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Review
. 2017 Nov 13;9(11):339.
doi: 10.3390/v9110339.

EBV and Apoptosis: The Viral Master Regulator of Cell Fate?

Leah Fitzsimmons  1 , Gemma L Kelly  2   3
Affiliations
Review

EBV and Apoptosis: The Viral Master Regulator of Cell Fate?

Leah Fitzsimmons et al. Viruses. .

Abstract

Epstein-Barr virus (EBV) was first discovered in cells from a patient with Burkitt lymphoma (BL), and is now known to be a contributory factor in 1-2% of all cancers, for which there are as yet, no EBV-targeted therapies available. Like other herpesviruses, EBV adopts a persistent latent infection in vivo and only rarely reactivates into replicative lytic cycle. Although latency is associated with restricted patterns of gene expression, genes are never expressed in isolation; always in groups. Here, we discuss (1) the ways in which the latent genes of EBV are known to modulate cell death, (2) how these mechanisms relate to growth transformation and lymphomagenesis, and (3) how EBV genes cooperate to coordinately regulate key cell death pathways in BL and lymphoblastoid cell lines (LCLs). Since manipulation of the cell death machinery is critical in EBV pathogenesis, understanding the mechanisms that underpin EBV regulation of apoptosis therefore provides opportunities for novel therapeutic interventions.

Keywords: BCL-2 family; EBV; apoptosis; genetic cooperation; growth transformation; latency; p53; virus cancers.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Patterns of latent gene expression found in Epstein–Barr virus (EBV)-associated malignancies and growth transformed B cell lines. Schematic showing: the Latency III EBV gene expression programme, as found in B cells transformed in vitro into lymphoblastoid cell lines (LCLs); Latency I EBV gene expression as found in the majority (85%) of EBV-positive Burkitt lymphomas (BL); Wp-restricted latency (Wp Latency), as found in a minority (15%) of EBV-positive BLs (termed Wp-BL); and Latency II EBV gene expression, which is found in EBV-positive Hodgkin lymphoma (HL) as well as the EBV-associated epithelial malignancies, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). Latent proteins (EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA3C, EBNA-LP, BHRF1, LMP1 and LMP2A/B) are shown in blue. Non-coding RNAs (EBERs, miR-BHRF1s and miR-BARTs) are shown in red, and selected latent promoters (Cp, Wp and Qp) are shown in green. Connecting lines denote splicing patterns, whilst blocks indicate exons. In Wp-BL, EBNA-LP is truncated due to a genomic deletion and is therefore denoted as t-EBNA-LP.
Figure 2
Figure 2
Temporal patterns of latent gene expression during growth transformation of primary resting B cells. Schematic showing the general transcription patterns of different classes of latent EBV genes during in vitro growth transformation of primary, resting B cells. Wp-derived transcripts preferentially give rise to BHRF1, EBNA2 and EBNA-LP in order to kick start cells into cycle, though they also encode EBNA-3A, -3B and -3C (EBNA3s) and EBNA1. Cp can encode all EBNAs and BHRF1. NC RNAs include EBER1, EBER2, miR-BARTs and miR-BHRF1s. Data are cumulative estimations based on transcriptional data published by Tierney et al. [33], Shannon-Lowe et al. [30], and Amoroso et al. [24].
Figure 3
Figure 3
Binding specificities and affinities of BCL-2 family members and EBV BHRF1. (a) Interactions between pro-survival and pro-death BCL-2 family members. Reported as Kd in nM as determined by surface plasmon resonance (BCL-2, BCL-xL and MCL-1) or isothermal calorimetry. Sources were: BCL-2 and BCL-xL [144,145,146], MCL-1 [144], A1 [147] and BHRF1 [124,133]. Colour coding was applied as follows: green 1–10 nM, pale green 11–50 nM, yellow 51–100 nM, pale orange 101–1000 nM, orange 1001–2000 nM, red 2000–100,000 nM. (b) Ribbon structure representation of BHRF1 (blue) bound to the BH3 domain of BAK (red). This graphic was prepared using the UCSF Chimera software package (developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco [148], supported by NIGMS P41-GM103311) using pdb accession code 2XPX [133].
Figure 4
Figure 4
Model of BCL-2 family-mediated intrinsic apoptosis. Schematic of interactions among different classes of BCL-2 family members in the intrinsic apoptosis pathway. Pro-survival, BCL-2-like proteins, including BHRF1 (green), inhibit both classes of pro-death proteins, though the affinities and specificities for these binding partners vary. BH3-only, pro-death proteins (orange) inhibit pro-survival BCL-2s through reciprocal binding and some can directly activate executioner pro-death BCL-2 homologues (only BIM, PUMA and t-BID are able to perform direct activation). The executioner BCL-2s, BAK and BAX exist as inactive monomers until activated by BH3-only proteins or disinhibited by pro-survival BCL-2s. Upon activation, BAK and/or BAX multimerise to form pores in the mitochondrial outer membrane, causing the release of cytochrome C (and other pro-apoptotic factors), which then activate APAF-1, leading to the assembly of the apoptosome, caspase cleavage and consequent cell destruction.
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