Epstein–Barr nuclear antigen 1 (EBNA1) is a multifunctional, dimeric

viral protein A viral protein is both a component and a product of a virus. Viral proteins are grouped according to their functions, and groups of viral proteins include structural proteins, nonstructural proteins, regulatory proteins, and accessory proteins. ...

associated with

Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is b ...

(EBV). It is the only EBV protein found in all EBV-related malignancies. It is important in establishing and maintaining the altered state that cells take when infected with EBV. EBNA1 has a

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...

–

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side ...

repeat sequence that separates the protein into amino- and carboxy-terminal domains. This sequence also seems to stabilize the protein, preventing proteasomal breakdown, as well as impairing

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...

processing and MHC class I-restricted antigen presentation. This thereby inhibits the

CD8 CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...

-restricted cytotoxic

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

response against virus-infected cells. EBNA1 is expressed from the Qp promoter during all latency programs. It is the only viral protein expressed in latency program I.

Function

EBNA1 is integral to many EBV functions including

gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wi ...

, extrachromosomal replication, and maintenance of the EBV episomal genome through positive and negative regulation of viral promoters. 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. EBNA1 binds to sequence-specific sites at the origin of viral replication ( oriP) within the viral

episome An episome is a special type of plasmid, which remains as a part of the eukaryotic genome without integration. Episomes manage this by replicating together with the rest of the genome and subsequently associating with metaphase chromosomes during m ...

. 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). EBNA1's specific binding ability, as well as its ability to tether EBV DNA to chromosomal DNA, allows EBNA1 to mediate replication and partitioning of the episome during division of the host cell. EBNA1 also interacts with some viral promoters via several mechanisms, 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).

Role in EBV-related malignancies

Though EBNA1 is a well-characterized protein, its role in

oncogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

is less well defined. It is consistently expressed in EBV-associated

tumors A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

. EBNA1 is the only identified latent protein-encoding genes that it consistently expressed in Burkitt's lymphoma cells 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 A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

mice and contribute to the survival of Burkitt's lymphoma in vitro. EBNA1 may regulate cellular genes during EBV's latency phase and thus regulate EBV associated tumors. Some studies suggest that it is possible that EBNA1 may be involved in the maintenance function in tumors. 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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

. Data also show that, though its role in extrachromosomal replication, EBNA1 also increases the growth of B cells, 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, however for optimal efficacy expansion protocols should use antigenic sequences from relevant EBV strains.

Role in epithelial to mesenchymal transition

EBNA1 has been linked to the

epithelial to mesenchymal transition Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...

(EMT) in

nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess ( fossa of Rosenmüller), accounting for 50% of cases. NPC occurs ...

cells. The link has been associated with the TGF-β1/

miR-200 In molecular biology, the miR-200 microRNA is a short RNA molecule. MicroRNAs function to regulate the expression levels of other genes by binding and cleaving mRNAs or inhibiting translation. The miR-200 family contains miR-200a, miR-200b, miR- ...

/ ZEB pathway.

References

{{DEFAULTSORT:Epstein-Barr Nuclear Antigen 1 Viral nonstructural proteins Epstein–Barr virus