N6-methyladnosine of vRNA facilitates influenza A virus replication by promoting the interaction of vRNA with polymerase proteins.

N6-methyladnosine (m6A) modification is present in both positive- and negative-strand RNA of influenza A virus (IAV) and affects the replication and pathogenicity of IAV. However, little is known about the regulatory mechanism of m6A in IAV RNA. In the present study, we identified the m6A methylation of the viral RNA of different IAV subtypes and confirmed that m6A modification promotes the polymerase activity and replication of IAV. By mutating m6A motifs on the multiple viral RNAs (vRNAs) of IAV, we revealed that m6A deficiency in vRNA suppresses the expression of viral genes and the replication of the virus in vitro. In addition, m6A deficiency in vRNA reduced the pathogenicity of IAV in a mouse model. Mechanistically, m6A deficiency in vRNA suppresses the assembly of the viral ribonucleoprotein (vRNP) complex by impairing the interaction between vRNA and vRNP proteins in an m6A methyltransferase-dependent manner, but not the m6A reader proteins. Together, our findings reveal an important role for m6A on viral RNAs in facilitating the activity of the polymerase complex and the replication and pathogenicity of IAV, which provides insights for the development of novel anti-influenza strategies.

Citation

Qian Wang, Shuai Xu, Wentao Shen, Yanli Wei, Lu Han, Zhengxiang Wang, Yingying Yu, Minxuan Liu, Junwen Liu, Guohua Deng, Hualan Chen, Qiyun Zhu. N6-methyladnosine of vRNA facilitates influenza A virus replication by promoting the interaction of vRNA with polymerase proteins. Proceedings of the National Academy of Sciences of the United States of America. 2025 Mar 18;122(11):e2411554122

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PMID: 40073063

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