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PMID: 27117054 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression.

Cell host & microbe ·Vol. 19 ·No. 5 ·2016-00-11 ·Pages 675-85

Kennedy EM, Bogerd HP, Kornepati AV, Kang D, Ghoshal D, Marshall JB, Poling BC, Tsai K, Gokhale NS, Horner SM, Cullen BR

Abstract

Covalent addition of a methyl group to adenosine N(6) (m(6)A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m(6)A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m(6)A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m(6)A sequencing techniques to precisely map several m(6)A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3' untranslated region (3' UTR). Viral 3' UTR m(6)A sites or analogous cellular m(6)A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m(6)A "reader" proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m(6)A editing and the resultant recruitment of YTHDF proteins as major positive regulators of HIV-1 mRNA expression.

MeSH Terms
3' Untranslated Regions CD4-Positive T-Lymphocytes/virology Cell Line Cloning, Molecular Gene Expression Regulation, Viral Genome, Viral HEK293 Cells HIV-1/genetics,metabolism Human Immunodeficiency Virus Proteins/genetics,metabolism Humans RNA Editing RNA, Messenger/genetics,metabolism RNA, Viral/genetics,metabolism RNA-Binding Proteins/genetics,metabolism Virus Replication/drug effects
Chemicals
3' Untranslated Regions Human Immunodeficiency Virus Proteins RNA, Messenger RNA, Viral RNA-Binding Proteins YTHDF2 protein, human
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kennedy Edward M
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Bogerd Hal P
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Kornepati Anand V R
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Kang Dong
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Ghoshal Delta
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Marshall Joy B
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Poling Brigid C
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Tsai Kevin
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Gokhale Nandan S
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
Horner Stacy M
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.
Cullen Bryan R
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: bryan.cullen@duke.edu.
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Article Info
Journal
Cell host & microbe
Abbr.
Cell Host Microbe
ISSN
1934-6069
DOI
10.1016/j.chom.2016.04.002
Email
bryan.cullen@duke.edu
Published
2016-00-11
Epub
2016-00-21
Pages
675-85
Language
English
Region
United States
NLM ID
101302316
PMCID
PMC4867121
Subset
IM
Grants
NIAID NIH HHS · R01 AI117780 · United States
NCI NIH HHS · T32 CA009111 · United States
NIAID NIH HHS · P30 AI064518 · United States
Corrections
CommentIn
PMID: 27173921
ErratumIn
PMID: 29241043
External Links
PubMed source DOI: 10.1016/j.chom.2016.04.002 PMC Full Text View journal details
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