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

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

  • Cell Rep. 2022 Jul 19;40(3):111107. doi: 10.1016/j.celrep.2022.111107.
Robert J J Jansens 1,  Ruth Verhamme 2,  Aashiq H Mirza 3,  Anthony Olarerin-George 3,  Cliff Van Waesberghe 2,  Samie R Jaffrey 3,  Herman W Favoreel 4
Affiliations

Affiliations

  • 1 Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium; Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
  • 2 Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium.
  • 3 Department of Pharmacology, Weill Medical College, Cornell University, New York, NY 10065, USA.
  • 4 Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, 9820 Merelbeke, Belgium. Electronic address: herman.favoreel@ugent.be.
PMID: 35858564 DOI: 10.1016/j.celrep.2022.111107
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.

Keywords

CP: Microbiology; CP: Molecular biology; PRV; US3; herpes; m6A; pseudorabies; writer complex.

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