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 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.
Highlights
An estimated 15% of cancers worldwide are caused by infectious agents like viruses
In order to define the mechanism of survival in the absence of Latent Membrane Protein 1 (LMP1) and NFkB activity early after infection, as well as through long-term outgrowth, we performed BH3 profiling to query apoptotic priming at the mitochondria of infected cells
Using lymphoblastoid cell lines (LCL) ChIPSeq data (Schmidt et al, 2015; Zhao et al, 2011), we found that one locus is bound by EBNA3A within a known Epstein-Barr virus (EBV) Super Enhancer (39 kb upstream of the BFL-1 transcription start site (TSS)) and the other region contains a single RelA peak, an NFkB transcription factor subunit strongly activated by LMP1 (Zhao et al, 2014) (Figure 6I)
Summary
Epstein-Barr virus (EBV) was the first human tumor virus discovered and is associated with malignancies of both B lymphocyte and epithelial cell origin. T cells prevent the development of EBV-associated malignancies and the virus persists quiescently in latently-infected memory B cells. In the absence of a healthy immune system, such as following organ transplant or HIV infection, EBV can transform B cells leading to markedly increased rates of lymphoma in these populations. Primary human B cell infection in vitro by EBV leads to their growth transformation and serves as a model for oncogenesis in EBV-associated lymphomas. This process requires the expression of six
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
