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] EBNA1 is expressed from the Qp promoter during all latency programs.[3] It is the only viral protein expressed in latency program I.[1][4]
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.[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 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).[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 malignanciesedit
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 for developing 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]
^ 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. PMID 12947043.
^ 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. PMID 19439552.
^ abcdefYoung, 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. S2CID 25803264.
^ 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. PMID 7540727. S2CID 4255748.
^ 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. PMID 12972608.
^ 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. PMID 12910248.
^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. PMID 17853891.
^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. PMID 8670812.
^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. PMID 23169501.
^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. PMID 24190575.
January 01, 1970
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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 EBNA1 is expressed from the Qp promoter during all latency programs 3 It is the only viral protein expressed in latency program I 1 4 Epstein Barr virus nuclear antigen 1 DNA binding domainIdentifiersSymbolEBV NA1PfamPF02905InterProIPR004186SCOP21b3t SCOPe SUPFAMAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summary Contents 1 Function 2 Role in EBV related malignancies 2 1 Role in epithelial to mesenchymal transition 3 ReferencesFunction editEBNA1 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 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 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 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 editThough 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 for developing 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 edit EBNA1 has been linked to the epithelial to mesenchymal transition EMT in nasopharyngeal carcinoma cells 11 The link has been associated with the TGF b1 miR 200 ZEB pathway References edit a b c d Humme 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 PMC 196914 PMID 12947043 a b c d 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 012260 0 PMC 2786306 PMID 19439552 a b c d e f 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 S2CID 25803264 a b c 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 Bibcode 1995Natur 375 685L doi 10 1038 375685a0 PMID 7540727 S2CID 4255748 a b c 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 a b c 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 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 PMC 2000340 PMID 17853891 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 PMC 450254 PMID 8670812 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 PMID 23169501 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 PMID 20562330 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 PMID 24190575 Retrieved from https en wikipedia org w index php title Epstein Barr virus nuclear antigen 1 amp oldid 1195185010, wikipedia, wiki, book, books, library,
