DNA-Binding-Defective Mutants of the Epstein-Barr Virus Lytic Switch Activator Zta Transactivate with Altered Specificities

Flemington, Erik K.; Lytle, J P; Cayrol, Corinne; Borrás, Ana M.; Speck, Samuel H.

doi:10.1128/mcb.14.5.3041-3052.1994

Cited by 16 publications

(1 citation statement)

References 45 publications

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“…pSG5-Rta and pSG5-Zta (aka pSVNaeZ) expression vectors have been previously described [ 72 , 73 ]. The Zta-d27/53, Zta-d102/153, and the Zta-dbm1 construct were kind gifts of Erik Flemington [ 74 , 75 ]. The Rta-Flag expression vector [ 76 ] was a kind gift of Lori Frappier.…”

Section: Methodsmentioning

confidence: 99%

Rta is the principal activator of Epstein-Barr virus epithelial lytic transcription

et al. 2022

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The transition from latent Epstein-Barr virus (EBV) infection to lytic viral replication is mediated by the viral transcription factors Rta and Zta. Although both are required for virion production, dissecting the specific roles played by Rta and Zta is challenging because they induce each other’s expression. To circumvent this, we constructed an EBV mutant deleted for the genes encoding Rta and Zta (BRLF1 and BZLF1, respectively) in the Akata strain BACmid. This mutant, termed EBVΔRZ, was used to infect several epithelial cell lines, including telomerase-immortalized normal oral keratinocytes, a highly physiologic model of EBV epithelial cell infection. Using RNA-seq, we determined the gene expression induced by each viral transactivator. Surprisingly, Zta alone only induced expression of the lytic origin transcripts BHLF1 and LF3. In contrast, Rta activated the majority of EBV early gene transcripts. As expected, Zta and Rta were both required for expression of late gene transcripts. Zta also cooperated with Rta to enhance a subset of early gene transcripts (Rtasynergy transcripts) that Zta was unable to activate when expressed alone. Interestingly, Rta and Zta each cooperatively enhanced the other’s binding to EBV early gene promoters, but this effect was not restricted to promoters where synergy was observed. We demonstrate that Zta did not affect Rtasynergy transcript stability, but increased Rtasynergy gene transcription despite having no effect on their transcription when expressed alone. Our results suggest that, at least in epithelial cells, Rta is the dominant transactivator and that Zta functions primarily to support DNA replication and co-activate a subset of early promoters with Rta. This closely parallels the arrangement in KSHV where ORF50 (Rta homolog) is the principal activator of lytic transcription and K8 (Zta homolog) is required for DNA replication at oriLyt.

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Section: Methodsmentioning

confidence: 99%

Rta is the principal activator of Epstein-Barr virus epithelial lytic transcription

et al. 2022

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The lytic phase of Epstein–Barr virus plays an important role in tumorigenesis

2022

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The Epstein–Barr virus latencyBamHI-Q promoter is positively regulated by STATs and Zta interference with JAK/STAT activation leads to loss ofBamHI-Q promoter activity

Chen

Lee

Wang

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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In Epstein-Barr virus (EBV)-associated tumors in nonimmunocompromised patients, EBV gene expression is highly restricted. EBV-encoded nuclear antigen (EBNA)-1 is expressed, whereas the immunogenic and proliferative EBNAs are not. This pattern of EBNA expression is generated by usage of the BamHI-Q promoter (Qp). We have determined that the JAK/STAT pathway positively regulates Qp activity. Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that is carried by the majority of the population as a latent, persistent infection. Primary exposure to EBV may result in infectious mononucleosis, and EBV is also associated with both B cell and epithelial malignancies (1). Different forms of EBV latency are recognized, and these are defined by the extent of latent viral gene expression (2). During primary exposure, EBV infection of B cells gives rise to a population of cells that express the full spectrum of EBV-encoded nuclear antigens (EBNAs) and latency membrane proteins (LMPs) as well as the BamHI-A rightward transcripts and the polymerase III transcribed, noncoding EBERs. This expression pattern, which has been termed latency III (3), is also seen in lymphoblastoid cell lines in culture. Among the genes expressed in latency III are those for the growth-proliferative and highly immunogenic EBNA-2-and EBNA-3-family proteins (4). The question of how a lifelong latent infection could persist in the face of an active cytotoxic T cell response has recently been clarified by the recognition that in vivo latency in healthy EBVseropositive individuals takes place in resting B cells with a memory B cell phenotype (5, 6). In these cells, EBV gene expression is extremely limited. The only viral transcripts consistently detected are those for LMP-2A and the BamHI-A rightward transcripts (7-9). EBV-associated tumors demonstrate a third pattern of latency-gene expression (latency I/II) in which only EBNA-1 and the BamHI-A rightward transcripts are expressed (latency I) or there is variable expression of the latency membrane proteins LMP-1, LMP-2A, and LMP-2B in additon to EBNA-1 and the BamHI-A rightward transcripts (latency II) (1).

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DNA-Binding-Defective Mutants of the Epstein-Barr Virus Lytic Switch Activator Zta Transactivate with Altered Specificities

Cited by 16 publications

References 45 publications

Rta is the principal activator of Epstein-Barr virus epithelial lytic transcription

Rta is the principal activator of Epstein-Barr virus epithelial lytic transcription

The lytic phase of Epstein–Barr virus plays an important role in tumorigenesis

The Epstein–Barr virus latencyBamHI-Q promoter is positively regulated by STATs and Zta interference with JAK/STAT activation leads to loss ofBamHI-Q promoter activity

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