Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies. Author summary: Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with several human malignancies. The life cycle of KSHV comprises latency and the lytic phase. The transition from latency to the lytic phase, known as reactivation, is crucial for viral replication and pathogenesis. Previous studies have established that KSHV reactivation is orchestrated by a viral transcription factor, RTA. However, the specific molecular mechanisms governing RTA stability have remained elusive. In this study, we demonstrate that KSHV RTA recruits two host deubiquitinases (DUBs), OTUD4, and USP7, to promote RTA deubiquitination and stabilization, facilitating viral reactivation. Intriguingly, the DUB activity of OTUD4 is dispensable; instead, OTUD4 serves as an adaptor protein that recruits USP7 to deubiquitinate and stabilize RTA. Our study not only unveils the mechanism by which KSHV exploits the OTUD4-USP7 deubiquitinases to enhance lytic reactivation but also provides insights into the development of novel antiviral therapeutic strategies targeting host deubiquitinase complexes. [ABSTRACT FROM AUTHOR]