ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus
The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds to a sequence element, ZV, located at nt −17 to −12 relative to the transcription initiation site of...
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| Format: | Online |
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Public Library of Science
2007
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134958/ |
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pubmed-21349582007-12-27 ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus Yu, Xianming Wang, Zhenxun Mertz, Janet E Research Article The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds to a sequence element, ZV, located at nt −17 to −12 relative to the transcription initiation site of the BZLF1 promoter, Zp, repressing transcription from Zp in a transient transfection assay. Here, we report the phenotype in the context of a whole EBV genome of a variant of EBV strain B95.8 containing a 2-bp substitution mutation in the ZV element of Zp that reduced, but did not eliminate, ZEB1 binding to Zp. Strikingly, epithelial 293 cells latently infected with the EBV ZV mutant spontaneously produced IE-, early-, and late-gene products and infectious virus, while wild-type (WT)-infected 293 cells did not and have never been reported to do so. Furthermore, treatment with the chemical inducers sodium butyrate and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to an additional order-of-magnitude production of infectious virus in the ZV mutant–infected 293 cells, but still no virus in the WT-infected 293 cells. Similarly, ZV mutant–infected Burkitt's lymphoma BJAB cells accumulated at least 10-fold more EBV IE mRNAs than did WT-infected BJAB cells, with TPA or sodium butyrate treatment leading to an additional 5- to 10-fold accumulation of EBV IE mRNAs in the ZV mutant–infected cells. Thus, we conclude that ZEB1 binding to Zp plays a central role in regulating the latent-lytic switch in EBV-infected epithelial and B cells, suggesting ZEB1 as a target for lytic-induction therapies in EBV-associated malignancies. Public Library of Science 2007-12 2007-12-14 /pmc/articles/PMC2134958/ /pubmed/18085824 http://dx.doi.org/10.1371/journal.ppat.0030194 Text en © 2007 Yu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Yu, Xianming Wang, Zhenxun Mertz, Janet E |
| spellingShingle |
Yu, Xianming Wang, Zhenxun Mertz, Janet E ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| author_facet |
Yu, Xianming Wang, Zhenxun Mertz, Janet E |
| author_sort |
Yu, Xianming |
| title |
ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| title_short |
ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| title_full |
ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| title_fullStr |
ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| title_full_unstemmed |
ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus |
| title_sort |
zeb1 regulates the latent-lytic switch in infection by epstein-barr virus |
| description |
The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds to a sequence element, ZV, located at nt −17 to −12 relative to the transcription initiation site of the BZLF1 promoter, Zp, repressing transcription from Zp in a transient transfection assay. Here, we report the phenotype in the context of a whole EBV genome of a variant of EBV strain B95.8 containing a 2-bp substitution mutation in the ZV element of Zp that reduced, but did not eliminate, ZEB1 binding to Zp. Strikingly, epithelial 293 cells latently infected with the EBV ZV mutant spontaneously produced IE-, early-, and late-gene products and infectious virus, while wild-type (WT)-infected 293 cells did not and have never been reported to do so. Furthermore, treatment with the chemical inducers sodium butyrate and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to an additional order-of-magnitude production of infectious virus in the ZV mutant–infected 293 cells, but still no virus in the WT-infected 293 cells. Similarly, ZV mutant–infected Burkitt's lymphoma BJAB cells accumulated at least 10-fold more EBV IE mRNAs than did WT-infected BJAB cells, with TPA or sodium butyrate treatment leading to an additional 5- to 10-fold accumulation of EBV IE mRNAs in the ZV mutant–infected cells. Thus, we conclude that ZEB1 binding to Zp plays a central role in regulating the latent-lytic switch in EBV-infected epithelial and B cells, suggesting ZEB1 as a target for lytic-induction therapies in EBV-associated malignancies. |
| publisher |
Public Library of Science |
| publishDate |
2007 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134958/ |
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1611419198063378432 |