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Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta.
J Gen Virol. 2018 06; 99(6):805-817.JG

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.

Authors+Show Affiliations

School of Life Sciences, University of Sussex, Brighton, East Sussex, UK. Present address: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK. Present address: RS Mehta Jain Department of Biochemistry and Cell Biology, Vision Research Foundation, Sankara Nethralaya, Chennai, India.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.School of Life Sciences, University of Sussex, Brighton, East Sussex, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29580369

Citation

Almohammed, Rajaei, et al. "Mechanism of Activation of the BNLF2a Immune Evasion Gene of Epstein-Barr Virus By Zta." The Journal of General Virology, vol. 99, no. 6, 2018, pp. 805-817.
Almohammed R, Osborn K, Ramasubramanyan S, et al. Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta. J Gen Virol. 2018;99(6):805-817.
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. The Journal of General Virology, 99(6), 805-817. https://doi.org/10.1099/jgv.0.001056
Almohammed R, et al. Mechanism of Activation of the BNLF2a Immune Evasion Gene of Epstein-Barr Virus By Zta. J Gen Virol. 2018;99(6):805-817. PubMed PMID: 29580369.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta. AU - Almohammed,Rajaei, AU - Osborn,Kay, AU - Ramasubramanyan,Sharada, AU - Perez-Fernandez,Ijiel Barak Naranjo, AU - Godfrey,Anja, AU - Mancini,Erika J, AU - Sinclair,Alison J, Y1 - 2018/03/26/ PY - 2018/3/28/pubmed PY - 2019/3/29/medline PY - 2018/3/28/entrez KW - BNLF2a KW - BZLF1 KW - Epstein-Barr virus KW - epigenetics KW - gene expression KW - immune evasion SP - 805 EP - 817 JF - The Journal of general virology JO - J. Gen. Virol. VL - 99 IS - 6 N2 - 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. SN - 1465-2099 UR - https://www.unboundmedicine.com/medline/citation/29580369/Mechanism_of_activation_of_the_BNLF2a_immune_evasion_gene_of_Epstein_Barr_virus_by_Zta_ L2 - http://jgv.microbiologyresearch.org/pubmed/content/journal/jgv/10.1099/jgv.0.001056 DB - PRIME DP - Unbound Medicine ER -