Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
- Duke University School of Medicine, United States
- Imperial College London, United Kingdom
- Harvard Medical School, United States
- University of Wisconsin School of Medicine and Public Health, United States
- Duke University, United States
Abstract
Latent Epstein-Barr virus (EBV) infection is causally linked to several human cancers. EBV expresses viral oncogenes that promote cell growth and inhibit the apoptotic response to uncontrolled proliferation. The EBV oncoprotein LMP1 constitutively activates NFB and is critical for survival of EBV-immortalized B cells. However, during early infection EBV induces rapid B cell proliferation with low levels of LMP1 and little apoptosis. Therefore, we sought to define the mechanism of survival in the absence of LMP1/NFB early after infection. We used BH3 profiling to query mitochondrial regulation of apoptosis and defined a transition from uninfected B cells (BCL-2) to early-infected (MCL-1/BCL-2) and immortalized cells (BFL-1). This dynamic change in B cell survival mechanisms is unique to virus-infected cells and relies on regulation of MCL-1 mitochondrial localization and BFL-1 transcription by the viral EBNA3A protein. This study defines a new role for EBNA3A in the suppression of apoptosis with implications for EBV lymphomagenesis.
Data availability
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EBNA2 ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE29498).
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The NF-kB genomic landscape in lymphoblastoid B-cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE55105).
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EBNA3C ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE52632).
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EBNA3A ChIP-SeqPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE59181).
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Histone modifications in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE29611).
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TF binding sites in LCLs (ENCODE)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE31477).
Article and author information
Author details
Funding
National Cancer Institute (R01-CA140337)
- Micah A Luftig
American Cancer Society (RSG-13-228-01-MPC)
- Micah A Luftig
Wellcome (099273/Z/12/Z)
- Quentin Bazot
- Martin J Allday
National Institute for Dental and Cranofacial Research (R01-DE025994)
- Joanne Dai
- Micah A Luftig
National Institute for Allergy and Infectious Diseases (5P30-AI064518)
- Micah A Luftig
National Cancer Institute (F31-CA180451)
- Alexander M Price
National Institute for Dental and Cranofacial Research (R01-DE023939)
- Eric C Johannsen
National Institute for Allergy and Infectious Diseases (T32-AI078985)
- Reza Djavadian
National Cancer Institute (R01-CA129974)
- Anthony Letai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Price et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection
eLife 6:e22509.
https://doi.org/10.7554/eLife.22509
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