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SRSF5-Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host-Directed Target Against Influenza Virus

Li, Qiuchen; Jiang, Zhimin; Ren, Shuning; Guo, Hui; Song, Zhimin; Chen, Saini; Gao, Xintao; Meng, Fanfeng; Zhu, Junda; Liu, Litao; Tong, Qi; Sun, Honglei; Sun, Yipeng; Pu, Juan; Chang, Kin Chow; Liu, Jinhua

SRSF5-Mediated Alternative Splicing of M Gene is Essential for Influenza A Virus Replication: A Host-Directed Target Against Influenza Virus Thumbnail


Authors

Qiuchen Li

Zhimin Jiang

Shuning Ren

Hui Guo

Zhimin Song

Saini Chen

Xintao Gao

Fanfeng Meng

Junda Zhu

Litao Liu

Qi Tong

Honglei Sun

Yipeng Sun

Juan Pu

KIN-CHOW CHANG KIN-CHOW.CHANG@NOTTINGHAM.AC.UK
Professor of Veterinary Molecular Medicine

Jinhua Liu



Abstract

Splicing of influenza A virus (IAV) RNA is an essential process in the viral life cycle that involves the co-opting of host factors. Here, it is demonstrated that induction of host serine and arginine-rich splicing factor 5 (SRSF5) by IAV facilitated viral replication by enhancing viral M mRNA splicing. Mechanistically, SRSF5 with its RRM2 domain directly bounds M mRNA at conserved sites (M mRNA position 163, 709, and 712), and interacts with U1 small nuclear ribonucleoprotein (snRNP) to promote M mRNA splicing and M2 production. Mutations introduced to the three binding sites, without changing amino acid code, significantly attenuates virus replication and pathogenesis in vivo. Likewise, SRSF5 conditional knockout in the lung protects mice against lethal IAV challenge. Furthermore, anidulafungin, an approved antifungal drug, is identified as an inhibitor of SRSF5 that effectively blocks IAV replication in vitro and in vivo. In conclusion, SRSF5 as an activator of M mRNA splicing promotes IAV replication and is a host-derived antiviral target.

Journal Article Type Article
Acceptance Date Aug 21, 2022
Online Publication Date Oct 18, 2022
Publication Date Dec 8, 2022
Deposit Date Oct 20, 2022
Publicly Available Date Oct 20, 2022
Journal Advanced Science
Electronic ISSN 2198-3844
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 9
Issue 34
Article Number 2203088
DOI https://doi.org/10.1002/advs.202203088
Keywords Research Article, Research Articles, alternative splicing, anidulafungin, influenza A viruses, SRSF5, U1 snRNP
Public URL https://nottingham-repository.worktribe.com/output/12619195
Publisher URL https://onlinelibrary.wiley.com/doi/10.1002/advs.202203088

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