Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta.
Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta.
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DOI：
10.1099/jgv.0.001056
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Sinclair AJ
中科院分区：
文献类型：
--
作者：
Almohammed R;Osborn K;Ramasubramanyan S;Perez-Fernandez IBN;Godfrey A;Mancini EJ;Sinclair AJ
人类γ疱疹病毒Epstein-Barr病毒（EBV）利用多种途径逃避细胞免疫应答。在EBV裂解性复制周期期间，表达的病毒蛋白质为细胞毒性T细胞的识别提供了极好的靶标。这是由病毒BNLF 2a基因抵消。在潜伏期的B细胞中，BNLF 2a不表达，我们发现其调控区嵌入抑制性染色质中。BNLF 2a的表达反映了病毒裂解周期转录调节因子Zta（BZLF 1，EB 1，ZEBRA）在B细胞中的表达，我们认为Zta在上调BNLF 2a中起作用。在经历EBV裂解复制的细胞中，我们鉴定了Zta与染色质相关的BNLF 2a启动子的两个不同的相互作用区域。我们确定了五个潜在的Zta响应元件（ZRE）的启动子之间的病毒分离株高度保守。Zta在体外与这些元件结合并激活上皮细胞和B细胞中BNLF 2a启动子的表达。我们还发现ZRE之间存在冗余。EBV基因组在其感染周期期间经历双相DNA甲基化周期。其中一个ZRE含有完整的CpG基序。我们表明，这可以是DNA甲基化在EBV潜伏期和Zta结合和启动子激活增强其甲基化。总之，我们发现BNLF 2a启动子直接被Zta靶向，并且近端ZRE内的DNA甲基化有助于激活。这一关键的病毒基因的调节过程中，从潜伏期的EBV重新激活的影响进行了讨论。
The human gamma herpes virus Epstein–Barr virus (EBV) exploits multiple routes to evade the cellular immune response. During the EBV lytic replication cycle, viral proteins are expressed that provide excellent targets for recognition by cytotoxic T cells. This is countered by the viral BNLF2a gene. In B cells during latency, where BNLF2a is not expressed, we show that its regulatory region is embedded in repressive chromatin. The expression of BNLF2a mirrors the expression of a viral lytic cycle transcriptional regulator, Zta (BZLF1, EB1, ZEBRA), in B cells and we propose that Zta plays a role in up-regulating BNLF2a. In cells undergoing EBV lytic replication, we identified two distinct regions of interaction of Zta with the chromatin-associated BNLF2a promoter. We identify five potential Zta-response elements (ZREs) in the promoter that are highly conserved between virus isolates. Zta binds to these elements in vitro and activates the expression of the BNLF2a promoter in both epithelial and B cells. We also found redundancy amongst the ZREs. The EBV genome undergoes a biphasic DNA methylation cycle during its infection cycle. One of the ZREs contains an integral CpG motif. We show that this can be DNA methylated during EBV latency and that both Zta binding and promoter activation are enhanced by its methylation. In summary, we find that the BNLF2a promoter is directly targeted by Zta and that DNA methylation within the proximal ZRE aids activation. The implications for regulation of this key viral gene during the reactivation of EBV from latency are discussed.
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影响因子：
5.4
作者：
Horst, Danielle;Burrows, Scott R.;Wiertz, Emmanuel J. H. J.
通讯作者：
Wiertz, Emmanuel J. H. J.
影响因子：
30.3
作者：
Arvey A;Tempera I;Tsai K;Chen HS;Tikhmyanova N;Klichinsky M;Leslie C;Lieberman PM
通讯作者：
Lieberman PM
影响因子：
6.7
作者：
Croft NP;Shannon-Lowe C;Bell AI;Horst D;Kremmer E;Ressing ME;Wiertz EJ;Middeldorp JM;Rowe M;Rickinson AB;Hislop AD
通讯作者：
Hislop AD
影响因子：
6.7
作者：
Bergbauer M;Kalla M;Schmeinck A;Göbel C;Rothbauer U;Eck S;Benet-Pagès A;Strom TM;Hammerschmidt W
通讯作者：
Hammerschmidt W
影响因子：
5.6
作者：
Buisson, Marlyse;Geoui, Thibault;Burmeister, Wim P.
通讯作者：
Burmeister, Wim P.