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

• Published in: Cell reports (Cambridge) 2022-07, Vol.40 (3), p.111107-111107, Article 111107
• Main Authors: Jansens, Robert J.J., Verhamme, Ruth, Mirza, Aashiq H., Olarerin-George, Anthony, Van Waesberghe, Cliff, Jaffrey, Samie R., Favoreel, Herman W.
• Format: Article
• Language: English
• Subjects: herpes; m6A; PRV; pseudorabies; US3; writer complex
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111107

Chemical modifications of mRNA, the so-called epitranscriptome, represent an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, N6-methyladenosine (m6A), is generated by a multi-subunit methyltransferase complex. We show that alphaherpesvirus kinases trigger phosphorylation of several components of the m6A methyltransferase complex, including METTL3, METTL14, and WTAP, which correlates with inhibition of the complex and a near complete loss of m6A levels in mRNA of virus-infected cells. Expression of the viral US3 protein is necessary and sufficient for phosphorylation and inhibition of the m6A methyltransferase complex. Although m6A methyltransferase complex inactivation is not essential for virus replication in cell culture, the consensus m6A methylation motif is under-represented in alphaherpesvirus genomes, suggesting evolutionary pressure against methylation of viral transcripts. Together, these findings reveal that phosphorylation can be associated with inactivation of the m6A methyltransferase complex, in this case mediated by the viral US3 protein. [Display omitted] •Alphaherpesvirus infection leads to a near complete loss of m6A levels in mRNA•Viral US3 kinase triggers phosphorylation and inactivation of the m6A writer complex•m6A writer complex inactivation correlates with its dissociation from chromatin Jansens et al. demonstrate that phosphorylation can be associated with inactivation of the m6A methyltransferase complex, in this case mediated by the alphaherpesviral US3 protein.