Abstract
Simple SummaryThe Epstein–Barr virus (EBV) has been implicated in several human neoplastic diseases. The EBV-1 can transform B cells into LCL more efficiently than EBV-2, and EBV-2 preferentially infects T-cell lymphocytes. The EBNA3A oncoprotein has an essential role in B-cell transformation. The six peptide motifs called nuclear localization signals (NLSs) from EBNA3A ensure nucleocytoplasmic protein trafficking. Multiple NLSs have been suggested to enhance EBNA3 function or different specificities to different cell types; however, a comprehensive assessment of their genetic variability has not been addressed. Our objective was to study the NLSs’ variability and their relationship with EBV types. Based on a comprehensive analysis of over a thousand EBNA3A sequences from different clinical manifestations and geographic locations, we found that EBNA3A from EBV-2 has two of the six NLSs altered, and genetic patterns in the NLSs are associated with EBV-1 and EBV-2.The Epstein–Barr virus (EBV) is a globally dispersed pathogen involved in several human cancers of B-cell and non-B-cell origin. EBV has been classified into EBV-1 and EBV-2, which have differences in their transformative ability. EBV-1 can transform B-cells into LCL more efficiently than EBV-2, and EBV-2 preferentially infects T-cell lymphocytes. The EBNA3A oncoprotein is a transcriptional regulator of virus and host cell genes, and is required in order to transform B-cells. EBNA3A has six peptide motifs called nuclear localization signals (NLSs) that ensure nucleocytoplasmic protein trafficking. The presence of multiple NLSs has been suggested to enhance EBNA3 function or different specificities in different cell types. However, studies about the NLS variability associated with EBV types are scarce. Based on a systematic sequence analysis considering more than a thousand EBNA3A sequences of EBV from different human clinical manifestations and geographic locations, we found differences in NLSs’ nucleotide structures among EBV types. Compared with the EBNA3A EBV-1, EBNA3A EBV-2 has two of the six NLSs altered, and these mutations were possibly acquired by recombination. These genetic patterns in the NLSs associated with EBV-1 and EBV-2 provide new information about the traits of EBNA3A in EBV biology.
Highlights
The Epstein–Barr Virus (EBV) is a human herpesvirus that belongs to the family Herpesviridae
Our results showed that EBNA3A from EBV-2 has two (NLS3 and NLS4) of the six nuclear localization signals (NLSs) altered, and that these non-synonymous mutations were possibly acquired by recombination
EBNA3A had six predicted NLSs [21], and we identified that six mutations that result in amino acid changes in the NLSs (NLS3, NLS4, and NLS5) present exclusively in EBV-2 strains
Summary
The Epstein–Barr Virus (EBV) is a human herpesvirus that belongs to the family Herpesviridae. EBV is related to the development of infectious mononucleosis (IM) [1], as well as potentially fatal neoplastic diseases, such as Burkitt lymphoma (BL) [2], nasopharyngeal cancer (NPC) [3], and gastric cancer (GC) [4]. The two types have functional differences in their ability to transform human B cells. EBV-1 induces the continuous proliferation (known as “transformation”) of human B cells more efficiently than EBV-2 in vitro [8,9]. EBV-2 has been associated with lower efficiency in immortalizing B lymphocytes in vitro, it has been detected in BL tumors [10]. Unlike EBV-1, which has a tropism for B lymphocytes, EBV-2 preferentially infects T-cells in cell culture [11]
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