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]

Epstein–Barr virus nuclear antigen 2
Identifiers
OrganismEpstein-Barr virus (strain B95-8)
SymbolEBNA2
UniProtP12978

Structure

EBNA2 has an acidic activation domain, which can interact with many different general transcription factors and co-activators.[3] 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.[3]

Mechanism

EBNA2 requires C-promoter binding factor 1 (CBF1) to aid in binding to its cis-responsive DNA element, the C promoter (Cp).[1][4] 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.[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.[4] EBNA2 is tethered to the EBNA2 responsive promoter elements by interacting with RBP-Jκ, a human recombination signal sequence binding protein.[4][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.[4] 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.[4] This supports the idea that EBNA2 acts as a functional equivalent of an activated Notch receptor.[4]

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]

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References
  1. Henkel T, Ling PD, Hayward SD, Peterson MG (July 1994). "Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa". Science. 265 (5168): 92–5. doi:10.1126/science.8016657. PMID 8016657.
  2. Wu DY, Kalpana GV, Goff SP, Schubach WH (September 1996). "Epstein-Barr virus nuclear protein 2 (EBNA2) binds to a component of the human SNF-SWI complex, hSNF5/Ini1". Journal of Virology. 70 (9): 6020–8. PMC 190622. PMID 8709224.
  3. Palermo RD, Webb HM, Gunnell A, West MJ (August 2008). "Regulation of transcription by the Epstein-Barr virus nuclear antigen EBNA 2". Biochemical Society Transactions. 36 (Pt 4): 625–8. doi:10.1042/BST0360625. PMID 18631129.
  4. Strobl LJ, Höfelmayr H, Stein C, Marschall G, Brielmeier M, Laux G, et al. (December 1997). "Both Epstein-Barr viral nuclear antigen 2 (EBNA2) and activated Notch1 transactivate genes by interacting with the cellular protein RBP-J kappa". Immunobiology. 198 (1–3): 299–306. doi:10.1016/S0171-2985(97)80050-2. PMID 9442401.
  5. Ling PD, Rawlins DR, Hayward SD (October 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 of the United States of America. 90 (20): 9237–41. doi:10.1073/pnas.90.20.9237. PMC 47542. PMID 8415684.
  6. Harada S, Kieff E (September 1997). "Epstein-Barr virus nuclear protein LP stimulates EBNA-2 acidic domain-mediated transcriptional activation". Journal of Virology. 71 (9): 6611–8. PMC 191939. PMID 9261383.
  7. Zimber-Strobl U, Kremmer E, Grässer F, Marschall G, Laux G, Bornkamm GW (January 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 (1): 167–75. PMC 413188. PMID 8381349.
  8. Waltzer L, Logeat F, Brou C, Israel A, Sergeant A, Manet E (December 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 (23): 5633–8. PMC 395528. PMID 7988560.
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