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Cell Host Microbe. 2016 Nov 9;20(5):654-665. doi: 10.1016/j.chom.2016.09.015. Epub 2016 Oct 20.

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection.

Author information

1
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; Tri-Institutional Program in Computational Biology and Medicine, New York City, NY 10065, USA.
3
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA.
4
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Yerkes National Primate Research Center, Atlanta, GA 30329, USA.
6
Duke Molecular Physiology Institute, Duke University, Durham NC 27701, USA.
7
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
8
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Programme in Emerging Infectious Disease, Duke-NUS Medical School, Singapore 169857, Singapore.
9
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
10
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10021, USA; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10021, USA. Electronic address: chm2042@med.cornell.edu.
11
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: stacy.horner@duke.edu.

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.

KEYWORDS:

Flaviviridae; HCV; N6-methyladenosine; RNA-modifications; West Nile; Zika; dengue; m(6)A; viral particle production; yellow fever

PMID:
27773535
PMCID:
PMC5123813
DOI:
10.1016/j.chom.2016.09.015
[Indexed for MEDLINE]
Free PMC Article

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