Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication

Abstract

IntroductionPseudorabies 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.MethodsHere, 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 DiscussionTaken 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.

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response

“…METTL14 collaborates with METTL3 in regulating the replication of various viruses, including HCV [ 48 ], HDV [ 49 ], IAV [ 50 ], HSV-1 [ 51 ] and HIV [ 52 ], suggesting a supporting role for METTL14 in these viral infections. However, in the case of viruses like PCV2 [ 53 ], PRV [ 54 ], VSV [ 55 ], and EBV [ 24 ], METTL14 is shown to play a crucial role in promoting their replication. Our findings are aligned with this observation, demonstrating that the knockdown of METTL14 notably impedes CSFV replication, while its overexpression leads to an increase in viral load.…”

The hidden RNA code: implications of the RNA epitranscriptome in the context of viral infections

“…Besides the immune response, m 6 A can regulate other biological processes during viral infections. For example, pseudorabies (PRV) exploits its US3 protein to reduce the m 6 A methylome as part of the PRV-induced metabolic dysfunction ( Jansens et al, 2022 ; Yu et al, 2023 ). Reduced m 6 A on a -ketoglutarate dehydrogenase transcripts also hindered itaconate accumulation and contributed to mRNA decay during VSV infection ( Liu et al, 2019 ).…”