Abstract
Latent Epstein-Barr virus (EBV) infection is strongly associated with several malignancies, including B-cell lymphomas and epithelial tumors. EBNA1 is a key antigen expressed in all EBV-associated tumors during latency that is required for maintenance of the EBV episome DNA and the regulation of viral gene transcription. However, the mechanism utilized by EBV to maintain latent infection at the levels of posttranslational regulation remains largely unclear. Here, we report that EBNA1 contains two SUMO-interacting motifs (SIM2 and SIM3), and mutation of SIM2, but not SIM3, dramatically disrupts the EBNA1 dimerization, while SIM3 contributes to the polySUMO2 modification of EBNA1 at lysine 477 in vitro. Proteomic and immunoprecipitation analyses further reveal that the SIM3 motif is required for the EBNA1-mediated inhibitory effects on SUMO2-modified STUB1, SUMO2-mediated degradation of USP7, and SUMO1-modified KAP1. Deletion of the EBNASIM motif leads to functional loss of both EBNA1-mediated viral episome maintenance and lytic gene silencing. Importantly, hypoxic stress induces the SUMO2 modification of EBNA1, and in turn the dissociation of EBNA1 with STUB1, KAP1 and USP7 to increase the SUMO1 modification of both STUB1 and KAP1 for reactivation of lytic replication. Therefore, the EBNA1SIM motif plays an essential role in EBV latency and is a potential therapeutic target against EBV-associated cancers.
Highlights
Epstein-Barr virus (EBV) was the first human tumor virus to be discovered
We found that EBNA1 contains a Small Ubiquitin-related modifier (SUMO)-interacting motif (SIM) named EBNA1SIM, which is required for EBNA1 to exert inhibitory effects on a SUMO2-modified complex (SC2) including STUB1, KAP1 and USP7
The results showed that deletion of either the SIM2 or SIM3 motif strikingly reduced the binding ability of EBNA1 to His-SUMO1 or His-SUMO2 recombinant protein, while deletion of SIM1 presented no effect (Fig 1B)
Summary
Epstein-Barr virus (EBV) was the first human tumor virus to be discovered. It was identified from Burkitt’s lymphoma (BL) in 1964, and accounts for approximately 2% of all cancer deaths in the world to date [1]. The EBV-encoded nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated malignancies [5]. EBNA1 is essential for viral genome DNA replication and maintenance and as well as controlling viral gene expression [2]. It has been demonstrated that EBNA1 is a multiple functional protein that interacts with numerous host proteins, such as EBP2 [6], USP7 [7], casein kinase 2 [8], Tankyrase 1 [9], PRMT5 and P32/ TAP [10], among others, playing a critical role in the onset, progression, and/or maintenance of its associated tumors [10,11]
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