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

Yinxing Zhu; Ruifang Wang; Jiahui Zou; Shan Tian; Luyao Yu; Yuanbao Zhou; Ying Ran; Meilin Jin; Huanchun Chen; Hongbo Zhou

doi:10.1371/journal.ppat.1011305

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

PLoS Pathog. 2023 Apr 13;19(4):e1011305. doi: 10.1371/journal.ppat.1011305. eCollection 2023 Apr.

Authors

Yinxing Zhu^{1

2}, Ruifang Wang^{1

2}, Jiahui Zou^{1

2}, Shan Tian^{1

2}, Luyao Yu^{1

2}, Yuanbao Zhou^{1

2}, Ying Ran^{1

2}, Meilin Jin^{1

2}, Huanchun Chen^{1

2

3}, Hongbo Zhou^{1

2

3}

Affiliations

¹ State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
² Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China.
³ Hubei Hongshan Laboratory, Wuhan, China.

Abstract

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.

Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Influenza A virus* / genetics
Influenza A virus* / metabolism
Influenza, Human* / genetics
Nerve Tissue Proteins / metabolism
RNA Splicing Factors / metabolism
RNA, Messenger / genetics
Virus Replication / genetics

Substances

RNA, Messenger
YTHDC1 protein, human
RNA Splicing Factors
Nerve Tissue Proteins

Grants and funding

This work was supported by the National Key Research and Development Program (2021YFD1800204 to H.Z.), the National Natural Science Foundation of China (32102645 to Y.Z., and 32025036 to H.Z.), China Postdoctoral Science Foundation (2020M680104 to Y.Z.), the Natural Science Foundation of Hubei Province (2021CFA016 to H.Z.), the Earmarked fund (CARS-41 to H.Z.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.