HDAC6 Triggers the ATM-Dependent DNA Damage Response To Promote PRV Replication

Pseudorabies virus (PRV) is a member of the subfamily Alphaherpesvirinae of the family Herpesviridae. PRV infection in swine can lead to high morbidity and mortality of swine, causing huge economic losses. Pseudorabies virus (PRV) infection is modulated by various cellular host factors. In this study, we investigated the role of histone deacetylase 6 (HDAC6) in this process. We determined HDAC6 expression in vitro and performed gene knockout, pharmacological inhibition analyses, immunofluorescence assays, and statistical analyses. We found that the pharmacological and genetic inhibition of HDAC6 significantly decreased PRV replication, whereas its overexpression promoted PRV replication. Additionally, we demonstrated that PRV infection can induce the phosphorylation of histone H2AX and lead to DNA damage response (DDR), and the ataxia telangiectasia mutated (ATM) inhibitor KU55933 inhibits DDR and PRV infection. Mechanistically, the HDAC6 inhibitor tubacin and HDAC6 knockout can decrease DDR. The results of this study suggested that HDAC6 may be a crucial factor in PRV-induced ATM-dependent DDR to promote PRV replication.IMPORTANCE Pseudorabies virus (PRV) is a member of the subfamily Alphaherpesvirinae of the family Herpesviridae. PRV infection in swine can lead to high morbidity and mortality of swine, causing huge economic losses. In particular, PRV variants can cause severe damage to the nervous and respiratory systems of humans, revealing that PRV may be a potential zoonotic pathogen. Vaccines for PRV have been developed that can delay or reduce the epidemic, but they currently cannot eliminate this disease completely. Therefore, studies should investigate new targets for the prevention and control of PRV infection. In this study, we demonstrated that HDAC6 can induce ataxia telangiectasia mutated-dependent DNA damage response to foster PRV replication, indicating that HDAC6 is a therapeutic target for PRV infection.

Automated summary

Pseudorabies virus (PRV) infection in swine can cause high morbidity and mortality, leading to significant economic losses. In this study, the role of histone deacetylase 6 (HDAC6) in PRV infection was investigated. The inhibition of HDAC6 significantly decreased PRV replication, while its overexpression promoted PRV replication. PRV infection induced DNA damage response (DDR), and HDAC6 inhibition and knockout decreased DDR, suggesting that HDAC6 may be a crucial factor in promoting PRV replication.