Genetic Patterns Found in the Nuclear Localization Signals (NLSs) Associated with EBV-1 and EBV-2 Provide New Insights into Their Contribution to Different Cell-Type Specificities

Abstract

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.

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

“…So far, two major EBV types, named type 1 and type 2 EBV, with nearly identical genomes except for the genes encoding some of the nuclear proteins, the EBV nuclear antigen (EBNA)-2 and EBNA-3A, -3B and -3C, have been identified [8,9]. Type 1 EBV is found ubiquitously worldwide and has a higher transformation efficiency of B cells, while type 2 EBV is mainly detected in Africa [10,11]. Primary infection mostly involves asymptomatic children prior to the age of 5 years and is rather rare in adults who more frequently acquire severe symptoms called infectious mononucleosis [12].…”

Epstein–Barr Virus Infection in Cancer

“…Zanella, L. et al [ 1 ] evaluated more than a thousand EBNA3A sequences of EBV from different human clinical manifestations and geographic locations and found differences in six peptide motifs called nuclear localization signals (NLSs) among the EBV types. EBNA3A from EBV-2 showed that two (NLS3 and NLS4) of the six NLSs were altered (non-canonical) compared with the EBNA3A EBV-1.…”

Worldwide Prevalence of Epstein–Barr Virus in Patients with Burkitt Lymphoma: A Systematic Review and Meta-Analysis

“…The EBV genome encodes more than 85 genes, which are involved in the pathogenesis of infection and initiating EBV-associated human disease. There are two major types of EBV: type 1 EBV, which is found worldwide, and type 2 EBV, which is mainly detected in Africa [ 3 ]. EBV is the most frequent cause of infectious mononucleosis, with primary infections commonly occurring asymptomatically in teenagers and young adults, especially college students, while in adults, the symptoms are more severe.…”