The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization

Abstract

Epstein-Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and-positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.

Immunology of EBV-Related Lymphoproliferative Disease in HIV-Positive Individuals

“…Latent viral proteins expression also modulate intracellular signaling cascades, leading to cellular immortalization ( 55 ). Examples of signaling cascades that EBV latent phase proteins engage in in latently infected and transformed cells are shown in Figure 1 , including pro-survival and anti-apoptotic functions of ENBA-1 ( 56 – 62 ), LMP-1/-2 ( 63 – 71 ), and EBNA-2,-3,-LP ( 72 – 74 ) are shown in Figure 1 .…”

Interferon-regulating activity of the CelAgrip drug and its influence on the formation of reactive oxygen species and expression of innate immunity genes in Burkitt’s lymphome cell cultures

“…J. Wang и соавт. полагают [33], что вирусоносительство связано с повышенной уязвимостью клеток к окислительному стрессу, и доказывают, что ядерный антиген ВЭБ способствует усилению клеточной антиоксидантной защиты. В нашем случае клетки Р3НR-1 в отличие от клеток Namalva характеризуются продукцией антигенов ВЭБ.…”

Mechanistic Insights into Chemoresistance Mediated by Oncogenic Viruses in Lymphomas

“…EBV-associated NK/T-cell lymphomas are highly resistant to CHOP, probably due to upregulation of P-gp, an energy-dependent efflux pump that excretes drugs from the cytoplasm to the extracellular space [119,120]. High expression of P-gp is also connected with ROS production, which is induced by EBV infection [121,122]. Previous work established that induction of intracellular ROS production under EBV latent infection elevated P-gp expression via the STAT1 pathway while downregulation of ROS by NecroX-5, an ROS scavenger, effectively attenuated P-gp-associated chemoresistance in EBV-positive NK/T-cell lymphoma [123].…”

“…LMP1 promoted excessive ROS production from EBV-related malignant cells through activation of NAD(P)H oxidases and induction of nuclear factor erythroid 2-related factor 2 (NRF2) [124,125]. Other studies showed that the expression of another EBV-associated protein, EBNA1, in either latent or lytic phases, regulated LMP1 expression [126], and upregulated cellular antioxidant defense to enable B-cell growth, transformation, and immortalization [122].…”