Published In

Volume / Issue

  • 20 / 5

Start / End Page

  • 654 - 665

PubMed ID

  • 27773535

Electronic International Standard Serial Number (EISSN)

  • 1934-6069

International Standard Serial Number (ISSN)

  • 1931-3128

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2016.09.015

Language

  • eng