Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection

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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 NFB 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/NFB 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

The following previously published data sets were used

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Article and author information

Author details

Alexander M Price

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

Competing interests
No competing interests declared.
Joanne Dai

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

Competing interests
No competing interests declared.
Quentin Bazot

Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom

Competing interests
No competing interests declared.
Luv Patel

Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.
Pavel A Nikitin

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

Competing interests
No competing interests declared.
Reza Djavadian

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, United States

Competing interests
No competing interests declared.
Peter S Winter

Department of Pharmacology and Cancer Biology, Duke University, Durham, United States

Competing interests
No competing interests declared.
Cristina A Salinas

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

Competing interests
No competing interests declared.
Ashley Perkins Barry

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

Competing interests
No competing interests declared.
Kris C Wood

Department of Pharmacology and Cancer Biology, Duke University, Durham, United States

Competing interests
No competing interests declared.
Eric C Johannsen

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, United States

Competing interests
No competing interests declared.
Anthony Letai

Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States

Competing interests
Anthony Letai, Is a paid advisor to, and his laboratory receives research sponsorship from, AbbVie, Astra-Zeneca, and Tetralogic..
Martin J Allday

Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom

Competing interests
No competing interests declared.
Micah A Luftig

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States

For correspondence
micah.luftig@duke.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-2964-1907

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

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.