N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I

Mijia Lu, Zijie Zhang, Miaoge Xue, Boxuan Simen Zhao, Olivia Harder, Anzhong Li, Xueya Liang, Thomas Z. Gao, Yunsheng Xu, Jiyong Zhou, Zongdi Feng, Stefan Niewiesk, Mark E. Peeples, Chuan He, Jianrong Li

Research output: Contribution to journalArticlepeer-review

Abstract

Internal N6-methyladenosine (m6A) modification is one of the most common and abundant modifications of RNA. However, the biological roles of viral RNA m6A remain elusive. Here, using human metapneumovirus (HMPV) as a model, we demonstrate that m6A serves as a molecular marker for innate immune discrimination of self from non-self RNAs. We show that HMPV RNAs are m6A methylated and that viral m6A methylation promotes HMPV replication and gene expression. Inactivating m6A addition sites with synonymous mutations or demethylase resulted in m6A-deficient recombinant HMPVs and virion RNAs that induced increased expression of type I interferon, which was dependent on the cytoplasmic RNA sensor RIG-I, and not on melanoma differentiation-associated protein 5 (MDA5). Mechanistically, m6A-deficient virion RNA induces higher expression of RIG-I, binds more efficiently to RIG-I and facilitates the conformational change of RIG-I, leading to enhanced interferon expression. Furthermore, m6A-deficient recombinant HMPVs triggered increased interferon in vivo and were attenuated in cotton rats but retained high immunogenicity. Collectively, our results highlight that (1) viruses acquire m6A in their RNA as a means of mimicking cellular RNA to avoid detection by innate immunity and (2) viral RNA m6A can serve as a target to attenuate HMPV for vaccine purposes.

Original languageEnglish (US)
Pages (from-to)584-598
Number of pages15
JournalNature Microbiology
Volume5
Issue number4
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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