Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, United States
Quentin Bazot
Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom
Luv Patel
Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Pavel A Nikitin
Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, United States
Reza Djavadian
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, United States; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, United States
Peter S Winter
Department of Pharmacology and Cancer Biology, Duke University, Durham, United States; Program in Genetics and Genomics, Duke University, Durham, United States
Cristina A Salinas
Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, United States
Ashley Perkins Barry
Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, United States
Kris C Wood
Department of Pharmacology and Cancer Biology, Duke University, Durham, United States
Eric C Johannsen
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, United States; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, United States
Anthony Letai
Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
Martin J Allday
Molecular Virology, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom
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 NFκB 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/NFκB 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.
