The Cooperative Functions of the EBNA3 Proteins Are Central to EBV Persistence and Latency

Abstract

The Epstein–Barr nuclear antigen 3 (EBNA3) family of proteins, comprising EBNA3A, EBNA3B, and EBNA3C, play pivotal roles in the asymptomatic persistence and life-long latency of Epstein–Barr virus (EBV) in the worldwide human population. EBNA3-mediated transcriptional reprogramming of numerous host cell genes promotes in vitro B cell transformation and EBV persistence in vivo. Despite structural and sequence similarities, and evidence of substantial cooperative activity between the EBNA3 proteins, they perform quite different, often opposing functions. Both EBNA3A and EBNA3C are involved in the repression of important tumour suppressive pathways and are considered oncogenic. In contrast, EBNA3B exhibits tumour suppressive functions. This review focuses on how the EBNA3 proteins achieve the delicate balance required to support EBV persistence and latency, with emphasis on the contribution of the Allday laboratory to the field of EBNA3 biology.

Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

“…The EBNA leader peptide (EBNA-LP) cooperates with EBNA2 for viral oncogene, like LMP1, expression 42 . EBNA3A and EBNA3C rescue infected cells that are driven into a proliferative state by EBNA2-dependent MYC expression via the down-regulation of the proapoptotic BIM and p16 INK4a proteins that respond to the hyperproliferation of the infected cells 43 . Furthermore, they prevent transition into lytic replication by suppression of BLIMP1 expression 44 .…”

“…This was recently queried using EBV deficient in EBNA3A and EBNA3C. As discussed above, these are essential latent EBV gene products that rescue EBV infected cells from cell death that is induced by EBNA2-driven proliferation 43 22 . This persistence was associated with EBNA2-driven proliferation during the first month of infection, which then, switched to EBV latency 0 persistence with only non-translated EBER expression after three months 22 .…”

Requirement for PRC1 subunit BMI1 in host gene activation by Epstein–Barr virus protein EBNA3C

“…These ChIP-seq experiments were carried out in cells with the same genetic background as cells used in a comprehensive ChIP-seq study exploring the localization of EBV latent proteins EBNA3A, EBNA3B and EBNA3C (22). Past studies had suggested or questioned possible relationships between the EBNA3s and both PRC1 and PRC2, but many unanswered questions remained [reviewed in (7)]. A stepwise approach that started with simple co-localizations between BMI1 and SUZ12 with histone modifications and the EBNA3s led to the discovery of a functional relationship between EBNA3C and BMI1, identifying a general principle for EBNA3C-mediated activation that holds true for several loci.…”

“…All nuclear antigens act to affect transcription in a way that allows or facilitates B-cell activation and, by extension, the viral life cycle. EBNA3A, EBNA3B and EBNA3C studied here have been shown to affect the expression of thousands of host genes, with EBNA3A and EBNA3C together able to act as repressors or activators and EBNA3B seemingly acting only as repressor (7).…”

“…The EBNA3s control genes epigenetically. Changes in histone acetylation have been observed at the promoters of all EBNA3-control genes tested, with repressed genes losing acetylation and activated genes gaining acetylation concurrently with changes in expression (reviewed in (7)). Numerous studies have also described EBNA3-repressed genes that are characterized by the presence of H3K27me3, the repressive epigenetic mark deposited by polycomb repressive complex (PRC)2 (8–15).…”