Alphaherpesvirus-mediated remodeling of the cellular transcriptome results in depletion of m6A-containing transcripts

• Published in: iScience 2023-08, Vol.26 (8), p.107310, Article 107310
• Main Authors: Jansens, Robert J.J., Olarerin-George, Anthony, Verhamme, Ruth, Mirza, Aashiq, Jaffrey, Samie, Favoreel, Herman W.
• Format: Article
• Language: English
• Subjects: Transcriptomics; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107310

The mechanisms by which viruses regulate host mRNAs during infection are still poorly understood. Several host transcripts that encode proteins that contribute to the anti-viral response contain the N6-methyladenosine nucleotide (m6A). In this study, we investigated if and how viruses from different (sub) families specifically affect m6A-containing host transcripts. Systematic analysis of host transcriptomes after infection with diverse types of viruses showed that m6A-methylated transcripts are selectively downregulated during infection with Sendai virus, African swine fever virus and the alphaherpesviruses herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV). Focusing on PRV and HSV-1, we found that downregulation of m6A-methylated transcripts depends on the YTHDF family of m6A-binding proteins, and correlates with localization of these proteins to enlarged P-bodies. Knockdown of YTHDF proteins in primary cells reduced PRV protein expression and increased expression of antiviral interferon-stimulated genes, suggesting that virus-induced depletion of host m6A-containing transcripts constitutes an immune evasion strategy. [Display omitted] •Alphaherpesvirus infection leads to selective depletion of m6A-methylated RNA•This selective depletion depends on the YTHDF family of m6A-binding proteins•YTHDF proteins relocalize to enlarged P-bodies during alphaherpesvirus infection•YTHDF knockdown leads to reduced viral protein and increased ISG expression Virology; Transcriptomics