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    Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling


    van Gent, Michiel and Braem, Steven G.E. and de Jonge, Annemieke and Delagic, Nezira and Peeters, Janneke G.C. and Moynagh, Paul N. and Kremmer, Elisabeth and Wiertz, Emmanuel and Ovaa, Huib and Griffin, Bryan D. and Ressing, Maaike E. (2014) Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling. PLoS Pathogens, 10 (2). e1003960. ISSN 1553-7374

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    Abstract

    Viral infection triggers an early host response through activation of pattern recognition receptors, including Toll-like receptors (TLR). TLR signaling cascades induce production of type I interferons and proinflammatory cytokines involved in establishing an anti-viral state as well as in orchestrating ensuing adaptive immunity. To allow infection, replication, and persistence, (herpes)viruses employ ingenious strategies to evade host immunity. The human gamma-herpesvirus Epstein-Barr virus (EBV) is a large, enveloped DNA virus persistently carried by more than 90% of adults worldwide. It is the causative agent of infectious mononucleosis and is associated with several malignant tumors. EBV activates TLRs, including TLR2, TLR3, and TLR9. Interestingly, both the expression of and signaling by TLRs is attenuated during productive EBV infection. Ubiquitination plays an important role in regulating TLR signaling and is controlled by ubiquitin ligases and deubiquitinases (DUBs). The EBV genome encodes three proteins reported to exert in vitro deubiquitinase activity. Using active site-directed probes, we show that one of these putative DUBs, the conserved herpesvirus large tegument protein BPLF1, acts as a functional DUB in EBV-producing B cells. The BPLF1 enzyme is expressed during the late phase of lytic EBV infection and is incorporated into viral particles. The N-terminal part of the large BPLF1 protein contains the catalytic site for DUB activity and suppresses TLR-mediated activation of NF-κB at, or downstream of, the TRAF6 signaling intermediate. A catalytically inactive mutant of this EBV protein did not reduce NF-κB activation, indicating that DUB activity is essential for attenuating TLR signal transduction. Our combined results show that EBV employs deubiquitination of signaling intermediates in the TLR cascade as a mechanism to counteract innate anti-viral immunity of infected hosts.

    Item Type: Article
    Additional Information: © 2014 van Gent et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Cite as: van Gent M, Braem SGE, de Jong A, Delagic N, Peeters JGC, Boer IGJ, et al. (2014) Epstein-Barr Virus Large Tegument Protein BPLF1 Contributes to Innate Immune Evasion through Interference with Toll-Like Receptor Signaling. PLoS Pathog 10(2): e1003960. https://doi.org/10.1371/journal.ppat.1003960
    Keywords: Epstein-Barr Virus Large Tegument Protein BPLF1; Innate Immune Evasion; Toll-Like Receptor Signaling;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 11034
    Identification Number: https://doi.org/10.1371/journal.ppat.1003960
    Depositing User: Professor Paul Moynagh
    Date Deposited: 10 Sep 2019 16:38
    Journal or Publication Title: PLoS Pathogens
    Publisher: Public Library of Science
    Refereed: Yes
    URI:

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