Transactivators Zta and Rta of Epstein–Barr virus promote G0/G1 to S transition in Raji cells: A novel relationship between lytic virus and cell cycle

Guo, Qingwei; Lü, Qian; Guo, Liang; Shi, Ming; Chen, Changguo; Lv, Xin; Yu, Ming; Hu, Meiru; Jiang, Guosheng

doi:10.1016/j.molimm.2010.02.017

Cited by 25 publications

(20 citation statements)

References 45 publications

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“…However, the expression of UNG2 was reported to peak in and throughout S phase and then decline to undetectable levels until the next S phase through the ubiquitin-proteasome pathway (61). Taking into account that EBV replication causes cell cycle arrest at the G 1 /S transition without cellular DNA replication (62,63), we suspect the decrease of UNG2 is caused by downregulated transcription or increased protein degradation.…”

Section: Discussionmentioning

confidence: 90%

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Liu

et al. 2014

J Virol

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Epstein-Barr virus (EBV) BKRF3 shares sequence homology with members of the uracil-N-glycosylase (UNG) protein family and has DNA glycosylase activity. Here, we explored how BKRF3 participates in the DNA replication complex and contributes to viral DNA replication. Exogenously expressed Flag-BKRF3 was distributed mostly in the cytoplasm, whereas BKRF3 was translocated into the nucleus and colocalized with the EBV DNA polymerase BALF5 in the replication compartment during EBV lytic replication. The expression level of BKRF3 increased gradually during viral replication, coupled with a decrease of cellular UNG2, suggesting BKRF3 enzyme activity compensates for UNG2 and ensures the fidelity of viral DNA replication. In immunoprecipitation-Western blotting, BKRF3 was coimmunoprecipitated with BALF5, the polymerase processivity factor BMRF1, and the immediate-early transactivator Rta. Coexpression of BMRF1 appeared to facilitate the nuclear targeting of BKRF3 in immunofluorescence staining. Residues 164 to 255 of BKRF3 were required for interaction with Rta and BALF5, whereas residues 81 to 166 of BKRF3 were critical for BMRF1 interaction in glutathione S-transferase (GST) pulldown experiments. Viral DNA replication was defective in cells harboring BKRF3 knockout EBV bacmids. In complementation assays, the catalytic mutant BKRF3(Q90L,D91N) restored viral DNA replication, whereas the leucine loop mutant BKRF3(H213L) only partially rescued viral DNA replication, coupled with a reduced ability to interact with the viral DNA polymerase and Rta. Our data suggest that BKRF3 plays a critical role in viral DNA synthesis predominantly through its interactions with viral proteins in the DNA replication compartment, while its enzymatic activity may be supplementary for uracil DNA glycosylase (UDG) function during virus replication. IMPORTANCECatalytic activities of both cellular UDG UNG2 and viral UDGs contribute to herpesviral DNA replication. To ensure that the enzyme activity executes at the right time and the right place in DNA replication forks, complex formation with other components in the DNA replication machinery provides an important regulation for UDG function. In this study, we provide the mechanism for EBV UDG BKRF3 nuclear targeting and the interacting domains of BKRF3 with viral DNA replication proteins. Through knockout and complementation approaches, we further demonstrate that in addition to UDG activity, the interaction of BKRF3 with viral proteins in the replication compartment is crucial for efficient viral DNA replication.

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Section: Discussionmentioning

confidence: 90%

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Liu

et al. 2014

J Virol

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“…Our study provides a basis for more extended explorations of this promising field. For instance, it seems plausible that translation of delivered BZLF1 transcripts activates resting cells and induces their cell-cycle entry (8,52), translated BHRF1 and BALF1 transcripts might protect the infected cells from activation-induced cell death (9), and noncoding packaged RNAs like miRNAs might control detrimental antiviral responses of the infected cell. tvRNAs, which encode viral IL-10, could also shape the cellular microenvironment (53) and thereby protect the EBV-infected cell from antiviral responses of the innate and adaptive immune system.…”

Section: Resultsmentioning

confidence: 99%

RNAs in Epstein–Barr virions control early steps of infection

Jochum

Ruiss

Moosmann

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Herpesviruses are dsDNA viruses, but their virions may additionally contain RNAs that can be transduced to recipient cells. The biological functions of herpes virion RNA species are unknown. Here we address this issue for EBV, a widespread human herpesvirus with oncogenic potential. We show that EBV-derived particles that include virions, virus-like particles, and subviral vesicles contain viral mRNAs, microRNAs, and other noncoding RNAs. Viral RNAs were transduced during infection and deployed immediate functions that enhanced EBV’s capacity to transform primary B cells. Among these transduced viral RNAs, BZLF1 transcripts transactivated viral promoters triggering the prelatent phase of EBV infection, noncoding EBV-encoded RNA transcripts induced cellular cytokine synthesis, and BNLF2a mRNA led to immune evasion that prevented T-cell responses to newly infected B cells. Hence, transduced viral RNAs govern critical processes immediately after infection of B cells with EBV and likely play important roles in herpesviral infection in general.

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“…20 In these cells TLR9 mRNA was expressed at a much higher level than in unstimulated naive B cells, which was markedly reduced by Syk inhibitor IV (Fig 6, A). In addition, these cells constitutively exhibited pronounced expression and phosphorylation of Syk.…”

Section: Traf6 Is a Key Syk-regulated Molecule In B-cell Subsets On Smentioning

confidence: 88%

Amplification of Toll-like receptor–mediated signaling through spleen tyrosine kinase in human B-cell activation

Iwata

Yamaoka

Niiro

et al. 2012

Journal of Allergy and Clinical Immunology

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Transactivators Zta and Rta of Epstein–Barr virus promote G0/G1 to S transition in Raji cells: A novel relationship between lytic virus and cell cycle

Cited by 25 publications

References 45 publications

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

Uracil DNA Glycosylase BKRF3 Contributes to Epstein-Barr Virus DNA Replication through Physical Interactions with Proteins in Viral DNA Replication Complex

RNAs in Epstein–Barr virions control early steps of infection

Amplification of Toll-like receptor–mediated signaling through spleen tyrosine kinase in human B-cell activation

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