Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

Jansens, Robert J. J.; Verhamme, Ruth; Mirza, Aashiq H.; Olarerin-George, Anthony O.; Waesberghe, Cliff Van; Jaffrey, Samie R.; Favoreel, Herman

doi:10.1016/j.celrep.2022.111107

Cited by 10 publications

(8 citation statements)

References 71 publications

(93 reference statements)

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“…After 24 hpi, both mRNA and protein levels of m 6 A regulators except YTHDF3 were significantly decreased, which was similar to many alphaherpesvirus that globally impair host mRNA stability and ongoing protein synthesis (Sandri-Goldin, 1994;Everly et al, 2002;Walsh and Mohr, 2011;Sciabica et al, 2014). Moreover, the expression of US3 of alphaherpesvirus was the cause of inactivation of methyltransferase complex (Jansens et al, 2022). Miraculously, the mRNA level of YTHDF3 was increased at 12 hpi, but its protein expression level decreased significantly.…”

Section: Discussionmentioning

confidence: 54%

“…Coincidentally, HSV-1 could reduce the m 6 A modification level after infecting host cells (Srinivas et al, 2021). Quantitative detection of the m 6 A modification level in all mRNA after infection with PRV or HSV-1 by mass spectrometry was also decreased (Jansens et al, 2022). PRV infection significantly reduced the m 6 A modification level of host RNAs.…”

Section: Discussionmentioning

confidence: 94%

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Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Cao

et al. 2023

Front. Microbiol.

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IntroductionPseudorabies virus (PRV) is the pathogenic virus of porcine pseudorabies (PR), belonging to the Herpesviridae family. PRV has a wide range of hosts and in recent years has also been reported to infect humans. N6-methyladenosine (m6A) modification is the major pathway of RNA post-transcriptional modification. Whether m6A modification participates in the regulation of PRV replication is unknown.MethodsHere, we investigated that the m6A modification was abundant in the PRV transcripts and PRV infection affected the epitranscriptome of host cells. Knockdown of cellular m6A methyltransferases METTL3 and METTL14 and the specific binding proteins YTHDF2 and YTHDF3 inhibited PRV replication, while silencing of demethylase ALKBH5 promoted PRV output. The overexpression of METTL14 induced more efficient virus proliferation in PRV-infected PK15 cells. Inhibition of m6A modification by 3-deazaadenosine (3-DAA), a m6A modification inhibitor, could significantly reduce viral replication.Results and DiscussionTaken together, m6A modification played a positive role in the regulation of PRV replication and gene expression. Our research revealed m6A modification sites in PRV transcripts and determined that m6A modification dynamically mediated the interaction between PRV and host.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 94%

Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Cao

et al. 2023

Front. Microbiol.

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“…Eighteen m 6 A marks were identified in respiratory syncytial viral mRNAs, the highest for any virus (Xue et al, 2019). During viral infection, m 6 A levels of host transcripts can increase or decrease depending on the particular m 6 A mark (Gokhale et al, 2016; Jansens et al, 2022; N. Li, Hui, et al, 2021; Lichinchi, Gao, et al, 2016; Lichinchi, Zhao, et al, 2016; Lichinchi & Rana, 2019; J. Liu et al, 2021; X. Qiu, Hua, et al, 2021; Selberg et al, 2021). Interestingly, cellular m 6 A methylation is almost completely inhibited in pseudorabies virus‐infected cells due to phosphorylation of the METTL3/METTL14/WTAP complex by viral proteins (Jansens et al, 2022).…”

Section: Roles Of M6a Mtases In Infectious Agents: Viruses and Parasitesmentioning

confidence: 99%

Section: Roles Of M 6 a Mtases In Infectious Agents: Viruses And Para...mentioning

confidence: 99%

Ghost authors revealed: The structure and function of human N⁶‐methyladenosine RNA methyltransferases

Breger,

Kunkler,

O'Leary

et al. 2023

WIREs RNA

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Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N6‐methyladenosine (m6A) is the most abundant modification in eukaryotic messenger RNA (mRNA) and has also been detected in non‐coding RNAs, including long non‐coding RNA, ribosomal RNA, and small nuclear RNA. In general, m6A marks can alter RNA secondary structure and initiate unique RNA–protein interactions that can alter splicing, mRNA turnover, and translation, just to name a few. Although m6A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m6A marks have been established only recently. Thus far, there are four confirmed human methyltransferases that catalyze the transfer of a methyl group from S‐adenosylmethionine (SAM) to the N6 position of adenosine, producing m6A: methyltransferase‐like protein (METTL) 3/METTL14 complex, METTL16, METTL5, and zinc‐finger CCHC‐domain‐containing protein 4. Though the methyltransferases have unique RNA targets, all human m6A RNA methyltransferases contain a Rossmann fold with a conserved SAM‐binding pocket, suggesting that they utilize a similar catalytic mechanism for methyl transfer. For each of the human m6A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m6A marks in human viruses and parasites, assigning m6A marks in the transcriptome to specific methyltransferases, small molecules targeting m6A methyltransferases, and the enzymes responsible for hypermodified m6A marks and their biological functions in humans. Understanding m6A methyltransferases is a critical steppingstone toward establishing the m6A epitranscriptome and more broadly the RNome.This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

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“…The methyltransferase complex (MTC) is the writer to catalyze the methylation of mRNA, whereas the demethylase erases the m6A. The MTC takes charge of the catalysis of m6A, which include METTL3 and other assistant units ( Jansens et al, 2022 ). And the RNA reader protein identified the m6A to exert relevant effects ( Zhou et al, 2020 ).…”

Section: Epigenetic Phenomenon and Cancermentioning

confidence: 99%

Recent advances in epigenetic anticancer therapeutics and future perspectives

Ren

Yang

et al. 2023

Front. Genet.

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Tumor development is frequently accompanied by abnormal expression of multiple genomic genes, which can be broadly viewed as decreased expression of tumor suppressor genes and upregulated expression of oncogenes. In this process, epigenetic regulation plays an essential role in the regulation of gene expression without alteration of DNA or RNA sequence, including DNA methylation, RNA methylation, histone modifications and non-coding RNAs. Therefore, drugs developed for the above epigenetic modulation have entered clinical use or preclinical and clinical research stages, contributing to the development of antitumor drugs greatly. Despite the efficacy of epigenetic drugs in hematologic caners, their therapeutic effects in solid tumors have been less favorable. A growing body of research suggests that epigenetic drugs can be applied in combination with other therapies to increase efficacy and overcome tumor resistance. In this review, the progress of epigenetics in tumor progression and oncology drug development is systematically summarized, as well as its synergy with other oncology therapies. The future directions of epigenetic drug development are described in detail.

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Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

Cited by 10 publications

References 71 publications

Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Ghost authors revealed: The structure and function of human N⁶‐methyladenosine RNA methyltransferases

Recent advances in epigenetic anticancer therapeutics and future perspectives

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Alphaherpesvirus US3 protein-mediated inhibition of the m6A mRNA methyltransferase complex

Cited by 10 publications

References 71 publications

Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Ghost authors revealed: The structure and function of human N6‐methyladenosine RNA methyltransferases

Recent advances in epigenetic anticancer therapeutics and future perspectives

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Ghost authors revealed: The structure and function of human N⁶‐methyladenosine RNA methyltransferases