The Epstein-Barr Virus Immediate-Early Protein BZLF1 Induces both a G2 and a Mitotic Block

ABSTRACT The Epstein-Barr virus immediate-early protein BZLF1 is a transcriptional activator that mediates the switch from latent to lytic infection. Here we demonstrate that BZLF1 induces both a G2 block and a mitotic block in HeLa cells and inhibits chromosome condensation. While the G2 block is associated with decreased cyclin B1 in host cells and can be rescued by overexpression of cyclin B1, the mechanism for the mitotic defect is as yet undetermined.

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The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

PLoS Pathogens ◽

10.1371/journal.ppat.1002516 ◽

2012 ◽

Vol 8 (2) ◽

pp. e1002516 ◽

Cited By ~ 29

Author(s):

Amanda R. Robinson ◽

Swee Sen Kwek ◽

Shannon C. Kenney

Keyword(s):

Transcription Factor ◽

B Cell ◽

Epstein Barr Virus ◽

Immediate Early ◽

Specific Transcription Factor ◽

Barr Virus ◽

Virus Latency ◽

Early Protein ◽

Epstein Barr

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Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by InhibitingBAD-Mediatedcaspase-3-Dependent Apoptosis

Journal of Virology ◽

10.1128/jvi.02794-15 ◽

2015 ◽

Vol 90 (3) ◽

pp. 1359-1368 ◽

Cited By ~ 21

Author(s):

Hyoji Kim ◽

Hoyun Choi ◽

Suk Kyeong Lee

Keyword(s):

Epstein Barr Virus ◽

Caspase 3 ◽

Immune Surveillance ◽

Virus Production ◽

Lytic Cycle ◽

Host Cells ◽

Immediate Early ◽

Progeny Virus ◽

Barr Virus ◽

Epstein Barr

ABSTRACTEpstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and thein vivotriggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR-BART20-5p directly targets the immediate early genesBRLF1andBZLF1as well asBcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels ofBRLF1andBZLF1were suppressed in cells followingBADknockdown and increased afterBADoverexpression. Progeny virus production was also downregulated by specific knockdown ofBAD. Our results demonstrated thatcaspase-3-dependent apoptosis is a prerequisite forBAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibitingBAD-mediatedcaspase-3-dependent apoptosis, which would trigger immediate early gene expression.IMPORTANCEEBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressingBAD-inducedcaspase-3-dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis.

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Epstein-Barr Virus Immediate-Early Proteins BZLF1 and BRLF1 Activate the ATF2 Transcription Factor by Increasing the Levels of Phosphorylated p38 and c-Jun N-Terminal Kinases

Journal of Virology ◽

10.1128/jvi.74.3.1224-1233.2000 ◽

2000 ◽

Vol 74 (3) ◽

pp. 1224-1233 ◽

Cited By ~ 130

Author(s):

Amy L. Adamson ◽

Dayle Darr ◽

Elizabeth Holley-Guthrie ◽

Robert A. Johnson ◽

Amy Mauser ◽

...

Keyword(s):

Transcription Factor ◽

Epstein Barr Virus ◽

Viral Latency ◽

Immediate Early ◽

Expression Vectors ◽

Protein Z ◽

Barr Virus ◽

Ebv Infection ◽

Early Protein ◽

Epstein Barr

ABSTRACT Expression of either Epstein-Barr virus (EBV) immediate-early protein BZLF1 (Z) or BRLF1 (R) is sufficient to convert EBV infection from the latent to lytic form. Disruption of viral latency requires transcriptional activation of the Z and R promoters. The Z and R proteins are transcriptional activators, and each immediate-early protein activates expression of the other immediate-early protein. Z activates the R promoter through a direct binding mechanism. However, R does not bind directly to the Z promoter. In this study, we demonstrate that the ZII element (a cyclic AMP response element site) in the Z promoter is required for efficient activation by R. The ZII element has been shown to be important for induction of lytic EBV infection by tetradecanoyl phorbol acetate and surface immunoglobulin cross-linking and is activated by Z through an indirect mechanism. We demonstrate that both R and Z activate the cellular stress mitogen-activated protein (MAP) kinases, p38 and JNK, resulting in phosphorylation (and activation) of the cellular transcription factor ATF2. Furthermore, we show that the ability of R to induce lytic EBV infection in latently infected cells is significantly reduced by inhibition of either the p38 kinase or JNK pathways. In contrast, inhibition of stress MAP kinase pathways does not impair the ability of Z expression vectors to disrupt viral latency, presumably because expression of Z under the control of a strong heterologous promoter bypasses the need to activate Z transcription. Thus, both R and Z can activate the Z promoter indirectly by inducing ATF2 phosphorylation, and this activity appears to be important for R-induced disruption of viral latency.

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Epstein-Barr Virus Immediate-Early Protein BZLF1 Is SUMO-1 Modified and Disrupts Promyelocytic Leukemia Bodies

Journal of Virology ◽

10.1128/jvi.75.5.2388-2399.2001 ◽

2001 ◽

Vol 75 (5) ◽

pp. 2388-2399 ◽

Cited By ~ 171

Author(s):

Amy L. Adamson ◽

Shannon Kenney

Keyword(s):

Cell Lines ◽

Transcriptional Activation ◽

Epstein Barr Virus ◽

Promyelocytic Leukemia ◽

Lytic Replication ◽

Immediate Early ◽

Barr Virus ◽

Early Protein ◽

Pml Bodies ◽

Epstein Barr

ABSTRACT Although the immediate-early proteins of both herpes simplex virus (HSV) and cytomegalovirus (CMV) are known to modify promyelocytic leukemia (PML) (ND10) bodies in the nucleus of the host cell, it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect. The PML protein is induced by interferon, involved in major histocompatibility complex class I presentation, and necessary for certain types of apoptosis. Therefore, it is likely that PML bodies function in an antiviral capacity. SUMO-1 modification of PML is known to be required for the formation of PML bodies. To examine whether Epstein-Barr virus (EBV) lytic replication interferes with PML bodies, we expressed the EBV immediate-early genes BZLF1 (Z) and BRLF1 (R) in EBV-positive cell lines and examined PML localization. Both Z and R expression resulted in PML dispersion in EBV-positive cells. Z but not R expression is sufficient to disrupt PML bodies in EBV-negative cell lines. We show that dispersion of PML bodies by Z requires a portion of the transcriptional activation domain of Z but not the DNA-binding function. As was previously reported for the HSV-1 ICP0 and CMV IE1 proteins, Z reduces the amount of SUMO-1-modified PML. We also found that Z itself is SUMO-1 modified (through amino acid 12) and that Z competes with PML for limiting amounts of SUMO-1. These results suggest that disruption of PML bodies is important for efficient lytic replication of EBV. Furthermore, Z may potentially alter the function of a variety of cellular proteins by inhibiting SUMO-1 modification.

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Inhibition of IFN-γ Signaling by an Epstein-Barr Virus Immediate-Early Protein

Immunity ◽

10.1016/s1074-7613(01)00226-6 ◽

2001 ◽

Vol 15 (5) ◽

pp. 787-799 ◽

Cited By ~ 101

Author(s):

Thomas E Morrison ◽

Amy Mauser ◽

Athena Wong ◽

Jenny P.-Y Ting ◽

Shannon C Kenney

Keyword(s):

Epstein Barr Virus ◽

Immediate Early ◽

Barr Virus ◽

Early Protein ◽

Ifn Γ ◽

Epstein Barr

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Expression of Epstein–Barr virus BZLF1 immediate-early protein induces p53 degradation independent of MDM2, leading to repression of p53-mediated transcription

Virology ◽

10.1016/j.virol.2009.03.017 ◽

2009 ◽

Vol 388 (1) ◽

pp. 204-211 ◽

Cited By ~ 34

Author(s):

Yoshitaka Sato ◽

Noriko Shirata ◽

Ayumi Kudoh ◽

Satoko Iwahori ◽

Sanae Nakayama ◽

...

Keyword(s):

Epstein Barr Virus ◽

Immediate Early ◽

Barr Virus ◽

Early Protein ◽

Epstein Barr

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Epstein-Barr Virus BZLF1 Gene, a Switch from Latency to Lytic Infection, Is Expressed as an Immediate-Early Gene after Primary Infection of B Lymphocytes

Journal of Virology ◽

10.1128/jvi.01416-06 ◽

2006 ◽

Vol 81 (2) ◽

pp. 1037-1042 ◽

Cited By ~ 73

Author(s):

Wangrong Wen ◽

Dai Iwakiri ◽

Koji Yamamoto ◽

Seiji Maruo ◽

Teru Kanda ◽

...

Keyword(s):

Protein Synthesis ◽

B Lymphocytes ◽

Epstein Barr Virus ◽

Lytic Infection ◽

Early Gene ◽

Immediate Early ◽

Barr Virus ◽

Ebv Infection ◽

Bzlf1 Gene ◽

Epstein Barr

ABSTRACT We demonstrate here that the Epstein-Barr virus (EBV) BZLF1 gene, a switch from latent infection to lytic infection, is expressed as early as 1.5 h after EBV infection in Burkitt's lymphoma-derived, EBV-negative Akata and Daudi cells and primary B lymphocytes. Since BZLF1 mRNA is expressed even when the cells are infected with EBV in the presence of anisomycin, an inhibitor of protein synthesis, its expression does not require prerequisite protein synthesis, indicating that BZLF1 is expressed as an immediate-early gene following primary EBV infection of B lymphocytes.

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The C-Mer Gene Is Induced by Epstein-Barr Virus Immediate-Early Protein BRLF1

Journal of Virology ◽

10.1128/jvi.78.21.11778-11785.2004 ◽

2004 ◽

Vol 78 (21) ◽

pp. 11778-11785 ◽

Cited By ~ 11

Author(s):

Yuling Li ◽

Nupam P. Mahajan ◽

Jennifer Webster-Cyriaque ◽

Prasanna Bhende ◽

Gregory K. Hong ◽

...

Keyword(s):

Epstein Barr Virus ◽

Retinal Pigment ◽

Retinal Pigment Epithelial Cells ◽

Immediate Early ◽

Lymphoblastoid Cells ◽

Barr Virus ◽

Early Protein ◽

Hairy Leukoplakia ◽

Immediate Early Proteins ◽

Epstein Barr

ABSTRACT BRLF1 (R) is one of two Epstein-Barr virus (EBV) immediate-early proteins that mediate the switch from the latent to the lytic form of viral replication. In this report, we show that R induces expression of the cellular C-mer gene in a variety of cell lines. C-mer expression was detected in lymphoblastoid cells immortalized with wild-type EBV but not in lymphoblastoid cells immortalized with an EBV that had BRLF1 deleted. Oral hairy leukoplakia tongue tissue, which contains the lytic form of EBV replication, also has enhanced C-mer expression. C-mer is a receptor tyrosine kinase activated by the ligand Gas6. C-mer is required for phagocytosis of apoptotic debris by monocytes/macrophages and retinal pigment epithelial cells and is capable of producing an antiapoptotic signal. Modulation of the C-mer signal transduction cascade by a variety of different approaches did not alter the ability of R to induce lytic EBV gene transcription. Therefore, C-mer activation may be important for some other aspect of lytic EBV infection.

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Activation of the ERK signal transduction pathway by Epstein–Barr virus immediate-early protein Rta

Journal of General Virology ◽

10.1099/vir.0.2008/003897-0 ◽

2008 ◽

Vol 89 (10) ◽

pp. 2437-2446 ◽

Cited By ~ 29

Author(s):

Yu-Hsiu Lee ◽

Ya-Fang Chiu ◽

Wen-Hung Wang ◽

Li-Kwan Chang ◽

Shih-Tung Liu

Keyword(s):

Signal Transduction ◽

Epstein Barr Virus ◽

Signal Transduction Pathway ◽

Early Gene ◽

Immediate Early ◽

Transduction Pathway ◽

Binding Studies ◽

Barr Virus ◽

Early Protein ◽

Epstein Barr

BRCA1-associated protein 2 (BRAP2) is known to interact with the kinase suppressor of Ras 1 (KSR1), inhibiting the ERK signal transduction cascade. This study found that an Epstein–Barr virus (EBV) immediate-early protein, Rta, is a binding partner of BRAP2 in yeast and confirmed the binding in vitro by a glutathione S-transferase pull-down assay and in vivo by co-immunoprecipitation in 293(maxi-EBV) cells. Binding studies also showed that Rta and KSR1 interacted with the C-terminal 202 aa region in BRAP2. Additionally, Rta appeared to prevent the binding of KSR1 to BRAP2, activating the ERK signal transduction pathway and the transcription of an EBV immediate-early gene, BZLF1. Activation of the ERK signal transduction pathway by Rta may be critical for the maintenance of the lytic state of EBV.

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