Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta

Rajaei Almohammed, Kay Osborn, Sharada Ramasubramanyan, Ijiel Barak Naranjo Perez-Fernandez, Anja Godfrey, Erika J. Mancini, Alison J. Sinclair (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Article number001056
Pages (from-to)805-817
Number of pages13
JournalJournal of General Virology
Volume99
Issue number6
Early online date26 Mar 2018
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Journal article
  • Gene expression
  • BZLF1
  • Epigenetics
  • Epstein-Barr virus
  • Immune evasion
  • BNLF2a
  • BZLF1
  • Epstein-Barr virus
  • Immune evasion
  • epigenetics
  • immune evasion
  • gene expression

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    Almohammed, R., Osborn, K., Ramasubramanyan, S., Perez-Fernandez, I. B. N., Godfrey, A., Mancini, E. J., & Sinclair, A. J. (2018). Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta. Journal of General Virology, 99(6), 805-817. [001056]. https://doi.org/10.1099/jgv.0.001056