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 196914Freely accessible. 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 193932Freely accessible. 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 450254Freely accessible. 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.
  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.
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