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.

Keywords: CDKI regulation; EBNA3 proteins; Epstein–Barr virus; epigenetic regulation; viral oncogenes; viral tumour suppressor.

Figure 1

Schematic showing structure of the homology domain between the Epstein–Barr virus (EBV) EBNA3 family of proteins. Numbers denote amino acid position within the prototype strain B95.8 protein.

Figure 2

EBNA3A and EBNA3C regulate CDKI at a transcriptional, translational, and protein levels. EBNA3A and EBNA3C bind cell transcription factors (TFs) including RBP-Jκ, CBF, and IRF4. This results in polycomb complex recruitment and deposition of chromatin marks on the loci of target genes. These chromatin marks can either repress transcription (the CDKIs p16^INK4a, p15^INK4b, and p18^INK4c) or activate transcription (miRNA221/222). EBNA3-mediated activation of miRNA221/222 leads to subsequent repression of the CDKI p27^KIP1 and p57^KIP2 via translation inhibition. EBNA3A and EBNA3C can also repress CKDI by targeting them for degradation. EBNA3A mechanisms are unclear, but EBNA3C has been shown to mediate Pim-1 catalysed phosphorylation and subsequent proteasomal degradation of p21^WAF1/CIP1.