Inhibition of the m6A mRNA methyltransferase complex by the alphaherpesvirus viral protein kinase US3

Published: 20 October 2021| Version 1 | DOI: 10.17632/nxn8cv2d2h.1
Robert Jansens


Chemical modifications of mRNA, the so-called epitranscriptome, have emerged as an additional layer of post-transcriptional regulation of gene expression. The most common epitranscriptomic modification, m6A, is generated by a large multi-subunit complex. Although the components that make up the m6A methyltransferase complex have been identified, it is currently largely unclear how the activity of this complex is regulated. Here we show that alphaherpesvirus kinases phosphorylate several components of the m6A methyltransferase complex, including METTL3, METTL14 and WTAP. Phosphorylation of these proteins correlates with inhibition of the m6A methyltransferase complex and a near complete loss of m6A levels in alphaherpesvirus-infected cells. Expression of the viral serine/threonine protein kinase US3 is necessary and sufficient for phosphorylation of METTL3 and METTL14 and inhibition of the m6A methyltransferase complex. Together, these findings provide the first evidence for phosphorylation that inactivates the m6A methyltransferase complex, in this case mediated by the viral US3 kinase.



Virology, RNA