Importance

N6-methyladenosine (m6A) modifications play an important role in regulating RNA fate, especially during viral infection. However, it remains unclear whether m6A modification can also act in any antiviral capacity. During Kaposi’s sarcoma-associated herpes virus infection, while most messenger RNAs are degraded by viral SOX nuclease, a subset of transcripts rigorously escapes degradation. Our study reveals that one such transcript, interleukin-6, acquires a m6A modification during infection, which allows it to recruit the m6A YTHDC2 reader. We show that this m6Modification with concomitant recruitment of YTHDC2 is essential to provide protection against SOX-induced decay. This suggests that m6A modification may contribute to the host’s efforts to regain control of the gene expression environment.

Summary

The role of N6-methyladenosine (m6A) modifications have been increasingly associated with a diverse set of roles in modulating viruses and influencing the outcome of viral infection. Here we report that the landscape of m6Deposition is radically shifted during lytic infection with Kaposi’s sarcoma-associated herpes virus (KSHV) for viral and host transcripts. Consistent with previous reports, we also found an overall decrease in host methylation in favor of viral messenger RNA (mRNA), as well as 5′ hypomethylation and 3′ hypermethylation. During lytic infection with KSHV, a major change in overall mRNA abundance is caused by the viral endoribonuclease SOX, which induces the decay of more than 70% of transcripts. Here, we reveal that the mRNA of interlukin-6 (IL-6), a well-characterized and SOX-resistant transcript, is m6Has changed during lytic infection. Furthermore, we show that this modification is in the resistance element IL-6 SOX, an RNA element in the IL-6 3′ untranslated region (UTR) that had previously been shown to be sufficient for protection against the SOX cleavage. We show that the presence of this m6Modification is required to confer SOX resistance to IL-6 mRNA. We then show that this modification recruits the m6A YTHDC2 reader thus discovered that YTHDC2 is necessary for the escape of the IL-6 transcript. These results shed light on how the host cell has evolved to use RNA modifications to circumvent viral manipulation of RNA fate upon KSHV infection.

Footnotes

    • Accepted January 13, 2022.
  • Author contributions: DM-F. and research designed by MM; DM-F., A. Cicerchia, A. Cadorette and VS conducted research; DM-F. data analyzed; and DM-F. and MM wrote the paper.

  • The authors declare no competing interests.

  • This article is a direct PNAS submission.

  • This article contains additional information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2116662119/-/DCSupplemental.