scholarly journals Structural, Functional, and Genetic Comparisons of Epstein-Barr Virus Nuclear Antigen 3A, 3B, and 3C Homologues Encoded by the Rhesus Lymphocryptovirus

2000 ◽  
Vol 74 (13) ◽  
pp. 5921-5932 ◽  
Author(s):  
Hua Jiang ◽  
Young-gyu Cho ◽  
Fred Wang
Keyword(s):  
B Cell ◽  
Transcriptional Activation ◽  
Rhesus Monkeys ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
In Vitro Assays ◽  
Barr Virus ◽  
Cell Immortalization ◽  
Epstein Barr

ABSTRACT EBNA-3A, -3B, and -3C are three latent infection nuclear proteins important for Epstein-Barr virus (EBV)-induced B-cell immortalization and the immune response to EBV infection. All three are hypothesized to function as transcriptional transactivators, but little is known about their precise mechanism of action or their role in EBV pathogenesis. We have cloned and studied the three EBNA-3 homologues from a closely related lymphocryptovirus (LCV) which naturally infects rhesus monkeys. The rhesus LCV EBNA-3A, -3B, and -3C homologues have 37, 40, and 36% amino acid identity with the EBV genes, respectively. Function, as measured by in vitro assays, also appears to be conserved with the EBV genes, since the rhesus LCV EBNA-3s can interact with the transcription factor RBP-Jκ and the rhesus LCV EBNA-3C encodes a Q/P-rich domain with transcriptional activation properties. In order to better understand the relationship between these EBV and rhesus LCV latent infection genes, we asked if the rhesus LCV EBNA-3 locus could be recombined into the EBV genome and if it could substitute for the EBV EBNA-3s when assayed for human B-cell immortalization. Recombination between the EBV genome and rhesus LCV DNA was reasonably efficient. However, these studies suggest that the rhesus LCV EBNA-3 locus was not completely interchangeable with the EBV EBNA-3 locus for B-cell immortalization and that at least one determinant of the species restriction for LCV-induced B-cell immortalization maps to the EBNA-3 locus. The overall conservation of EBNA-3 structure and function between EBV and rhesus LCV indicates that rhesus LCV infection of rhesus monkeys can provide an important animal model for studying the role of the EBNA-3 genes in LCV pathogenesis.

scholarly journals The Epstein-Barr Virus EBNA-LP Protein Preferentially Coactivates EBNA2-Mediated Stimulation of Latent Membrane Proteins Expressed from the Viral Divergent Promoter

2005 ◽  
Vol 79 (7) ◽  
pp. 4492-4505 ◽  
Author(s):  
RongSheng Peng ◽  
Stephanie C. Moses ◽  
Jie Tan ◽  
Elisabeth Kremmer ◽  
Paul D. Ling
Keyword(s):  
B Cell ◽  
Transcriptional Activation ◽  
Epstein Barr Virus ◽  
Type I ◽  
Barr Virus ◽  
Cell Immortalization ◽  
Cellular Cofactor ◽  
Epstein Barr ◽  
Transformed Cell Lines ◽  
Stimulation Of

ABSTRACT The mechanistic contribution of the Epstein-Barr virus (EBV) EBNA-LP protein to B-cell immortalization remains an enigma. However, previous studies have indicated that EBNA-LP may contribute to immortalization by enhancing EBNA2-mediated transcriptional activation of the LMP-1 gene. To gain further insight into the potential role EBNA-LP has in EBV-mediated B-cell immortalization, we asked whether it is a global or gene-specific coactivator of EBNA2 and whether coactivation requires interaction between these proteins. In type I Burkitt's lymphoma cells, we found that EBNA-LP strongly coactivated EBNA2 stimulation of LMP-1 and LMP2B RNAs, which are expressed from the viral divergent promoter. Surprisingly, the viral LMP2A gene and cellular CD21 and Hes-1 genes were induced by EBNA2 but showed no further induction after EBNA-LP coexpression. We also found that EBNA-LP did not stably interact with EBNA2 in coimmunoprecipitation assays, even though the conditions were adequate to observe specific interactions between EBNA2 and its cellular cofactor, CBF1. Colocalization between EBNA2 and EBNA-LP was not detectable in EBV-transformed cell lines or transfected type I Burkitt's cells. Finally, no significant interactions between EBNA2 and EBNA-LP were found with mammalian two-hybrid assays. From this data, we conclude that EBNA-LP is not a global coactivator of EBNA2 targets, but it preferentially coactivates EBNA2 stimulation of the viral divergent promoter. While this may require specific transient interactions between these proteins that only occur in the context of the divergent promoter, our data strongly suggest that EBNA-LP also cooperates with EBNA2 through mechanisms that do not require direct or indirect complex formation between these proteins.

scholarly journals Epstein–Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes

2014 ◽  
Vol 112 (2) ◽  
pp. 554-559 ◽  
Author(s):  
Stefanie C. S. Schmidt ◽  
Sizun Jiang ◽  
Hufeng Zhou ◽  
Bradford Willox ◽  
Amy M. Holthaus ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Protein Complexes ◽  
Nuclear Antigen ◽  
Lymphoblastoid Cell Lines ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

Epstein–Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up-regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16INK4A and p14ARF-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16INK4A and p14ARF, enabling continuous cell proliferation. Analyses of the EBNA3A human genome-wide ChIP-seq landscape revealed 37% of 10,000 EBNA3A sites to be at strong enhancers; 28% to be at weak enhancers; 4.4% to be at active promoters; and 6.9% to be at weak and poised promoters. EBNA3A colocalized with BATF-IRF4, ETS-IRF4, RUNX3, and other B-cell Transcription Factors (TFs). EBNA3A sites clustered into seven unique groups, with differing B-cell TFs and epigenetic marks. EBNA3A coincidence with BATF-IRF4 or RUNX3 was associated with stronger EBNA3A ChIP-Seq signals. EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1. ChIP-re-ChIP revealed complexes of EBNA3A on DNA with BATF. These data strongly support a model in which EBNA3A is tethered to DNA through a BATF-containing protein complexes to enable continuous cell proliferation.

scholarly journals The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization

Oncogene ◽  
2019 ◽  
Vol 39 (3) ◽  
pp. 603-616 ◽  
Author(s):  
Jiayu Wang ◽  
Noemi Nagy ◽  
Maria G. Masucci
Keyword(s):  
Dna Damage ◽  
B Cell ◽  
Cell Lines ◽  
Cellular Response ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Ebv Infection ◽  
Cell Immortalization ◽  
Epstein Barr

Abstract Epstein–Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and -positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.

scholarly journals Notch1, Notch2, and Epstein-Barr virus–encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus–infected B cells

Blood ◽  
2009 ◽  
Vol 113 (22) ◽  
pp. 5506-5515 ◽  
Author(s):  
Hella Kohlhof ◽  
Franziska Hampel ◽  
Reinhard Hoffmann ◽  
Helmut Burtscher ◽  
Ulrich H. Weidle ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Expression Analysis ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
A Genome ◽  
Cell Immortalization ◽  
Epstein Barr

AbstractThe canonical mode of transcriptional activation by both the Epstein-Barr viral protein, Epstein-Barr virus–encoded nuclear antigen 2 (EBNA2), and an activated Notch receptor (Notch-IC) requires their recruitment to RBPJ, suggesting that EBNA2 uses the Notch pathway to achieve B-cell immortalization. To gain further insight into the biologic equivalence between Notch-IC and EBNA2, we performed a genome-wide expression analysis, revealing that Notch-IC and EBNA2 exhibit profound differences in the regulation of target genes. Whereas Notch-IC is more potent in regulating genes associated with differentiation and development, EBNA2 is more potent in inducing viral and cellular genes involved in proliferation, survival, and chemotaxis. Because both EBNA2 and Notch-IC induced the expression of cell cycle–associated genes, we analyzed whether Notch1-IC or Notch2-IC can replace EBNA2 in B-cell immortalization. Although Notch-IC could drive quiescent B cells into the cell cycle, B-cell immortalization was not maintained, partially due to an increased apoptosis rate in Notch-IC–expressing cells. Expression analysis revealed that both EBNA2 and Notch-IC induced the expression of proapoptotic genes, but only in EBNA2-expressing cells were antiapoptotic genes strongly up-regulated. These findings suggest that Notch signaling in B cells and B-cell lymphomas is only compatible with proliferation if pathways leading to antiapototic signals are active.

scholarly journals Limited nucleotide pools restrict Epstein–Barr virus-mediated B-cell immortalization

Oncogenesis ◽  
2017 ◽  
Vol 6 (6) ◽  
pp. e349-e349 ◽  
Author(s):  
A Y Hafez ◽  
J E Messinger ◽  
K McFadden ◽  
G Fenyofalvi ◽  
C N Shepard ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Nucleotide Pools ◽  
Cell Immortalization ◽  
Epstein Barr

HAUSP/USP7 as an Epstein–Barr virus target

2004 ◽  
Vol 32 (5) ◽  
pp. 731-732 ◽  
Author(s):  
M.N. Holowaty ◽  
L. Frappier
Keyword(s):  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
High Affinity ◽  
Cellular Immortalization ◽  
Epstein Barr ◽  
Epstein Barr Nuclear Antigen

USP7 (also called HAUSP) is a de-ubiquitinating enzyme recently identified as a key regulator of the p53–mdm2 pathway, which stabilizes both p53 and mdm2. We have discovered that the Epstein–Barr nuclear antigen 1 protein of Epstein–Barr virus binds with high affinity to USP7 and disrupts the USP7–p53 interaction. The results have important implications for the role of Epstein–Barr nuclear antigen 1 in the cellular immortalization that is typical of an Epstein–Barr virus latent infection.

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