Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Pei-Lun Yu; Rui Wu; San-Jie Cao; Yi-Ping Wen; Xiao-Bo Huang; Shan Zhao; Yi-Fei Lang; Qin Zhao; Ju-Chun Lin; Sen-Yan Du; Shu-Min Yu; Qi-Gui Yan

doi:10.3389/fmicb.2023.1087484

Pseudorabies virus exploits N⁶-methyladenosine modification to promote viral replication

Front Microbiol. 2023 Feb 3:14:1087484. doi: 10.3389/fmicb.2023.1087484. eCollection 2023.

Authors

Pei-Lun Yu^{1

2}, Rui Wu^{1

2}, San-Jie Cao^{1

2}, Yi-Ping Wen^{1

2}, Xiao-Bo Huang^{1

2}, Shan Zhao^{1

2}, Yi-Fei Lang^{1

2}, Qin Zhao^{1

2}, Ju-Chun Lin², Sen-Yan Du^{1

2}, Shu-Min Yu², Qi-Gui Yan^{1

2}

Affiliations

¹ Department of Preventive Veterinary Medicine, Swine Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
² Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China.

Abstract

Introduction: Pseudorabies virus (PRV) is the pathogenic virus of porcine pseudorabies (PR), belonging to the Herpesviridae family. PRV has a wide range of hosts and in recent years has also been reported to infect humans. N⁶-methyladenosine (m⁶A) modification is the major pathway of RNA post-transcriptional modification. Whether m⁶A modification participates in the regulation of PRV replication is unknown.

Methods: Here, we investigated that the m⁶A modification was abundant in the PRV transcripts and PRV infection affected the epitranscriptome of host cells. Knockdown of cellular m⁶A methyltransferases METTL3 and METTL14 and the specific binding proteins YTHDF2 and YTHDF3 inhibited PRV replication, while silencing of demethylase ALKBH5 promoted PRV output. The overexpression of METTL14 induced more efficient virus proliferation in PRV-infected PK15 cells. Inhibition of m⁶A modification by 3-deazaadenosine (3-DAA), a m⁶A modification inhibitor, could significantly reduce viral replication.

Results and discussion: Taken together, m⁶A modification played a positive role in the regulation of PRV replication and gene expression. Our research revealed m⁶A modification sites in PRV transcripts and determined that m⁶A modification dynamically mediated the interaction between PRV and host.

Keywords: N6-methyladenosine; m6A regulators; pseudorabies virus; regulation; replication.