Host Ubiquitin-Specific Proteases Regulate All Stages of Herpesvirus Infection

Herpesviruses are a large group of double-stranded-DNA viruses that replicate their genomes in the nucleus, forming large replication compartments during lytic infection. Herpesviruses are known to modulate host DNA replication and DNA damage-repair proteins to promote their replication. Ubiquitination is a cellular process that can alter protein stability, localization, and availability, including that of multiple proteins involved in genome maintenance. Ubiquitin-specific proteases (USPs) are a class of deubiquitinating enzymes (DUBs) that counter this process by removing ubiquitin chains, thus acting as another level of regulation. Proteins from each of the three herpesvirus subfamilies (alpha-, beta-, and gammaherpesviruses) have been reported to interact with at least one host USP, and USP7 in particular is reported as a target in representatives of all three subfamilies. In this review, we give an up-to-date summary of herpesviruses–USPs interactions, with special emphasis on DNA replication, and how these interactions could shape infection outcomes. We also examine published proteomic datasets for herpesvirus-driven host-proteome modulation and offer a framework for future directions to prioritize potentially important, understudied USPs. Lastly, we visit herpesvirus-encoded DUBs and highlight their roles in viral replication by remodeling ubiquitin signaling, discussing viral DUBs and virus–USP interfaces as proposed antiviral targets.