Epstein–Barr virus nuclear antigen 1

Epstein–Barr nuclear antigen 1 (EBNA1) is a multifunctional, dimeric viral protein associated with Epstein–Barr virus (EBV).^[1] It is the only EBV protein found in all EBV-related malignancies.^[2][3] It is important in establishing and maintaining the altered state that cells take when infected with EBV.^[2] EBNA1 has a glycine–alanine repeat sequence that separates the protein into amino- and carboxy-terminal domains.^[3] This sequence also seems to stabilize the protein, preventing proteasomal breakdown, as well as impairing antigen processing and MHC class I-restricted antigen presentation. This thereby inhibits the CD8-restricted cytotoxic T cell response against virus-infected cells.^[4] EBNA1 is expressed from the Qp promoter during all latency programs.^[3] It is the only viral protein expressed in latency program I.^[1][4]

EBNA1 is integral to many EBV functions including gene regulation, extrachromosomal replication, and maintenance of the EBV episomal genome through positive and negative regulation of viral promoters.^[2][5] Studies show that the phosphorylation of ten specific sites on EBNA1 regulates these functions. When phosphorylation does not occur, replication and transcription activities of the protein are significantly decreased.^[2] EBNA1 binds to sequence-specific sites at the origin of viral replication (oriP) within the viral episome. The oriP has four EBNA1 binding sites (called the Dyad Symmetry; DS) where replication is initiated as well as a 20-site repeat segment (called the Family of Repeats; FR).^[6] EBNA1's specific binding ability, as well as its ability to tether EBV DNA to chromosomal DNA,^[7] allows EBNA1 to mediate replication and partitioning of the episome during division of the host cell.^[3][4] EBNA1 also interacts with some viral promoters via several mechanisms,^[5] further contributing to transcriptional regulation of EBNA1 itself as well as the other EBNAs (2 and 3) and of EBV latent membrane protein 1 (LMP1).^[3]

Though EBNA1 is a well-characterized protein, its role in oncogenesis is less well defined. It is consistently expressed in EBV-associated tumors.^[1] EBNA1 is the only identified latent protein-encoding genes that it consistently expressed in Burkitt's lymphoma cells^[6] and is believed to contribute to EBV malignancies through B cell-directed expression. This expression has the ability to produce B-cell lymphomas in transgenic mice and contribute to the survival of Burkitt's lymphoma in vitro.^[3] EBNA1 may regulate cellular genes during EBV's latency phase and thus regulate EBV associated tumors.^[5] Some studies suggest that it is possible that EBNA1 may be involved in the maintenance function in tumors.^[6] Transgenic mice expressing EBNA1 in B cell lines showed a predisposition for developing B cell lymphoma, thus demonstrating that EBNA1 is a viral oncogene and that it likely plays a role in B cell neoplasia.^[8] Data also show that, though its role in extrachromosomal replication, EBNA1 also increases the growth of B cells,^[1] thus aiding in the formation of malignancies. Adoptive ex vivo transfer of EBNA-1-specific T cells is a feasible and well-tolerated therapeutic option,^[9] however for optimal efficacy expansion protocols should use antigenic sequences from relevant EBV strains.^[10]

EBNA1 has been linked to the epithelial to mesenchymal transition (EMT) in nasopharyngeal carcinoma cells.^[11] The link has been associated with the TGF-β1/miR-200/ZEB pathway.