Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.
Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.
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DOI：
10.18632/oncotarget.14540
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发表时间：
2017-01-31
期刊：
影响因子：
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通讯作者：
Lieberman PM
中科院分区：
文献类型：
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作者：
Dheekollu J;Malecka K;Wiedmer A;Delecluse HJ;Chiang AK;Altieri DC;Messick TE;Lieberman PM
EB病毒（Epstein-Barr Virus，EBV）潜伏感染是地方性鼻咽癌（Nasopharyngeal Carcinoma，NPC）的主要致病因子。NPC相关变异体已在EBV编码的核抗原EBNA 1中鉴定。在这里，我们解决了NPC衍生的EBNA 1 DNA结合域（DBD）的X射线晶体结构，并显示在远离DNA结合界面的表面上发现了变体氨基酸。我们表明，NPC衍生的EBNA 1是妥协的DNA复制和附加体维护功能。含有NPC EBNA 1 DBD的重组病毒在B细胞感染的早期阶段使原代B淋巴细胞永生化和抑制裂解性转录的能力受损。我们确定生存素作为一种宿主蛋白缺乏结合的鼻咽癌变异体的EBNA 1，并表明，生存素耗尽妥协EBV附加体维持在多种细胞类型。我们认为，EBNA 1的地方性变异通过改变使潜伏感染不稳定的关键调控相互作用，在EBV驱动的致癌作用中发挥重要作用。
Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.