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Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome

Title: Epstein-Barr virus nuclear antigen EBNA-LP is essential for transforming naive B cells, and facilitates recruitment of transcription factors to the viral genome
Authors: Szymula, A
Palermo, RD
Bayoumy, A
Groves, IJ
Abdulla, MB
Holder, B
White, RE
Item Type: Journal Article
Abstract: The Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) is the first viral latency-associated protein produced after EBV infection of resting B cells. Its role in B cell transformation is poorly defined, but it has been reported to enhance gene activation by the EBV protein EBNA2 in vitro. We generated EBNA-LP knockout (LPKO) EBVs containing a STOP codon within each repeat unit of internal repeat 1 (IR1). EBNA-LP-mutant EBVs established lymphoblastoid cell lines (LCLs) from adult B cells at reduced efficiency, but not from umbilical cord B cells, which died approximately two weeks after infection. Adult B cells only established EBNA-LP-null LCLs with a memory (CD27+) phenotype. Quantitative PCR analysis of virus gene expression after infection identified both an altered ratio of the EBNA genes, and a dramatic reduction in transcript levels of both EBNA2-regulated virus genes (LMP1 and LMP2) and the EBNA2-independent EBER genes in the first 2 weeks. By 30 days post infection, LPKO transcription was the same as wild-type EBV. In contrast, EBNA2-regulated cellular genes were induced efficiently by LPKO viruses. Chromatin immunoprecipitation revealed that EBNA2 and the host transcription factors EBF1 and RBPJ were delayed in their recruitment to all viral latency promoters tested, whereas these same factors were recruited efficiently to several host genes, which exhibited increased EBNA2 recruitment. We conclude that EBNA-LP does not simply co-operate with EBNA2 in activating gene transcription, but rather facilitates the recruitment of several transcription factors to the viral genome, to enable transcription of virus latency genes. Additionally, our findings suggest that EBNA-LP is essential for the survival of EBV-infected naïve B cells.
Issue Date: 20-Feb-2018
Date of Acceptance: 21-Jan-2018
URI: http://hdl.handle.net/10044/1/61370
DOI: https://dx.doi.org/10.1371/journal.ppat.1006890
ISSN: 1553-7366
Publisher: Public Library of Science (PLoS)
Journal / Book Title: PLoS Pathogens
Volume: 14
Issue: 2
Copyright Statement: © 2018 Szymula et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council
Funder's Grant Number: MR/L008432/1
MR/N010388/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
BURKITTS-LYMPHOMA
GENE-EXPRESSION
MASS-SPECTROMETRY
PROTEIN X-1
LEADER
EBV
DNA
IMMORTALIZATION
ACTIVATION
PROMOTER
Adult
B-Lymphocytes
Cell Transformation, Viral
Cells, Cultured
Epstein-Barr Virus Infections
Female
Gene Expression Regulation, Viral
Genome, Viral
HEK293 Cells
Herpesvirus 4, Human
Humans
Infant, Newborn
Leukemia, B-Cell
Pregnancy
Promoter Regions, Genetic
Protein Binding
Transcription Factors
Viral Proteins
0605 Microbiology
1107 Immunology
1108 Medical Microbiology
Publication Status: Published
Article Number: e1006890
Online Publication Date: 2018-02-20
Appears in Collections:Department of Medicine
Faculty of Medicine



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