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

Almohammed, Rajaei, Osborn, Kay, Ramasubramanyan, Sharada, Naranjo Perez-Fernandez, Ijiel Barak, Godfrey, Anja, Mancini, Erika J and Sinclair, Alison J (2018) Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta. Journal of General Virology, 99. pp. 805-817. ISSN 0022-1317

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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.

Item Type: Article
Keywords: virus, gene expression, immune evasion, cancer
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Gene Expression Research Group
Haematology Research Group
Subjects: Q Science
Q Science > QL Zoology
Q Science > QR Microbiology
Q Science > QR Microbiology > QR0355 Virology
Related URLs:
Depositing User: Alison Sinclair
Date Deposited: 10 Apr 2018 15:09
Last Modified: 01 Jul 2019 12:46

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Project NameSussex Project NumberFunderFunder Ref
Deciphering the complex mechanisms that reprogram gene expression during Epstein Barr Virus replicatG0803MRC-MEDICAL RESEARCH COUNCILMR/J001708/1
Working with the enemy: how does a cellular protein combine with two viral proteins to reprogram gene expression?UnsetUNIVERSITY OF SUSSEXRDF4-002