N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

Publication date: Available online 20 October 2016
Source:Cell Host & Microbe
Author(s): 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
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.

Graphical abstract

Teaser

N6-methyladenosine (m⁶A) post-transcriptionally regulates RNA function. Gokhale et al. demonstrate that the RNA genomes of HCV, ZIKV, DENV, YFV, and WNV are modified by m⁶A. Depletion of cellular machinery that regulates m⁶A or introduction of m⁶A-abrogating mutations within HCV RNA increase viral particle production, suggesting that m⁶A negatively regulates HCV.


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