N 6 -methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I

• Published in: Nature microbiology Vol. 5; no. 4; p. 584
• Main Authors: Lu, Mijia, Zhang, Zijie, Xue, Miaoge, Zhao, Boxuan Simen, Harder, Olivia, Li, Anzhong, Liang, Xueya, Gao, Thomas Z, Xu, Yunsheng, Zhou, Jiyong, Feng, Zongdi, Niewiesk, Stefan, Peeples, Mark E, He, Chuan, Li, Jianrong
• Format: Journal Article
• Language: English
• Published: England 01.04.2020
• Subjects: A549 Cells; Adenosine - analogs & derivatives; Adenosine - immunology; Adenosine - metabolism; Animals; Chlorocebus aethiops; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - immunology; Gene Expression Regulation; Genome, Viral - immunology; HeLa Cells; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immune Evasion - genetics; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - immunology; Interferon-beta - genetics; Interferon-beta - immunology; Interferon-Induced Helicase, IFIH1 - genetics; Interferon-Induced Helicase, IFIH1 - immunology; Metapneumovirus - genetics; Metapneumovirus - growth & development; Metapneumovirus - immunology; NF-kappa B - genetics; NF-kappa B - immunology; Paramyxoviridae Infections - genetics; Paramyxoviridae Infections - immunology; Paramyxoviridae Infections - virology; Receptors, Immunologic; RNA, Viral - genetics; RNA, Viral - immunology; Sigmodontinae; Signal Transduction; THP-1 Cells; Vero Cells; Virion - genetics; Virion - growth & development; Virion - immunology
• ISSN: 2058-5276
• DOI: 10.1038/s41564-019-0653-9

Internal N -methyladenosine (m A) modification is one of the most common and abundant modifications of RNA. However, the biological roles of viral RNA m A remain elusive. Here, using human metapneumovirus (HMPV) as a model, we demonstrate that m A serves as a molecular marker for innate immune discrimination of self from non-self RNAs. We show that HMPV RNAs are m A methylated and that viral m A methylation promotes HMPV replication and gene expression. Inactivating m A addition sites with synonymous mutations or demethylase resulted in m A-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, m A-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, m A-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 m A in their RNA as a means of mimicking cellular RNA to avoid detection by innate immunity and (2) viral RNA m A can serve as a target to attenuate HMPV for vaccine purposes.