Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-κB signaling during productive replication

Shinichi Saito, Takayuki Murata, Teru Kanda, Hiroki Isomura, Yohei Narita, Atsuko Sugimoto, Daisuke Kawashima, Tatsuya Tsurumi

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52 Citations (Scopus)

Abstract

Epstein-Barr virus (EBV), a human oncogenic herpesvirus that establishes a lifelong latent infection in the host, occasionally enters lytic infection to produce progeny viruses. The EBV oncogene latent membrane protein 1 (LMP1), which is expressed in both latent and lytic infection, constitutively activates the canonical NF-κB (p65) pathway. Such LMP1-mediated NF-κB activation is necessary for proliferation of latently infected cells and inhibition of viral lytic cycle progression. Actually, canonical NF-κB target gene expression was suppressed upon the onset of lytic infection. TRAF6, which is activated by conjugation of polyubiquitin chains, associates with LMP1 to mediate NF-κB signal transduction. We have found that EBV-encoded BPLF1 interacts with and deubiquitinates TRAF6 to inhibit NF-κB signaling during lytic infection. HEK293 cells with BPLF1-deficient recombinant EBV exhibited poor viral DNA replication compared with the wild type. Furthermore, exogenous expression of BPLF1 or p65 knockdown in cells restored DNA replication of BPLF1-deficient viruses, indicating that EBV BPLF1 deubiquitinates TRAF6 to inhibit NF-κB signal transduction, leading to promotion of viral lytic DNA replication

Original languageEnglish
Pages (from-to)4060-4070
Number of pages11
JournalJournal of Virology
Volume87
Issue number7
DOIs
Publication statusPublished - 04-2013

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Saito, S., Murata, T., Kanda, T., Isomura, H., Narita, Y., Sugimoto, A., Kawashima, D., & Tsurumi, T. (2013). Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-κB signaling during productive replication. Journal of Virology, 87(7), 4060-4070. https://doi.org/10.1128/JVI.02020-12