Protein Degradation by Gammaherpesvirus RTAs: More Than Just Viral Transactivators

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the Gammaherpesvirus subfamily that encodes several viral proteins with intrinsic E3 ubiquitin ligase activity or the ability to hijack host E3 ubiquitin ligases to modulate the host’s immune response and to support the viral life cycle. This review focuses specifically on how the immediate-early KSHV protein RTA (replication and transcription activator) hijacks the host’s ubiquitin–proteasome pathway (UPP) to target cellular and viral factors for protein degradation to allow for robust lytic reactivation. Notably, RTA’s targets are either potent transcription repressors or they are activators of the innate and adaptive immune response, which block the lytic cycle of the virus. This review mainly focuses on what is currently known about the role of the E3 ubiquitin ligase activity of KSHV RTA in the regulation of the KSHV life cycle, but we will also discuss the potential role of other gammaherpesviral RTA homologs in UPP-mediated protein degradation.