N4-acetylcytidine regulates the replication and pathogenicity of enterovirus 71

Chemical modifications are important for RNA function and metabolism. N4-acetylcytidine (ac4C) is critical for the translation and stability of mRNA. Although ac4C is found in RNA viruses, the detailed mechanisms through which ac4C affects viral replication are unclear. Here, we reported that the 5 ' untranslated region of the enterovirus 71 (EV71) genome was ac4C modified by the host acetyltransferase NAT10. Inhibition of NAT10 and mutation of the ac4C sites within the internal ribosomal entry site (IRES) suppressed EV71 replication. ac4C enhanced viral RNA translation via selective recruitment of PCBP2 to the IRES and boosted RNA stability. Additionally, ac4C increased the binding of RNA-dependent RNA polymerase (3D) to viral RNA. Notably, ac4C-deficient mutant EV71 showed reduced pathogenicity in vivo. Our findings highlighted the essential role of ac4C in EV71 infection and provided insights into potential antiviral treatments.

Automated summary

Chemical modification of RNA plays a crucial role in its function and metabolism. This study identified that N4-acetylcytidine (ac4C) modification of the enterovirus 71 (EV71) genome by NAT10, a host acetyltransferase, is essential for viral replication. ac4C enhances viral translation and stability, and facilitates the binding of RNA-dependent RNA polymerase to viral RNA. Moreover, a mutant EV71 lacking ac4C showed reduced pathogenicity in vivo. These findings uncover the importance of ac4C in EV71 infection and provide insights into potential antiviral treatments.