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EBV Exploits RNA m⁶A Modification to Promote Cell Survival and Progeny Virus Production During Lytic Cycle.

ABSTRACT: N6-methyladenosine (m⁶A) mediates various biological processes by affecting RNA stability, splicing, and translational efficiency. The roles of m⁶A modification in Epstein-Barr virus (EBV) infection in the lytic phase are unclear. Here, knockout of the m⁶A methyltransferase, N6-methyladenosine methyltransferase-like 3 (METTL3), or inhibition of methylation by DAA or UZH1a decreased the expression of viral lytic proteins and reduced progeny virion production. Interestingly, cell growth and viability were decreased by induction of the lytic cycle in METTL3-knockout or inhibitor-treated cells. Apoptosis was induced in those conditions possibly because of a decreased level of the anti-apoptotic viral protein, BHRF1. Therefore, m⁶A shows potential as a target of lytic induction therapy for EBV-associated cancers, including Burkitt lymphoma.

SUBMITTER: Yanagi Y

PROVIDER: S-EPMC9240777 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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EBV Exploits RNA m6A Modification to Promote Cell Survival and Progeny Virus Production During Lytic Cycle.

Yanagi Yusuke Y Watanabe Takahiro T Hara Yuya Y Sato Yoshitaka Y Kimura Hiroshi H Murata Takayuki T

Frontiers in microbiology 20220615

N6-methyladenosine (m6A) mediates various biological processes by affecting RNA stability, splicing, and translational efficiency. The roles of m6A modification in Epstein-Barr virus (EBV) infection in the lytic phase are unclear. Here, knockout of the m6A methyltransferase, N6-methyladenosine methyltransferase-like 3 (METTL3), or inhibition of methylation by DAA or UZH1a decreased the expression of viral lytic proteins and reduced progeny virion production. Inte ...[more]

PMID: 35783391

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Project description:BackgroundReactivation of Epstein Barr virus (EBV) leads to modulation of the viral and cellular epitranscriptome. N6-methyladenosine (m6A) modification is a type of RNA modification that regulates metabolism of mRNAs. Previous reports demonstrated that m6A modification affects the stability and metabolism of EBV encoded mRNAs. However, the effect of reactivation on reprograming of the cellular mRNAs, and how this contributes to successful induction of lytic reactivation is not known.MethodsMethylated RNA immunoprecipitation sequencing (MeRIP-seq), transcriptomic RNA sequencing (RNA-seq) and RNA pull-down PCR were used to screen and validate differentially methylated targets. Western blotting, quantitative real-time PCR (RT-qPCR) and immunocytochemistry were used to investigate the expression and localization of different proteins. RNA stability and polysome analysis assays were used to detect the half-lives and translation efficiencies of downstream genes. Insertion of point mutation to disrupt the m6A methylation sites was used to verify the effect of m6A methylation on its stability and expression levels.ResultsWe report that during EBV reactivation the m6A eraser ALKBH5 is significantly downregulated leading to enhanced methylation of the cellular transcripts DTX4 and TYK2, that results in degradation of TYK2 mRNAs and higher efficiency of translation of DTX4 mRNAs. This resulted in attenuation of IFN signaling that promoted progression of viral lytic replication. Furthermore, inhibition of m6A methylation of these transcripts led to increased production of IFN, and a substantial reduction in viral copy number, which suggests abrogation of lytic viral replication.ConclusionOur findings illuminate the significance of m6A modification in overcoming the innate immune response during EBV reactivation. We now report that during lytic reactivation EBV targets the RNA methylation system of the host to attenuate the innate immune response by suppressing the interferon signaling which facilitates successful lytic replication of the virus.

Dataset Information

EBV Exploits RNA m⁶A Modification to Promote Cell Survival and Progeny Virus Production During Lytic Cycle.

Publications

EBV Exploits RNA m<sup>6</sup>A Modification to Promote Cell Survival and Progeny Virus Production During Lytic Cycle.

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