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Epstein–Barr virus nuclear antigen 1

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(Redirected fromEBV nuclear antigen 1)

Epstein Barr virus nuclear antigen-1, DNA-binding domain
Identifiers
SymbolEBV-NA1
PfamPF02905
InterProIPR004186
SCOP21b3t/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

Epstein–Barr nuclear antigen 1(EBNA1) is a multifunctional, dimericviral proteinassociated withEpstein–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 aglycine–alaninerepeat sequence that separates the protein intoamino-andcarboxy-terminaldomains.[3]This sequence also seems to stabilize the protein, preventingproteasomal breakdown,as well as impairingantigenprocessing andMHCclass I-restricted antigen presentation. This thereby inhibits theCD8-restrictedcytotoxic T cellresponse against virus-infected cells.[4]EBNA1 is expressed from theQp promoterduring all latency programs.[3]It is the only viral protein expressed in latency program I.[1][4]

Function

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EBNA1 is integral to many EBV functions includinggene 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 binds to sequence-specific sites at the origin of viral replication (oriP) within the viralepisome.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).[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 viralpromotersvia 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]

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Though EBNA1 is a well-characterized protein, its role inoncogenesisis less well defined. It is consistently expressed in EBV-associatedtumors.[1]EBNA1 is the only identified latent protein-encoding genes that it consistently expressed inBurkitt's lymphomacells[6]and is believed to contribute to EBV malignancies throughB cell-directed expression. This expression has the ability to produce B-cell lymphomas intransgenicmice 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 for developing B cell lymphoma, thus demonstrating that EBNA1 is a viral oncogene and that it likely plays a role in B cellneoplasia.[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

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EBNA1 has been linked to theepithelial to mesenchymal transition(EMT) innasopharyngeal carcinomacells.[11]The link has been associated with theTGF-β1/miR-200/ZEBpathway.

References

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  1. ^abcdHumme, Siblille; et al. (2003)."The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold".PNAS.100(19): 10989–10994.Bibcode:2003PNAS..10010989H.doi:10.1073/pnas.1832776100.PMC196914.PMID12947043.
  2. ^abcdDuellman, 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.0.012260-0.PMC2786306.PMID19439552.
  3. ^abcdefYoung, Lawrence S.; Alan B. Rickinson (2004). "Epstein–Barr Virus: 40 Years On".Nature Reviews Cancer.4(10): 757–68.doi:10.1038/nrc1452.PMID15510157.S2CID25803264.
  4. ^abcLevitskaya 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.Bibcode:1995Natur.375..685L.doi:10.1038/375685a0.PMID7540727.S2CID4255748.
  5. ^abcKennedy, 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.PMC193932.PMID12972608.
  6. ^abcYoung, 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.PMID12910248.
  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 EMBO Journal.26(19): 4252–4262.doi:10.1038/sj.emboj.7601853.PMC2000340.PMID17853891.
  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.doi:10.1002/j.1460-2075.1996.tb00674.x.PMC450254.PMID8670812.
  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 (January 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.PMID23169501.
  10. ^Jones, K; Nourse JP; Morrison L; Nguyen-Van D; Moss DJ; Burrows SR; Gandhi MK. (September 2010)."Expansion of EBNA1-specific effector T cells in posttransplantation lymphoproliferative disorders".Blood.116(13): 2245–52.doi:10.1182/blood-2010-03-274076.PMID20562330.
  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.PMID24190575.
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