Year: 2022
Type: article
Abstract: 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.
Source: Cell Reports
Institutions: Cornell University, Ghent University
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Belgian American Educational Foundation, Princeton University, Northwestern University, University of Chicago, Fonds Wetenschappelijk Onderzoek, Universiteit Gent, Universidad Autónoma de Madrid, Vlaamse regering, National Institutes of Health, Bijzonder Onderzoeksfonds UGent, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: G6524432257, Cancer Pharmacology, Tunneling nanotubes induced by the US3 protein of alphaherpesviruses, Viral control of the epitranscriptome: alphaherpesvirus-induced m6A mRNA demethylation, Characterizing the transcriptome-wide location and function of 8oxoG, Engineering RNA-activated fluorescence switches for imaging RNA and RNA biology, New mechanisms and technologies for understanding post-transcriptional gene regulation in neurons
OpenAlex ID: W4286250853