Abstract
Reactivation of Kaposi’s sarcoma-associated herpesvirus (KSHV) is important for persistent infection in the host as well as viral oncogenesis. The replication and transcription activator (RTA) encoded by KSHV ORF50 plays a central role in the switch from viral latency to lytic replication. Given that RTA is a transcriptional activator and RTA expression is sufficient to activate complete lytic replication, RTA must possess an elaborate mechanism for regulating its protein abundance. Previous studies have demonstrated that RTA could be degraded through the ubiquitin-proteasome pathway. A protein abundance regulatory signal (PARS), which consists of PARS I and PARS II, at the C-terminal region of RTA modulates its protein abundance. In the present study, we identified a host protein named Nuclear receptor coactivator 2 (NCOA2), which can interact with RTA in vitro and in vivo. We further showed that NCOA2 binds to the PARS II domain of RTA. We demonstrated that NCOA2 enhances RTA stability and prevents the proteasome-mediated degradation of RTA by competing with MDM2, an E3 ubiquitin ligase of RTA that interacts with the PARS II domain. Moreover, overexpression of NCOA2 in KSHV-infected cells significantly enhanced the expression level of RTA, which promotes the expression of RTA downstream viral lytic genes and lytic replication. In contrast, silencing of endogenous NCOA2 downregulated the expression of viral lytic genes and impaired viral lytic replication. Interestingly, we also found that RTA upregulates the expression of NCOA2 during lytic reactivation. Taken together, our data support the conclusion that NCOA2 is a novel RTA-binding protein that promotes RTA-driven lytic reactivation by increasing the stability of RTA, and the RTA-NCOA2 positive feedback regulatory loop plays an important role in KSHV reactivation.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8, is an oncogenic γ herpesvirus closely associated with an endothelial neoplasm, Kaposi’s sarcoma (KS), and two other lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3]
Reactivation of KSHV from latency to lytic replication plays an important role in viral spread, establishment of lifelong latent infection and disease progression
Further study revealed that Nuclear receptor coactivator 2 (NCOA2) competes with the E3 ubiquitin ligase of replication and transcription activator (RTA), MDM2, to interact with the protein abundance regulatory signal (PARS) II domain of RTA, which inhibits RTA degradation and enhances the stability of RTA
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8, is an oncogenic γ herpesvirus closely associated with an endothelial neoplasm, Kaposi’s sarcoma (KS), and two other lymphoproliferative diseases, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [1,2,3]. KSHV has two types of life cycles: latency and lytic replication [4]. KSHV evades host immunity by establishing a lifelong latent infection. In this phase, KSHV exhibits highly restricted gene expression patterns, and few viral particles are produced [5, 6]. Latent infection is the default life cycle of KSHV, the virus can be reactivated from latency by physiological stimuli, leading to the production of mature viruses [7,8,9,10]. HIV/AIDS patients receiving antiherpetic drugs to block lytic replication showed a reduced incidence of KS, confirming the role of lytic DNA replication and gene products in KSHV-mediated tumorigenesis [15,16,17]. Identifying the molecular events during the lytic replication cycle is critical to understanding KSHV pathogenesis and developing promising strategies to disrupt persistent KSHV infection and prevent the occurrence of KSHV-related diseases
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