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] The EBNA1 transcript area originates at the Qp promoter during latency phases I and II.[3] It is the only viral protein expressed during the first latency phase.[1][4]

Function

EBNA1 is integral in 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 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.[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]

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.[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 to 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]

Role in epithelial to mesenchymal transition

EBNA1 has recently 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.

References

  1. 1 2 3 4 Humme, Siblille; et al. (2003). "The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold". PNAS 100 (19): 10989–10994. doi:10.1073/pnas.1832776100. PMC 196914. PMID 12947043.
  2. 1 2 3 4 Duellman, Sarah J., Katie L. Thompson, Joshua J. Coon, Richard R Burgess (2009). "Phosphorylation sites of Epstein–Barr Virus EBNA1 regulate its function". J Gen Virol. 90 (9): 2251–9. doi:10.1099/vir.0.0122260-0.
  3. 1 2 3 4 5 6 Young, Lawrence S., Alan B. Rickinson (2004). "Epstein–Barr Virus: 40 Years On". Nature Reviews – Cancer 4 (10): 757–68. doi:10.1038/nrc1452. PMID 15510157.
  4. 1 2 3 Levitskaya J, Coram M, Levitsky V; et al. (1995). "Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1". Nature 375 (6533): 685–8. doi:10.1038/375685a0. PMID 7540727.
  5. 1 2 3 Kennedy, Gregory, Bill Sugden (2003). "EBNA1, a Bifunctional Transcription Activator". Molecular and Cellular Biology 23 (19): 6901–6908. doi:10.1128/MCB.23.19.6901-6908.2003. PMC 193932. PMID 12972608.
  6. 1 2 3 Young, Lawrence S., Paul G. Murry (2003). "Epstein–Barr Virus and oncogenesis: from latent genes to tumors". Oncogene 22 (33): 5108–5121. doi:10.1038/sj.onc.1206556. PMID 12910248.
  7. ↑ Nanbo, Asuka, Arthur Sugden, Bill Sugden (2007). "The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells". The European Molecular Biology Organization Journal 26 (19): 4252–4262. doi:10.1038/sj.emboj.7601853.
  8. ↑ Wilson, J.B., J.L. Bell, A.J. Levine (1996). "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. PMC 450254. PMID 8670812.
  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. (Jan 2013). "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 31 (1): 39–48. doi:10.1200/JCO.2011.39.8495. PMID 23169501. Cite uses deprecated parameter |coauthors= (help)
  10. ↑ Jones, K; Nourse JP; Morrison L; Nguyen-Van D; Moss DJ; Burrows SR; Gandhi MK. (Sep 2010). "Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders" (PDF). Blood 116 (13): 2245–52. doi:10.1182/blood-2010-03-274076. PMID 20562330.
  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 (1 February 2014). "Epstein-Barr virus nuclear antigen 1 (EBNA1) protein induction of epithelial-mesenchymal transition in nasopharyngeal carcinoma cells". Cancer 120 (3): 363–372. doi:10.1002/cncr.28418. Cite uses deprecated parameter |coauthors= (help)
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