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AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome.
Proc Natl Acad Sci U S A. 2010 Jan 12; 107(2):850-5.PN

Abstract

EBV, a member of the herpes virus family, is a paradigm for human tumor viruses and a model of viral latency amenable for study in vitro. It induces resting human B lymphocytes to proliferate indefinitely in vitro and initially establishes a strictly latent infection in these cells. BZLF1, related to the cellular activating protein 1 (AP-1) family of transcription factors, is the viral master gene essential and sufficient to mediate the switch to induce the EBV lytic phase in latently infected B cells. Enigmatically, after infection BZLF1 is expressed very early in the majority of primary B cells, but its early expression fails to induce the EBV lytic phase. We show that the early expression of BZLF1 has a critical role in driving the proliferation of quiescent naïve and memory B cells but not of activated germinal center B cells. BZLF1's initial failure to induce the EBV lytic phase relies on the viral DNA at first being unmethylated. We have found that the eventual and inevitable methylation of viral DNA is a prerequisite for productive infection in stably, latently infected B cells which then yield progeny virus lacking cytosine-phosphatidyl-guanosine (CpG) methylation. This progeny virus then can repeat EBV's epigenetically regulated, biphasic life cycle. Our data indicate that the viral BZLF1 protein is crucial both to establish latency and to escape from it. Our data also indicate that EBV has evolved to appropriate its host's mode of methylating DNA for its own epigenetic regulation.

Authors+Show Affiliations

Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20080764

Citation

Kalla, Markus, et al. "AP-1 Homolog BZLF1 of Epstein-Barr Virus Has Two Essential Functions Dependent On the Epigenetic State of the Viral Genome." Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 2, 2010, pp. 850-5.
Kalla M, Schmeinck A, Bergbauer M, et al. AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. Proc Natl Acad Sci USA. 2010;107(2):850-5.
Kalla, M., Schmeinck, A., Bergbauer, M., Pich, D., & Hammerschmidt, W. (2010). AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. Proceedings of the National Academy of Sciences of the United States of America, 107(2), 850-5. https://doi.org/10.1073/pnas.0911948107
Kalla M, et al. AP-1 Homolog BZLF1 of Epstein-Barr Virus Has Two Essential Functions Dependent On the Epigenetic State of the Viral Genome. Proc Natl Acad Sci USA. 2010 Jan 12;107(2):850-5. PubMed PMID: 20080764.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. AU - Kalla,Markus, AU - Schmeinck,Anne, AU - Bergbauer,Martin, AU - Pich,Dagmar, AU - Hammerschmidt,Wolfgang, Y1 - 2009/12/22/ PY - 2010/1/19/entrez PY - 2010/1/19/pubmed PY - 2010/2/27/medline SP - 850 EP - 5 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 107 IS - 2 N2 - EBV, a member of the herpes virus family, is a paradigm for human tumor viruses and a model of viral latency amenable for study in vitro. It induces resting human B lymphocytes to proliferate indefinitely in vitro and initially establishes a strictly latent infection in these cells. BZLF1, related to the cellular activating protein 1 (AP-1) family of transcription factors, is the viral master gene essential and sufficient to mediate the switch to induce the EBV lytic phase in latently infected B cells. Enigmatically, after infection BZLF1 is expressed very early in the majority of primary B cells, but its early expression fails to induce the EBV lytic phase. We show that the early expression of BZLF1 has a critical role in driving the proliferation of quiescent naïve and memory B cells but not of activated germinal center B cells. BZLF1's initial failure to induce the EBV lytic phase relies on the viral DNA at first being unmethylated. We have found that the eventual and inevitable methylation of viral DNA is a prerequisite for productive infection in stably, latently infected B cells which then yield progeny virus lacking cytosine-phosphatidyl-guanosine (CpG) methylation. This progeny virus then can repeat EBV's epigenetically regulated, biphasic life cycle. Our data indicate that the viral BZLF1 protein is crucial both to establish latency and to escape from it. Our data also indicate that EBV has evolved to appropriate its host's mode of methylating DNA for its own epigenetic regulation. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/20080764/AP_1_homolog_BZLF1_of_Epstein_Barr_virus_has_two_essential_functions_dependent_on_the_epigenetic_state_of_the_viral_genome_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20080764 DB - PRIME DP - Unbound Medicine ER -