title: Epstein-Barr virus large tegument protein BPLF1 contributes to innate immune evasion through interference with toll-like receptor signaling.
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.
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van Gent
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Braem
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Annemieke
authors.initials: A
authors.lastname: de Jong
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Ireland.
authors.forename: Nezira
authors.initials: N
authors.lastname: Delagic
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Janneke G C
authors.initials: JG
authors.lastname: Peeters
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Ingrid G J
authors.initials: IG
authors.lastname: Boer
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Ireland.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, München, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Wiertz
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Griffin
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands ; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D004854:Herpesvirus 4, Human; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D007113:Immunity, Innate; D015151:Immunoblotting; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: C495488:BPLF1 protein, Epstein-Barr virus; D051193:Toll-Like Receptors; D054334:Viral Regulatory and Accessory Proteins