Epstein-Barr virus deubiquitinase downregulates TRAF6-mediated NF-κB signaling during productive replication.
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.
Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Shinichi
S
Saito
Takayuki
T
Murata
Teru
T
Kanda
Hiroki
H
Isomura
Yohei
Y
Narita
Atsuko
A
Sugimoto
Daisuke
D
Kawashima
Tatsuya
T
Tsurumi
D000704:Analysis of Variance; D022202:Chromosomes, Artificial, Bacterial; D017931:DNA Primers / Q000235:genetics; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D014763:Viral Matrix Proteins / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
C495488:BPLF1 protein, Epstein-Barr virus; D017931:DNA Primers; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014763:Viral Matrix Proteins; D054334:Viral Regulatory and Accessory Proteins; D008156:Luciferases