The ubiquitin-proteasome system is essential for efficient propagation of Pseudorabies virus.

Pseudorabies virus (PRV) is a pathogen that affects multiple animal species and can infect nearly all mammals, with pigs being its natural host. PRV infection in pigs causes significant economic losses in global pig industry. The ubiquitin-proteasome system (UPS) plays a crucial role in cellular protein homeostasis by regulating protein quality. Nevertheless, the interplay between PRV and UPS is not well understood. In this study, We investigated the role of UPS in PRV replication. We found that the proteasome inhibitors (MG132, Lactacystin, and Bortezomib) significantly decreased PRV replication in a dose dependent manner. The suppression of the UPS primarily occurs at the early stage of virus replication. MG132 impaired the PRV uncoating process. In addition, PRV infection dramatically reduced the expression of poly-ubiquitin and free ubiquitin. Ectopic expression of ubiquitin in MG132-treated cells partially mitigated the inhibitory effect of MG132 on PRV proliferation. These findings suggest that PRV exploits the UPS to enhance its own replication.