Canonical NF-κB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation

Benjamin E. Gewurz, Jessica C. Mar, Megha Padi, Bo Zhao, Nicholas P. Shinners, Kaoru Takasaki, Edward Bedoya, James Y. Zou, Ellen Cahir-Mcfarland, John Quackenbush, Elliott Kieff

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) transforms rodent fibroblasts and is expressed in most EBV-associated malignancies. LMP1 (transformation effector site 2[TES2]/C-terminal activation region 2 [CTAR2]) activates NF-κB, p38, Jun N-terminal protein kinase (JNK), extracellular signalregulated kinase (ERK), and interferon regulatory factor 7 (IRF7) pathways. We have investigated LMP1 TES2 genome-wide RNA effects at 4 time points after LMP1 TES2 expression in HEK-293 cells. By using a false discovery rate (FDR) of <0.001 after correction for multiple hypotheses, LMP1 TES2 caused >2-fold changes in 1,916 mRNAs; 1,479 RNAs were upregulated and 437 were downregulated. In contrast to tumor necrosis factor alpha (TNF-κ) stimulation, which transiently upregulates many target genes, LMP1 TES2 maintained most RNA effects through the time course, despite robust and sustained induction of negative feedback regulators, such as IκBα and A20. LMP1 TES2-regulated RNAs encode many NF-κB signaling proteins and secondary interacting proteins. Consequently, many LMP1 TES2-regulated RNAs encode proteins that form an extensive interactome. Gene set enrichment analyses found LMP1 TES2-upregulated genes to be significantly enriched for pathways in cancer, B- and T-cell receptor signaling, and Toll-like receptor signaling. Surprisingly, LMP1 TES2 and IκBα superrepressor coexpression decreased LMP1 TES2 RNA effects to only 5 RNAs, with FDRs of <0.001-fold and >2-fold changes. Thus, canonical NF-κB activation is critical for almost all LMP1 TES2 RNA effects in HEK-293 cells and a more significant therapeutic target than previously appreciated.

Original languageEnglish (US)
Pages (from-to)6764-6773
Number of pages10
JournalJournal of virology
Volume85
Issue number13
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Gewurz, B. E., Mar, J. C., Padi, M., Zhao, B., Shinners, N. P., Takasaki, K., Bedoya, E., Zou, J. Y., Cahir-Mcfarland, E., Quackenbush, J., & Kieff, E. (2011). Canonical NF-κB activation is essential for Epstein-Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. Journal of virology, 85(13), 6764-6773. https://doi.org/10.1128/JVI.00422-11