Researchers from LSU Health Sciences Center (LSUHSC) say that they have unraveled the mechanism by which EBNA1 activates gene expression required for immortalization of the Epstein-Barr virus (EBV). They also report that environmental conditions such as oxygen tension and oxidative stress modulate EBNA1's capacity to self-associate and therefore to activate gene expression.
The findings are published in the online issue of PLoS Pathogens in a paper titled, “Zinc Coordination Is Required for and Regulates Transcription Activation by Epstein-Barr Nuclear Antigen 1.”
EBV infects human B cells and immortalizes them, which results in diseases that range from infectious mononucleosis to malignancies such as lymphomas. During immortalization, EBV expresses a small number of viral genes that modulate cellular proliferation and differentiation.
It has been known that Epstein-Barr nuclear antigen 1 (EBNA1), one of the genes expressed by EBV, activates the expression of the other viral genes required for immortalization. Additionally, previous research has shown that a small domain termed UR1, which is 25 amino acids long, is essential for EBNA1 to activate transcription.
The LSUHSC team found that EBNA1 uses the micronutrient zinc to self-associate and that self-association is necessary for it to activate gene expression. They found that UR1 coordinates zinc through a pair of essential cysteines contained within it. Point mutants of EBNA1 that disrupt zinc coordination also prevent self-association and do not activate transcription cooperatively, the investigators add.
The researchers also demonstrated, using a lymphoblastoid cell line, that UR1 acts as a molecular sensor that regulates the ability of EBNA1 to activate transcription in response to changes in redox and oxygen partial pressure.
The gene-expression profile and proliferative phenotype of EBV-infected cells is known to vary in differing environmental niches in the human body, such as lymph nodes and in peripheral circulation. The scientists hypothesize that these differences arise as a consequence of varying oxygen tension in these microenvironments.