Karlsson Questa H, Schelcher Celine, Verrall Elizabeth, Petosa Carlo, Sinclair Alison J
School of Life Sciences, University of Sussex, Brighton, UK.
Biochem Soc Trans. 2008 Aug;36(Pt 4):637-9. doi: 10.1042/BST0360637.
EBV (Epstein-Barr virus) alternates between latency and lytic replication. During latency, the viral genome is largely silenced by host-driven methylation of CpG motifs and in the switch to the lytic cycle this epigenetic silencing is overturned. A key event is the activation of the viral protein Zta with three ZREs (Zta-response elements) from the BRLF1 promoter (referred to as Rp). Two of these ZREs contain CpG motifs and are methylated in the latent genome. Biochemical analyses and molecular modelling of Zta bound to methylated RpZRE3 indicate the precise contacts made between a serine and a cysteine residue of Zta with methyl cytosines. A single point mutant of Zta, C189S, is defective in binding to the methylated ZREs both in vitro and in vivo. This was used to probe the functional relevance of the interaction. ZtaC189S was not able to activate Rp in a B-cell line, demonstrating the relevance of the interaction with methylated ZREs. This demonstrates that Zta plays a role in overturning the epigenetic control of viral latency.
爱泼斯坦-巴尔病毒（EBV）在潜伏和裂解复制之间交替。在潜伏期间，病毒基因组因宿主驱动的CpG基序甲基化而基本沉默，而在向裂解周期转变时，这种表观遗传沉默被推翻。一个关键事件是病毒蛋白Zta的激活，它带有来自BRLF1启动子（称为Rp）的三个Zta反应元件（ZRE）。其中两个ZRE包含CpG基序，在潜伏基因组中被甲基化。对与甲基化的RpZRE3结合的Zta进行的生化分析和分子建模表明，Zta的一个丝氨酸残基和一个半胱氨酸残基与甲基化胞嘧啶之间形成了精确的接触。Zta的一个单点突变体C189S在体外和体内与甲基化ZRE的结合均有缺陷。这被用于探究这种相互作用的功能相关性。ZtaC189S无法在B细胞系中激活Rp，证明了与甲基化ZRE相互作用的相关性。这表明Zta在推翻病毒潜伏的表观遗传控制中发挥作用。
