Increasing evidences suggest that the methyltransferase NSUN2 catalyzes 5-methylcytosine (m5C) modifications on viral RNAs, which are essential for the replication of various viruses. Despite the function of m5C deposition is well characterized, other potential roles of NSUN2 in regulating viral replication remain largely unknown. In this study, the m5C modified residues catalyzed by NSUN2 on enterovirus 71 (EV71) RNAs were mapped. NSUN2, along with m5C modifications, played multiple roles during the EV71 life cycle. Functional m5C modified nucleotides increased the translational efficiency and stability of EV71 RNAs. Additionally, NSUN2 was found to target the viral protein VP1 for binding and promote its stability by inhibiting the ubiquitination. Furthermore, both viral replication and pathogenicity in mice were largely attenuated when functional m5C residues were mutated. Taken together, this study characterizes distinct pathways mediated by NSUN2 in regulating EV71 replication, and highlights the importance of its catalyzed m5C modifications on EV71 RNAs for the viral replication and pathogenicity.

中文翻译：

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NSUN2 介导调节肠道病毒 71 复制的不同途径


越来越多的证据表明，甲基转移酶 NSUN2 催化病毒 RNA 上的 5-甲基胞嘧啶 (m5C) 修饰，这对于各种病毒的复制至关重要。尽管 m5C 沉积的功能已得到很好的表征，但 NSUN2 在调节病毒复制中的其他潜在作用仍然很大程度上未知。在本研究中，对肠道病毒 71 (EV71) RNA 上 NSUN2 催化的 m5C 修饰残基进行了定位。 NSUN2 与 m5C 修饰一起在 EV71 生命周期中发挥了多种作用。功能性 m5C 修饰核苷酸提高了 EV71 RNA 的翻译效率和稳定性。此外，还发现 NSUN2 能够靶向病毒蛋白 VP1 进行结合，并通过抑制泛素化来提高其稳定性。此外，当功能性 m5C 残基发生突变时，病毒在小鼠中的复制和致病性均大幅减弱。总而言之，这项研究描述了 NSUN2 在调节 EV71 复制中介导的不同途径，并强调了其催化的 EV71 RNA 上的 m5C 修饰对于病毒复制和致病性的重要性。