Wang Qian, Xu Shuai, Shen Wentao, Wei Yanli, Han Lu, Wang Zhengxiang, Yu Yingying, Liu Minxuan, Liu Junwen, Deng Guohua, Chen Hualan, Zhu Qiyun
State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, People's Republic of China.
Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, People's Republic of China.
Proc Natl Acad Sci U S A. 2025 Mar 18;122(11):e2411554122. doi: 10.1073/pnas.2411554122. Epub 2025 Mar 12.
6-methyladnosine (mA) 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 mA in IAV RNA. In the present study, we identified the mA methylation of the viral RNA of different IAV subtypes and confirmed that mA modification promotes the polymerase activity and replication of IAV. By mutating mA motifs on the multiple viral RNAs (vRNAs) of IAV, we revealed that mA deficiency in vRNA suppresses the expression of viral genes and the replication of the virus in vitro. In addition, mA deficiency in vRNA reduced the pathogenicity of IAV in a mouse model. Mechanistically, mA deficiency in vRNA suppresses the assembly of the viral ribonucleoprotein (vRNP) complex by impairing the interaction between vRNA and vRNP proteins in an mA methyltransferase-dependent manner, but not the mA reader proteins. Together, our findings reveal an important role for mA 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.
6-甲基腺苷（mA）修饰存在于甲型流感病毒（IAV）的正链和负链RNA中，并影响IAV的复制和致病性。然而，关于IAV RNA中mA的调控机制知之甚少。在本研究中，我们鉴定了不同IAV亚型病毒RNA的mA甲基化，并证实mA修饰促进了IAV的聚合酶活性和复制。通过突变IAV多个病毒RNA（vRNA）上的mA基序，我们发现vRNA中的mA缺陷会抑制病毒基因的表达以及病毒在体外的复制。此外，vRNA中的mA缺陷降低了IAV在小鼠模型中的致病性。从机制上讲，vRNA中的mA缺陷通过以mA甲基转移酶依赖的方式损害vRNA与vRNP蛋白之间的相互作用来抑制病毒核糖核蛋白（vRNP）复合物的组装，但不影响mA识别蛋白。总之，我们的研究结果揭示了病毒RNA上的mA在促进聚合酶复合物活性以及IAV的复制和致病性方面的重要作用，这为开发新型抗流感策略提供了思路。
