Epstein-Barr virus-derived EBNA2 regulates STAT3 activation
Open accessAbstract
The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.
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HTLV-I, Epstein-Barr virus and papilloma virus activate STAT3 and NF-κB.
“Both hepatitis B and hepatitis C viruses, which induce hepatitis and cause hepatocellular carcinoma, activate STAT3 (328–330), while HTLV-I, Epstein–Barr virus and papilloma virus activate STAT3 and NF-κB (311, 331, 332).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [331]
The Introduction reports STAT3 activation in HTLV-I-transformed T cells and Epstein–Barr virus-related lymphoma cell lines. A title in the References mentions NF-κB activation induced by an Epstein–Barr virus protein, but the paper does not address papilloma virus or establish the claim that all three viruses activate both STAT3 and NF-κB. No page numbers are available in our copy. (LLM, conf=0.84)
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Research works printed but not linked: 3
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“Moreover, EBNA2 was shown to be a transcriptional co-activator of STAT3 (36).”
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STAT3 roles in viral infection: antiviral or proviral?
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Margolskee, E. M., Jobanputra, V., Jain, P., Chen, J., Ganapathi, K. A., Nahum, O., Levy, B., Morscio, J., Murty, V., Tousseyn, T., et al. (2016) · OncoTarget · doi:10.18632/oncotarget.9400 · Cited by 55 · see citing works
Murakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53 · see citing works
“Moreover, many viral proteins, including the hepatitis C virus Core protein and EBNA2 from the Epstein–Barr virus, are strong STAT3 activators (Yoshida et al., 2002; Muromoto et al., 2009).”
Yao, D.-F., Ruan, L.-W., Lu, H.-S., Shi, H., & Xu, X. (2016) · Fish and Shellfish Immunology · doi:10.1016/j.fsi.2016.10.051 · Cited by 48
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“LMP1 upregulates STAT3 (49) and EBNA-2 enhances the activity of STAT3 (50).”
BackgroundThe Dynamic Interface of Viruses with STATs
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Zhong, L., Xie, C.-Q., Zhang, L.-L., Yang, Y.-L., Liu, Y.-T., Zhao, G.-X., Bu, G.-L., Tian, X.-S., Jiang, Z.-Y., Yuan, B.-Y., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2766-0 · Cited by 28 · see citing works
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Šimičić, P., Batović, M., Marković, A. S., & Židovec-Lepej, S. (2024) · Viruses · doi:10.3390/v16040564 · Cited by 25 · see citing works
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“STAT3 can directly up-regulate the expression of CD30 by binding to the CD30 promoter region in ALCL cell lines, and it can also bind to two highly conserved STAT3 sites in the CD30 intron, which indirectly suggests that they may be potential enhancer regions (75).”
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Debnath, M., Nagappa, M., Subbanna, M., Sundaravadivel, P., Talukdar, P. M., Shivakumar, V., Wahatule, R., Dutta, D., Binukumar, B., Sinha, S., et al. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.08.001 · Cited by 17
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“STAT3 signaling is also stimulated by human gammaherpesvirus gene products such as Kaposi’s sarcoma-associated herpesvirus (KSHV) viral IL-6 (vIL-6) (11–14), kaposin B (15), and viral-G-protein-coupled receptor (v-GPCR) (16, 17) and EpsteinBarr virus (EBV) LMP-1 (18, 19) and EBNA2 (20); and STAT3 levels influence lyti…”
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“A number of tumor viruses can activate the STAT3 pathway, including HCMV, EBV, HPV, HTLV virus, and hepatitis B virus [Figure 6].[113,138,183,204] STAT3 can also be activated by other noninfectious stresses, including direct lipopolysaccharide stimulation through toll-like receptor 4 immune activation, UV light induct…”
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“In addition, EBV and KSHV encode cytokine homologues (vIL-10 and vIL-6) that activate STAT3, as well as other viral factors that lead to an increase in STAT3 tyrosine phosphorylation (32-43).”
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Wu, C.-C., Chen, M.-S., Lee, T.-Y., Huang, T.-S., Cho, D.-Y., & Chen, J.-Y. (2024) · Viral immunology · doi:10.1089/vim.2023.0118 · Cited by 6 · see citing works
“EBAN2 induces IFN-stimulated gene production and STAT3 activity to repress the production of inflam-matory mediators (Ho and Ivashkiv, 2006; Muromoto et al., 2009).”
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Self-citationEpstein Barr virus EBNA2 : interactions of intrinsically disordered proteins with host cell factors.
Geenen, E. (2013) · doi:10.70675/100f530ezfbe0z45dfzbc07za98f56e10d5a
“Cellular assays investigating the STAT3-EBAN2 interaction Prior to this work, the interaction between STAT3 and EBNA2 had been described using luciferase-STAT3 promoter assays and co-immunoprecipitation (Ikeda et al., 2009; Muromoto et al., 2009a) with no indication of binding regions or affinities.”
BackgroundMethodResultInfluentialRole of Stat3 in nasopharyngeal carcinoma
Pan, Y.-B. (2013) · doi:10.13172/2053-3918-1-2-1101
Sano, S. (2010) · doi:10.2336/nishinihonhifu.72.229
- Authors
- Muromoto, R., Ikeda, O., Okabe, K., Togi, S., Kamitani, S., Fujimuro, M., Harada, S., Oritani, K., & Matsuda, T.
- Affiliations
- Hokkaido University (JP)
- University of Yamanashi (JP)
- National Institute of Infectious Diseases (JP)
- The University of Osaka (JP)
- Corresponding author
- Matsuda, Tadashi
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 378
- Issue
- 3
- Pages
- 439-443
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2012689489
- Cited by
- 42
- References
- 0
- Citations by year
- 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 7 · 2017: 1 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 1.41
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- Epstein-Barr virus, EBNA2, STAT3, transcriptional coactivator, LMP1, DNA-binding activity, transcriptional activation, cell transformation, interleukin-6 family cytokines
- MeSH terms
- Herpesvirus 4, Human, HeLa Cells, Humans, Viral Matrix Proteins, Viral Proteins, Transcriptional Activation, Epstein-Barr Virus Nuclear Antigens, STAT3 Transcription Factor
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