Epstein-Barr Virus Immediate-Early Protein BZLF1 Inhibits Tumor Necrosis Factor Alpha-Induced Signaling and Apoptosis by Downregulating Tumor Necrosis Factor Receptor 1

Morrison, Thomas E.; Mauser, Amy; Klingelhutz, Aloysius J.; Kenney, Shannon C.

doi:10.1128/jvi.78.1.544-549.2004

Cited by 71 publications

(70 citation statements)

References 40 publications

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“…For instance, the nonpolyadenylated untranslated RNAs, EBER-1 and -2, expressed during latency, inhibit the activation of the dsRNA-stimulated protein kinase R, thereby providing resistance to IFN-induced apoptosis (49). Various immunoevasive capabilities have also been assigned to the immediate-early transactivator BZLF1, including association with the NF-kB subunit p65, resulting in its nuclear location while impairing its transcriptional ability (50), inhibition of IRF7, thereby hampering type I IFN production during viral reactivation (51), and downregulation of the TNFR gene promoter activity compromising the effects of TNF-a on an infected cell (52). More recently, the EBV tegument protein LF2 was shown to block dimerization of IRF7, whereas the virionassociated kinase BGLF4 was found to curtail IRF3 transactivation ability (53,54).…”

Section: Discussionmentioning

confidence: 99%

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Gent

Griffin

Berkhoff

et al. 2011

The Journal of Immunology

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Viruses use a wide range of strategies to modulate the host immune response. The human gammaherpesvirus EBV, causative agent of infectious mononucleosis and several malignant tumors, encodes proteins that subvert immune responses, notably those mediated by T cells. Less is known about EBV interference with innate immunity, more specifically at the level of TLR-mediated pathogen recognition. The viral dsDNA sensor TLR9 is expressed on B cells, a natural target of EBV infection. Here, we show that EBV particles trigger innate immune signaling pathways through TLR9. Furthermore, using an in vitro system for productive EBV infection, it has now been possible to compare the expression of TLRs by EBV− and EBV+ human B cells during the latent and lytic phases of infection. Several TLRs were found to be differentially expressed either in latently EBV-infected cells or after induction of the lytic cycle. In particular, TLR9 expression was profoundly decreased at both the RNA and protein levels during productive EBV infection. We identified the EBV lytic-phase protein BGLF5 as a protein that contributes to downregulating TLR9 levels through RNA degradation. Reducing the levels of a pattern-recognition receptor capable of sensing the presence of EBV provides a mechanism by which the virus could obstruct host innate antiviral responses.

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Section: Discussionmentioning

confidence: 99%

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Gent

Griffin

Berkhoff

et al. 2011

The Journal of Immunology

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“…pSG-BZLF-1 and the mutants pSG-BZLF-1 ⌬TA and pSG-BZLF-1 A185K were gifts from Shannon Kenney and have been described (50). The LMP-1, pcDNA-CD4, EGFP-IRF-7, and Tap-2 CAT plasmids have been described before (91); pISRE-luc construct was purchased from BD Biosciences/ Clontech.…”

Section: Methodsmentioning

confidence: 99%

Interferon Regulatory Factor 7 Is Negatively Regulated by the Epstein-Barr Virus Immediate-Early Gene,BZLF-1

Hahn¹,

Huye

Ning

et al. 2005

J Virol

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“…These two proteins are activators of viral and cellular gene expression, play essential roles in lytic viral DNA replication, and impinge on many host cell processes, such as signal transduction, cell cycle control, and cellular senescence (10,27,30,31). The bzlf1 and brlf1 genes are not expressed during latency, but all external stimuli known to activate the EBV lytic cascade induce their expression (3,16,28,39,48).…”

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confidence: 99%

Cellular Immediate-Early Gene Expression Occurs Kinetically Upstream of Epstein-Barr Virus bzlf1 and brlf1 following Cross-Linking of the B Cell Antigen Receptor in the Akata Burkitt Lymphoma Cell Line

Gradoville²,

Miller

2010

J Virol

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The Epstein-Barr virus (EBV) lytic activator genes bzlf1 and brlf1 are conventionally referred to as immediate-early (IE) genes. However, previous studies showed that the earliest expression of these genes was blocked by cycloheximide when the EBV lytic cycle was induced by histone deacetylase (HDAC) inhibitors and protein kinase C agonists. Anti-IgG activates a complex signal transduction pathway that leads to EBV lytic activation in the Akata cell line. Here we demonstrate that in Akata cells, where lytic cycle activation occurs very rapidly after anti-IgG treatment, de novo protein synthesis is also required for induction of bzlf1 and brlf1 expression. New protein synthesis is required up to 1.25 h after application of anti-IgG; bzlf1 and brlf1 mRNAs can be detected 1.5 h after anti-IgG. Five cellular IE genes were shown to be expressed by 1 h after addition of anti-IgG, and their expression preceded that of bzlf1 and brlf1. These include early growth response genes (egr1, egr2, and egr3) and nuclear orphan receptors (nr4a1 and nr4a3). These genes were activated by anti-IgG treatment of Akata cells with and without the EBV genome; therefore, their expression was not dependent on expression of any EBV gene product. EGR1, EGR2, and EGR3 proteins were kinetically upstream of ZEBRA and Rta proteins. Expression of EGR1, ZEBRA, and Rta proteins were inhibited by bisindolylmaleimide X, a selective inhibitor of PKC. The findings suggest a revised model in which the signal transduction cascade activated by cross-linking of the B cell receptor induces expression of cellular IE genes, such as early growth response and nuclear orphan receptor genes, whose products, in turn, regulate bzlf1 and brlf1 expression.Two Epstein-Barr virus (EBV) genes, bzlf1 and brlf1, encode protein products, ZEBRA and Rta, that control the transition from viral latency to lytic replication (12,13,23,34,46). These two proteins are activators of viral and cellular gene expression, play essential roles in lytic viral DNA replication, and impinge on many host cell processes, such as signal transduction, cell cycle control, and cellular senescence (10,27,30,31). The bzlf1 and brlf1 genes are not expressed during latency, but all external stimuli known to activate the EBV lytic cascade induce their expression (3,16,28,39,48). Therefore, a central question is, "What controls the expression of these two EBV lytic activator genes?" We refer to this question as the "upstream problem" in lytic activation (29,44).A full understanding of the upstream events has been elusive for several reasons. Many mechanically heterogeneous stimuli activate the lytic cascade in cultured lymphoid cells, where the molecular events can be readily analyzed. Each cell line seems to respond to the inducing stimuli in an idiosyncratic fashion (3,16,28,39,48). The lytic cycle-inducing agents vary in the duration of exposure required to elicit a response. Moreover, the cells vary in their response time (11). It is not yet known whether the many pathways engaged by the diverse sti...

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Epstein-Barr Virus Immediate-Early Protein BZLF1 Inhibits Tumor Necrosis Factor Alpha-Induced Signaling and Apoptosis by Downregulating Tumor Necrosis Factor Receptor 1

Cited by 71 publications

References 40 publications

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

EBV Lytic-Phase Protein BGLF5 Contributes to TLR9 Downregulation during Productive Infection

Interferon Regulatory Factor 7 Is Negatively Regulated by the Epstein-Barr Virus Immediate-Early Gene,BZLF-1

Cellular Immediate-Early Gene Expression Occurs Kinetically Upstream of Epstein-Barr Virus bzlf1 and brlf1 following Cross-Linking of the B Cell Antigen Receptor in the Akata Burkitt Lymphoma Cell Line

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