N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

Nandan S. Gokhale, Alexa B.R. McIntyre, Michael J. McFadden, Allison E. Roder, Edward M. Kennedy, Jorge A. Gandara, Sharon E. Hopcraft, Kendra M. Quicke, Christine Vazquez, Jason Willer, Olga R. Ilkayeva, Brittany A. Law, Christopher L. Holley, Mariano A. Garcia-Blanco, Matthew J. Evans, Mehul S. Suthar, Shelton S. Bradrick, Christopher E. Mason, Stacy M. Horner

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)654-665
Number of pages12
JournalCell Host and Microbe
Volume20
Issue number5
DOIs
StatePublished - Nov 9 2016

Keywords

  • Flaviviridae
  • HCV
  • N6-methyladenosine
  • RNA-modifications
  • West Nile
  • Zika
  • dengue
  • mA
  • viral particle production
  • yellow fever

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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  • Cite this

    Gokhale, N. S., McIntyre, A. B. R., McFadden, M. J., Roder, A. E., Kennedy, E. M., Gandara, J. A., Hopcraft, S. E., Quicke, K. M., Vazquez, C., Willer, J., Ilkayeva, O. R., Law, B. A., Holley, C. L., Garcia-Blanco, M. A., Evans, M. J., Suthar, M. S., Bradrick, S. S., Mason, C. E., & Horner, S. M. (2016). N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection. Cell Host and Microbe, 20(5), 654-665. https://doi.org/10.1016/j.chom.2016.09.015