EBV nuclear antigen 1
Encyclopedia
Epstein-Barr nuclear antigen 1 (EBNA1) is a multifunctional, dimeric viral protein
associated with Epstein-Barr virus
. It is the only viral protein of Epstein-Barr that is found in all EBV-related malignancies. It is important in establishing and maintaining the altered state that cells take when infected with EBV. EBNA1 possesses a glycine
-alanine
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
processing and MHC
class I-restricted antigen presentation. This thereby inhibits the CD8
-restricted cytotoxic T cell
response against virus-infected cells. The EBNA1 transcript area originates at the Qp promoter during latency phases I and II. It is the only viral protein expressed during the first latency phase.
, 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 acts through sequence-specific binding to the plasmid origin of viral replication (oriP
) within the viral episome. The oriP has four EBNA1 binding sites where replication is initiated as well as a 20-site repeat segment which also enhances the presence of the protein. 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).
-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. 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 to B cell lymphoma, thus demonstrating that EBNA1 is a viral oncogene and that it likely plays a role in B cell neoplasia
. 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.
Viral protein
A viral protein is a protein generated by a virus.Many are structural, forming the viral envelope and capsid. However, there are also viral nonstructural proteins and viral regulatory and accessory proteins.More than 490 have been identified....
associated with Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
. It is the only viral protein of Epstein-Barr that is found in all EBV-related malignancies. It is important in establishing and maintaining the altered state that cells take when infected with EBV. EBNA1 possesses a glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
repeat sequence that separates the protein into amino- and carboxy-terminal domains. This sequence also seems to stabilize the protein, preventing proteasomal breakdown
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, as well as impairing antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
processing and MHC
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
class I-restricted antigen presentation. This thereby inhibits the CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
-restricted cytotoxic T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
response against virus-infected cells. The EBNA1 transcript area originates at the Qp promoter during latency phases I and II. It is the only viral protein expressed during the first latency phase.
Function of EBNA1
EBNA1 is integral in many EBV functions including gene regulation, extrachromosomal replicationExtrachromosomal DNA
Extrachromosomal DNA is DNA located or maintained in a cell apart from the chromosomes....
, 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 acts through sequence-specific binding to the plasmid origin of viral replication (oriP
Ori (genetics)
Ori is the DNA sequence that signals for the origin of replication, sometimes referred to simply as origin. In E. coli, ori is some 250 nucleotides in length for the chromosomal origin...
) within the viral episome. The oriP has four EBNA1 binding sites where replication is initiated as well as a 20-site repeat segment which also enhances the presence of the protein. 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 of EBNA1 in EBV related malignancies
Though EBNA1 is a well-characterized protein, its role in oncogenesis is less well-defined. It is consistently expressed in EBV-associated tumors. 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 cellB cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
-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. 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 to B cell lymphoma, thus demonstrating that EBNA1 is a viral oncogene and that it likely plays a role in B cell neoplasia
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
. 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.