Study in PLoS Pathogens suggests that zinc is essential to EBNA1’s ability to trigger necessary gene expression.

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.

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