Abstract
Epstein-Barr virus (EBV) is highly ubiquitous in human population and establishes a lifelong asymptomatic infection within the infected host unless the immune system is compromised. Following initial infection in the oropharyngeal epithelial cells, EBV primarily infects naive B-lymphocytes and develops a number of B-cell lymphomas particularly in immune-deficient individuals. In vitro, EBV can also infect and subsequently transform quiescent B-lymphocytes into continuously proliferating lymphoblastoid cell lines (LCLs) resembling EBV-induced lymphoproliferative disorders in which a subset of latent transcripts are detected. Genetic studies revealed that EBNA-3 family comprising of three adjacent genes in the viral genome—EBNA-3A and -3C, but not -3B, are critical for B-cell transformation. Nevertheless, all three proteins appear to significantly contribute to maintain the overall proliferation and viability of transformed cells, suggesting a critical role in lymphoma development. Apart from functioning as important viral transcriptional regulators, EBNA-3 proteins associate with many cellular proteins in different signaling networks, providing a suitable platform for lifelong survival of the virus and concurrent lymphoma development in the infected host. The chapter describes the function of each these EBV nuclear antigen 3 proteins employed by the virus as a means to understand viral pathogenesis of several EBV-associated B-cell malignancies.
Highlights
Epstein-Barr virus (EBV) nuclear antigen, EBNA-3, comprising of three closely related proteins namely EBNA-3A, -3B, and -3C, was suggested to be generated by a series of gene duplication events during gammaherpesvirus evolution as they share limited but significant amino acid sequence homology (Saha and Robertson, 2013)
All EBNA-3 transcripts are alternatively spliced from very long mRNAs initiated at the latency C-promoter (Cp), which is active in EBV transformed lymphoblastoid cell lines (LCLs) but blocked in several EBV-associated cancers through hypermethylation [reviewed in (Robertson et al, 1995; Saha and Robertson, 2013; Allday et al, 2015)]
EBNA-3 proteins demonstrated extensive redundant biological functions, genetic studies using recombinant viruses revealed that only EBNA-3A and -3C but not -3B are essential for B-cell transformation in vitro (Maruo et al, 2005, 2006, 2011; Saha and Robertson, 2013)
Summary
Epstein-Barr virus (EBV) nuclear antigen, EBNA-3, comprising of three closely related proteins namely EBNA-3A, -3B, and -3C, was suggested to be generated by a series of gene duplication events during gammaherpesvirus evolution as they share limited but significant amino acid (aa) sequence homology (Saha and Robertson, 2013). Unlike of the other viral genes there are no known viral homologs in other closely related primate lymphocryptoviruses. They share a similar gene structure with a shorter 5′- and a longer 3′-exons arranged in a tandem array in the EBV episome. EBNA-3 proteins demonstrated extensive redundant biological functions, genetic studies using recombinant viruses revealed that only EBNA-3A and -3C but not -3B are essential for B-cell transformation in vitro (Maruo et al, 2005, 2006, 2011; Saha and Robertson, 2013).
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