Epstein–Barr virus nuclear antigen 2

The Epstein–Barr virus nuclear antigen 2 (EBNA-2) is one of the six EBV viral nuclear proteins expressed in latently infected B lymphocytes is a transactivator protein. EBNA2 is involved in the regulation of latent viral transcription and contributes to the immortalization of EBV infected cells.[1][2] EBNA2 acts as an adapter molecule that binds to cellular sequence-specific DNA-binding proteins, JK recombination signal-binding protein (RBP-JK), and PU.1 as well as working with multiple members of the RNA polymerase II transcription complex.[1]

EBNA2 requires C-promoter binding factor 1 (CBF1) to aid in binding to its cis-responsive DNA element, the C promoter (Cp).[1][3] Binding occurs during infection, to generate a 120kb transcript that encodes all nuclear antigens required for immortalization by EBV.2 Mutation of EBNA2 amino acid 323 and 324, which are located within a highly conserved amino acid motif, abolished the interaction with CBF1.3 This same mutation also abolished the ability of EBNA-2 to activate the Cp.[4]

EBNA2 has an acidic activation domain, which can interact with many different general transcription factors and co-activators.[5] Regulation of transcription initiation and elongation by EBNA 2 is done part through cyclin-dependent kinase 9 (CDK9) dependent phosphorylation of the RNA polymerase C-terminal domain.[5]

EBNA-LP and EBNA2 are the first two proteins expressed in latent infection of primary B lymphocytes.[6] EBNA-LP stimulates EBNA2 activation of the LMP1 promoter and of the LMP1/LMP2B bidirectional transcriptional regulatory element whereas EBNA-LP alone only has a negative effect.[6]

EBNA2 transactivates the promoters of the latent membrane antigens LMP, TP1 and TP2.[7] Additionally, EBNA2 interacts with an EBNA2 responsive cis-element of the TP1 promoter.[7] Interactions with both the TP1 and LMP/TP2 promoters occur at at least one binding site for the cellular repressor protein RBP-Jκ.[3] EBNA2 is tethered to the EBNA2 responsive promoter elements by interacting with RBP-Jκ, a human recombination signal sequence binding protein.[3][8]

Specific responsive elements that share the core sequence GTGGGAA have been discovered in several of the promoters activated by EBNA2.[8] A similar core sequence has recently been identified as a binding site in RBP-Jκ.[8] The binding of RBP-Jκ is not sufficient for EBNA2-mediated trans activation.[3] An activated form of the Notch receptor can transactivate a reporter construct containing a hexamer of the two RBP-Jκ binding sites of the TP1 promoter.[3] This supports the idea that EBNA2 acts as a functional equivalent of an activated Notch receptor.[3]

EBNA2 also interacts with the human homolog of the yeast transcription factor (SNF5 hSNF5/Ini1) as it coelutes with both hSNF5/Ini1 and BRG1.[7] BRG1 is a human homolog of SWI/SNF2.[2] However, this interaction is restricted to a subpopulation of phosphorylated viral EBNA2.[2] EBNA2-hSNF5/Ini1 interaction adds credit to the idea that EBNA2 facilitates transcriptional transactivation by acting as a transcription adapter molecule.[2] Possibly, EBNA2 engages the hSNF-SWI complex to generate an open chromatin conformation at the EBNA2-responsive target genes.[2] This then potentiates the function of the RBP-JK-EBNA2-polymerase II transcription complex.[2]

References

  1. 1 2 3 Henkel, T., P. D. Ling, S. D. Hayward, and M. G. Peterson. (1994). "Mediation of Epstein-Barr Virus EBNA2 Transactivation by Recombination Signal-binding Protein J Kappa.". Science. 265: 92–95. doi:10.1126/science.8016657.
  2. 1 2 3 4 5 6 Wu, D. Y., G. V. Kalpana, S. P. Goff, and W. H. Schubach. (1996). "Epstein-Barr Virus Nuclear Protein 2 (EBNA2) Binds to a Component of the Human SNF-SWI Complex, HSNF5/Ini1". The Journal of Virology.
  3. 1 2 3 4 5 6 Strobl, Lothar J., Heike Höfelmayr, Charlotte Stein, Gabriele Marschall, Markus Brielmeier, Gerhard Laux, Georg W. Bornkamm, and Ursula Zimber-Strobl. (1997). "Both Epstein-Barr Viral Nuclear Antigen 2 (EBNA2) and Activated Notch1 Transactivate Genes by Interacting with the Cellular Protein RBP-Jκ". Immunobiology.
  4. ↑ Ling, P. D.; D. R. Rawlins & S. D. Hayward. (1993). "The Epstein-Barr Virus Immortalizing Protein EBNA-2 Is Targeted to DNA by a Cellular Enhancer-binding Protein". Proceedings of the National Academy of Sciences. 90: 9237–9241. doi:10.1073/pnas.90.20.9237.
  5. 1 2 Palermo, Richard D., Helen M. Webb, Andrea Gunnell, and Michelle J. West (2008). "Regulation of Transcription by the Epstein–Barr Virus Nuclear Antigen EBNA 2". Biochm. Soc. Trans. Biochemical Society Transactions.
  6. 1 2 Harada, S. & E. Kieff (1997). "Epstein-Barr Virus Nuclear Protein LP Stimulates EBNA-2 Acidic Domain-mediated Transcriptional Activation". Journal of Virology.
  7. 1 2 3 Zimber-Strobl, U., E. Kremmer, F. Grasser, G. Marschall, G. Laux, and G. W. Bornkamm. (1993). "The Epstein-Barr Virus Nuclear Antigen 2 Interacts with an EBNA2 Responsive Cis-element of the Terminal Protein 1 Gene Promoter". The EMBO Journal. 12: 167–75. PMC 413188 Freely accessible. PMID 8381349.
  8. 1 2 3 Waltzer, L., F. Logeat, C. Brou, A. Israel, A. Sergeant, and E. Manet. (1994). "The Human J Kappa Recombination Signal Sequence Binding Protein (RBP-J Kappa) Targets the Epstein-Barr Virus EBNA2 Protein to Its DNA Responsive Elements". The EMBO Journal. 13: 5633–8. PMC 395528 Freely accessible. PMID 7988560.
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