N6-methyladenosine reader protein YTHDC1 regulates influenza A virus NS segment splicing and replication

N6-methyladenosine (m(6)A) modification on viral RNAs has a profound impact on infectivity. m(6)A is also a highly pervasive modification for influenza viral RNAs. However, its role in virus mRNA splicing is largely unknown. Here, we identify the m(6)A reader protein YTHDC1 as a host factor that associates with influenza A virus NS1 protein and modulates viral mRNA splicing. YTHDC1 levels are enhanced by IAV infection. We demonstrate that YTHDC1 inhibits NS splicing by binding to an NS 3 ' splicing site and promotes IAV replication and pathogenicity in vitro and in vivo. Our results provide a mechanistic understanding of IAV-host interactions, a potential therapeutic target for blocking influenza virus infection, and a new avenue for the development of attenuated vaccines. Author summaryInfluenza A virus (IAV) causes significant morbidity and mortality in humans and animals worldwide. Although we have learned a lot about the influenza virus over the past several decades, the detailed interaction patterns between host proteins and viral proteins that lead to infection remain underexplored. Here, we determined that YTHDC1, an m(6)A reader, was required for influenza virus replication. Our research suggests that YTHDC1 inhibits NS splicing by binding to an NS 3 ' splicing site and promotes IAV replication and pathogenicity in vitro and in vivo. Our results provide an uncovered new mechanism into the biology and pathogenicity of the influenza A virus.