Journal Article

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

Bazot, Quentin, Luftig, Micah A, Barry, Ashley Perkins, Patel, Luv, Johannsen, Eric C, Djavadian, Reza, Winter, Peter S, Nikitin, Pavel A, Price, Alexander M, Allday, Martin J, Letai, Anthony, Dai, Joanne, Salinas, Cristina A, Wood, Kris C

2017

Overview

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. Over 90% of adults around the world are infected with the Epstein-Barr virus. Like other closely related viruses, such as those that cause chicken pox and cold sores, an infection lasts for the rest of the person’s life, although the virus generally remains in a latent or dormant state. However, under certain conditions the latent viruses can cause cancers to develop; in fact, it is estimated that such infections are responsible for nearly 2% of all cancer deaths worldwide. One way that healthy human cells prevent cancer is by triggering their own death in a process called apoptosis. The Epstein-Barr virus can block apoptosis, therefore making the cells more likely to become cancerous. Previous research identified one protein in the Epstein-Barr virus that promotes cancer by preventing infected cells from dying as normal. However, even in the absence of this protein, Epstein-Barr virus-infected cells remain resistant to apoptosis. This suggests that the virus has another way of blocking cell death. Price et al. have now used a technique that stresses living cells in a way that reveals which proteins prevent apoptosis to study human cells infected with the Epstein-Barr virus. This revealed that soon after infection, the virus could force the human cell to produce MCL-1, a protein that prevents cell death. Later, the Epstein-Barr virus enlisted a second human protein called BFL-1, which makes the infected cell further resistant to apoptosis. Price et al. discovered that a protein in the Epstein-Barr virus called EBNA3A controls the production of the MCL-1 and BFL-1 proteins. In the future, developing therapies that target these proteins may lead to new treatments for cancers caused by the Epstein-Barr virus. Such treatments would be likely to have fewer side effects for patients than traditional chemotherapies.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Apoptosis / B cell / B cells / B-Lymphocytes - physiology / B-Lymphocytes - virology / Bcl-2 protein / BH3 Profiling / Cancer / Cancer Biology / Cell cycle / Cell proliferation / Cell Survival / Cells, Cultured / Deoxyribonucleic acid / DNA / enhancer / Epstein-Barr virus / Epstein-Barr Virus Nuclear Antigens - metabolism / Genomics / Health aspects / Herpesvirus 4, Human - physiology / Host-Pathogen Interactions / Humans / Infections / Laboratories / Localization / Lymphocytes B / Lymphoma / Mcl-1 protein / Medicine / Mice / Microbiology and Infectious Disease / Minor Histocompatibility Antigens - metabolism / Mitochondria / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / NF-κB protein / Proteins / Proto-Oncogene Proteins c-bcl-2 - metabolism / Public health / Transcription / Virology / Viruses