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

doi:10.1016/j.chom.2016.09.015

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 journal › Article › peer-review

384 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 language	English (US)
Pages (from-to)	654-665
Number of pages	12
Journal	Cell Host and Microbe
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.chom.2016.09.015
State	Published - Nov 9 2016
Externally published	Yes

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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10.1016/j.chom.2016.09.015

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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

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 2016, 'N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection', Cell Host and Microbe, vol. 20, no. 5, pp. 654-665. https://doi.org/10.1016/j.chom.2016.09.015

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title = "N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection",

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, mA, viral particle production, yellow fever",

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

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = nov,

day = "9",

doi = "10.1016/j.chom.2016.09.015",

language = "English (US)",

volume = "20",

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T1 - N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

AU - Gokhale, Nandan S.

AU - McIntyre, Alexa B.R.

AU - McFadden, Michael J.

AU - Roder, Allison E.

AU - Kennedy, Edward M.

AU - Gandara, Jorge A.

AU - Hopcraft, Sharon E.

AU - Quicke, Kendra M.

AU - Vazquez, Christine

AU - Willer, Jason

AU - Ilkayeva, Olga R.

AU - Law, Brittany A.

AU - Holley, Christopher L.

AU - Garcia-Blanco, Mariano A.

AU - Evans, Matthew J.

AU - Suthar, Mehul S.

AU - Bradrick, Shelton S.

AU - Mason, Christopher E.

AU - Horner, Stacy M.

PY - 2016/11/9

Y1 - 2016/11/9

N2 - 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.

AB - 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.

KW - Flaviviridae

KW - HCV

KW - N6-methyladenosine

KW - RNA-modifications

KW - West Nile

KW - Zika

KW - dengue

KW - mA

KW - viral particle production

KW - yellow fever

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AN - SCOPUS:84994796605

SN - 1931-3128

VL - 20

SP - 654

EP - 665

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 5

ER -

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

Abstract

Keywords

ASJC Scopus subject areas

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