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Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters.
PLoS Pathog. 2009 Mar; 5(3):e1000356.PP

Abstract

The switch between latent and lytic Epstein-Barr virus (EBV) infection is mediated by the viral immediate-early (IE) protein, BZLF1 (Z). Z, a homologue of c-jun that binds to AP1-like motifs (ZREs), induces expression of the BRLF1 (R) and BRRF1 (Na) viral proteins, which cooperatively activate transcription of the Z promoter and thereby establish a positive autoregulatory loop. A unique feature of Z is its ability to preferentially bind to, and activate, the methylated form of the BRLF1 promoter (Rp). To date, however, Rp is the only EBV promoter known to be regulated in this unusual manner. We now demonstrate that the promoter driving transcription of the early BRRF1 gene (Nap) has two CpG-containing ZREs (ACGCTCA and TCGCCCG) that are only bound by Z in the methylated state. Both Nap ZREs are highly methylated in cells with latent EBV infection. Z efficiently activates the methylated, but not unmethylated, form of Nap in reporter gene assays, and both ZREs are required. Z serine residue 186, which was previously shown to be required for Z binding to methylated ZREs in Rp, but not for Z binding to the AP1 site, is required for Z binding to methylated Nap ZREs. The Z(S186A) mutant cannot activate methylated Nap in reporter gene assays and does not induce Na expression in cells with latent EBV infection. Molecular modeling studies of Z bound to the methylated Nap ZREs help to explain why methylation is required for Z binding, and the role of the Z Ser186 residue. Methylation-dependent Z binding to critical viral promoters may enhance lytic reactivation in latently infected cells, where the viral genome is heavily methylated. Conversely, since the incoming viral genome is initially unmethylated, methylation-dependent Z activation may also help the virus to establish latency following infection.

Authors+Show Affiliations

McArdle Laboratory, Departments of Oncology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19325883

Citation

Dickerson, Sarah J., et al. "Methylation-dependent Binding of the Epstein-barr Virus BZLF1 Protein to Viral Promoters." PLoS Pathogens, vol. 5, no. 3, 2009, pp. e1000356.
Dickerson SJ, Xing Y, Robinson AR, et al. Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. PLoS Pathog. 2009;5(3):e1000356.
Dickerson, S. J., Xing, Y., Robinson, A. R., Seaman, W. T., Gruffat, H., & Kenney, S. C. (2009). Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. PLoS Pathogens, 5(3), e1000356. https://doi.org/10.1371/journal.ppat.1000356
Dickerson SJ, et al. Methylation-dependent Binding of the Epstein-barr Virus BZLF1 Protein to Viral Promoters. PLoS Pathog. 2009;5(3):e1000356. PubMed PMID: 19325883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylation-dependent binding of the epstein-barr virus BZLF1 protein to viral promoters. AU - Dickerson,Sarah J, AU - Xing,Yongna, AU - Robinson,Amanda R, AU - Seaman,William T, AU - Gruffat,Henri, AU - Kenney,Shannon C, Y1 - 2009/03/27/ PY - 2008/12/09/received PY - 2009/02/27/accepted PY - 2009/3/28/entrez PY - 2009/3/28/pubmed PY - 2009/5/7/medline SP - e1000356 EP - e1000356 JF - PLoS pathogens JO - PLoS Pathog. VL - 5 IS - 3 N2 - The switch between latent and lytic Epstein-Barr virus (EBV) infection is mediated by the viral immediate-early (IE) protein, BZLF1 (Z). Z, a homologue of c-jun that binds to AP1-like motifs (ZREs), induces expression of the BRLF1 (R) and BRRF1 (Na) viral proteins, which cooperatively activate transcription of the Z promoter and thereby establish a positive autoregulatory loop. A unique feature of Z is its ability to preferentially bind to, and activate, the methylated form of the BRLF1 promoter (Rp). To date, however, Rp is the only EBV promoter known to be regulated in this unusual manner. We now demonstrate that the promoter driving transcription of the early BRRF1 gene (Nap) has two CpG-containing ZREs (ACGCTCA and TCGCCCG) that are only bound by Z in the methylated state. Both Nap ZREs are highly methylated in cells with latent EBV infection. Z efficiently activates the methylated, but not unmethylated, form of Nap in reporter gene assays, and both ZREs are required. Z serine residue 186, which was previously shown to be required for Z binding to methylated ZREs in Rp, but not for Z binding to the AP1 site, is required for Z binding to methylated Nap ZREs. The Z(S186A) mutant cannot activate methylated Nap in reporter gene assays and does not induce Na expression in cells with latent EBV infection. Molecular modeling studies of Z bound to the methylated Nap ZREs help to explain why methylation is required for Z binding, and the role of the Z Ser186 residue. Methylation-dependent Z binding to critical viral promoters may enhance lytic reactivation in latently infected cells, where the viral genome is heavily methylated. Conversely, since the incoming viral genome is initially unmethylated, methylation-dependent Z activation may also help the virus to establish latency following infection. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/19325883/Methylation_dependent_binding_of_the_epstein_barr_virus_BZLF1_protein_to_viral_promoters_ L2 - http://dx.plos.org/10.1371/journal.ppat.1000356 DB - PRIME DP - Unbound Medicine ER -