Open AccessSTUB1 is targeted by the SUMO-interacting motif of EBNA1 to maintain Epstein-Barr Virus latency
Author(s) -
Yuyan Wang,
Shujuan Du,
Changlian Zhu,
Chong Wang,
Nuoya Yu,
Zhengxi Lin,
Gan Jin,
Yi Guo,
Xinxin Huang,
Yuping He,
Erle S. Robertson,
Di Qu,
Fang Wei,
Qiliang Cai
Publication year - 2020
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1008447
Subject(s) - lytic cycle , sumo protein , gene silencing , biology , virus latency , microbiology and biotechnology , viral replication , cancer research , virus , virology , gene , genetics , ubiquitin
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 EBNA SIM 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 EBNA1 SIM motif plays an essential role in EBV latency and is a potential therapeutic target against EBV-associated cancers.