1. Cancer Biology
  2. Microbiology and Infectious Disease
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Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection

  1. Alexander M Price
  2. Joanne Dai
  3. Quentin Bazot
  4. Luv Patel
  5. Pavel A Nikitin
  6. Reza Djavadian
  7. Peter S Winter
  8. Cristina A Salinas
  9. Ashley Perkins Barry
  10. Kris C Wood
  11. Eric C Johannsen
  12. Anthony Letai
  13. Martin J Allday
  14. Micah A Luftig  Is a corresponding author
  1. Duke University School of Medicine, United States
  2. Imperial College London, United Kingdom
  3. Harvard Medical School, United States
  4. University of Wisconsin School of Medicine and Public Health, United States
  5. Duke University, United States
Research Article
  • Cited 12
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Cite this article as: eLife 2017;6:e22509 doi: 10.7554/eLife.22509

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.

Article and author information

Author details

  1. Alexander M Price

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  2. Joanne Dai

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  3. Quentin Bazot

    Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Luv Patel

    Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Pavel A Nikitin

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  6. 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.
  7. Peter S Winter

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  8. Cristina A Salinas

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  9. Ashley Perkins Barry

    Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, United States
    Competing interests
    No competing interests declared.
  10. Kris C Wood

    Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  11. 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.
  12. 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..
  13. Martin J Allday

    Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  14. 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.
    ORCID icon "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.

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Publication history

  1. Received: October 19, 2016
  2. Accepted: April 19, 2017
  3. Accepted Manuscript published: April 20, 2017 (version 1)
  4. Version of Record published: May 10, 2017 (version 2)

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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