Epstein–Barr virus nuclear antigen 1 explained

Epstein–Barr nuclear antigen 1 (EBNA1) is a multifunctional, dimeric viral protein associated with Epstein–Barr virus (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.[1] EBNA1 has a glycinealanine repeat sequence that separates the protein into amino- and carboxy-terminal domains.[2] 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.[3] EBNA1 is expressed from the Qp promoter during all latency programs.[2] It is the only viral protein expressed in latency program I.[3]

Function

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.[1] 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.[1] 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). EBNA1's specific binding ability, as well as its ability to tether EBV DNA to chromosomal DNA,[4] allows EBNA1 to mediate replication and partitioning of the episome during division of the host cell.[2] [3] 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).[2]

Role 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 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.[2] 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.[7] Data also show that, though its role in extrachromosomal replication, EBNA1 also increases the growth of B cells,[8] 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]

Role in epithelial to mesenchymal transition

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.

Notes and References

  1. Duellman, Sarah J. . Katie L. Thompson . Joshua J. Coon . Richard R Burgess . Phosphorylation sites of Epstein–Barr Virus EBNA1 regulate its function . J Gen Virol . 90 . 9 . 2251–9 . 2009 . 10.1099/vir.0.012260-0. 19439552 . 2786306 .
  2. 10.1038/nrc1452 . Young, Lawrence S. . Alan B. Rickinson . Epstein–Barr Virus: 40 Years On . Nature Reviews Cancer . 4 . 10 . 757–68 . 2004 . 15510157 . 25803264 .
  3. Levitskaya J, Coram M, Levitsky V . Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1 . Nature . 375 . 6533 . 685–8 . 1995 . 7540727 . 10.1038/375685a0. 1995Natur.375..685L . 4255748 . etal.
  4. Nanbo, Asuka . Arthur Sugden . Bill Sugden . The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells . The EMBO Journal. 26 . 19. 4252–4262 . 2007 . 10.1038/sj.emboj.7601853. 17853891 . 2000340 .
  5. 10.1128/MCB.23.19.6901-6908.2003 . Kennedy, Gregory . Bill Sugden . EBNA1, a Bifunctional Transcription Activator . Molecular and Cellular Biology . 23 . 19 . 6901–6908 . 2003 . 12972608 . 193932.
  6. Young, Lawrence S. . Paul G. Murry . Epstein–Barr Virus and oncogenesis: from latent genes to tumors. Oncogene . 22. 33 . 5108–5121. 2003. 12910248. 10.1038/sj.onc.1206556. free.
  7. Wilson, J.B. . J.L. Bell . A.J. Levine . Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice . The European Molecular Biology Organization Journal . 15 . 12. 3117–3126. 1996. 450254 . 8670812. 10.1002/j.1460-2075.1996.tb00674.x .
  8. Humme, Siblille . The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold . PNAS . 100 . 19 . 10989–10994. 2003 . 10.1073/pnas.1832776100. 12947043. 196914. 2003PNAS..10010989H . etal. free .
  9. Icheva V, Kayser S, Wolff D, Tuve S, Kyzirakos C, Bethge W, Greil J, Albert MH, Schwinger W, Nathrath M, Schumm M, Stevanovic S, Handgretinger R, Lang P, Feuchtinger T . Adoptive transfer of epstein-barr virus (EBV) nuclear antigen 1-specific t cells as treatment for EBV reactivation and lymphoproliferative disorders after allogeneic stem-cell transplantation . J Clin Oncol . Jan 2013 . 31 . 1 . 39–48 . 10.1200/JCO.2011.39.8495 . 23169501. free .
  10. Jones. K. Nourse JP . Morrison L . Nguyen-Van D . Moss DJ . Burrows SR . Gandhi MK. . Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders. Blood. Sep 2010. 116. 13. 2245–52. 10.1182/blood-2010-03-274076. 20562330. free.
  11. Wang. Lu . Tian, Wen-Dong . Xu, Xia . Nie, Biao . Lu, Juan . Liu, Xiong . Zhang, Bao . Dong, Qi . Sunwoo, John B. . Li, Gang . Li, Xiang-Ping . Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells . Cancer . 1 February 2014 . 120 . 3 . 363–372 . 10.1002/cncr.28418 . 24190575. free .