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

• Published in: PLoS pathogens Vol. 19; no. 4; p. e1011305
• Main Authors: Zhu, Yinxing, Wang, Ruifang, Zou, Jiahui, Tian, Shan, Yu, Luyao, Zhou, Yuanbao, Ran, Ying, Jin, Meilin, Chen, Huanchun, Zhou, Hongbo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2023; Public Library of Science (PLoS)
• Subjects: Antibodies; Biology and life sciences; Gene expression; Humans; Infections; Infectivity; Influenza; Influenza A; Influenza A virus - genetics; Influenza A virus - metabolism; Influenza, Human - genetics; Medicine and health sciences; mRNA; N6-methyladenosine; Nerve Tissue Proteins - metabolism; NS1 protein; Pathogenicity; Pathogens; Protein expression; Proteins; Replication; Research and Analysis Methods; RNA Splicing Factors - metabolism; RNA, Messenger - genetics; Splicing; Therapeutic targets; Vaccines; Virus Replication - genetics; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011305

N6-methyladenosine (m6A) modification on viral RNAs has a profound impact on infectivity. m6A is also a highly pervasive modification for influenza viral RNAs. However, its role in virus mRNA splicing is largely unknown. Here, we identify the m6A 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.