近日，国际学术期刊PLOS Pathogens在线发表病毒学国家重点实验室蓝柯研究组题为“NCOA2 promotes lyticreactivation of Kaposi’s sarcoma-associated herpesvirus by enhancing theexpression of the master switch protein RTA”（NCOA2通过增强开关蛋白RTA的表达促进卡波氏肉瘤病毒的裂解复制）的论文。该研究揭示了宿主蛋白核受体辅助激活因子NCOA2通过增强KSHV再激活开关蛋白RTA的表达从而促进KSHV再激活裂解复制的功能机制。
蓝柯研究组长期从事KSHV生命周期调控及致瘤机制研究，为探索宿主分子对RTA的调控作用，他们通过质谱等技术筛选到一个新的RTA结合蛋白NCOA2。研究发现，在KSHV再激活裂解复制的过程中，NCOA2被RTA招募至其C末端的PARS II 结构域，从而抑制MDM2介导的RTA蛋白酶体途径的泛素化降解，使得RTA表达更加稳定，最终促进KSHV再激活裂解复制的完成。
Figure：The interaction between endogenous NCOA2 and RTA.
Author summary:Reactivation of KSHV from latency to lytic replication plays an important role in viral spread, establishment of lifelong latent infection and disease progression. RTA, the lytic switch protein, is essential and sufficient for triggering the full viral lytic program. Here, we report a host protein named NCOA2 as a novel RTA-binding protein. Direct interaction of NCOA2 with RTA increased the expression level of RTA. Further study revealed that NCOA2 competes with the E3 ubiquitin ligase of RTA, MDM2, to interact with the PARS II domain of RTA, which inhibits RTA degradation and enhances the stability of RTA. In the context of KSHV-infected cells, we showed that NCOA2 plays an important role in promoting RTA-driven lytic reactivation.
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.