Interferon regulatory factor 7 is involved in the growth of Epstein–Barr virus-transformed human B lymphocytes

2015 ◽  
Vol 195 ◽  
pp. 112-118 ◽  
Author(s):  
Dongsheng Xu ◽  
Yanyan Zhang ◽  
Lingjun Zhao ◽  
Mingxia Cao ◽  
Amy Lingel ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr

scholarly journals Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties

2004 ◽  
Vol 78 (23) ◽  
pp. 12987-12995 ◽  
Author(s):  
Luwen Zhang ◽  
Jun Zhang ◽  
Que Lambert ◽  
Channing J. Der ◽  
Luis Del Valle ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
3T3 Cells ◽  
Barr Virus ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

ABSTRACT Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas.

scholarly journals Interferon Regulatory Factor 7 Mediates Activation of Tap-2 by Epstein-Barr Virus Latent Membrane Protein 1

2001 ◽  
Vol 75 (1) ◽  
pp. 341-350 ◽  
Author(s):  
Luwen Zhang ◽  
Joseph S. Pagano
Keyword(s):  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Interferon Regulatory Factor ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr

ABSTRACT Transporter associated with antigen processing 2 (Tap-2) is responsible for ATP-dependent transport of peptides from the cytosol to the endoplasmic reticulum, where peptides bind to newly synthesized human leukocyte antigen (HLA) class I molecules, which are essential for cellular immune responses. Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) has been shown to induce the expression of Tap-2. In this study, the induction of endogenous Tap-2 by LMP-1 is shown to be associated with and requires the expression of interferon regulatory factor 7 (IRF-7). In DG75 Burkitt's lymphoma (BL) cells, in which LMP-1 induces the expression of IRF-7, LMP-1 induced endogenous Tap-2, and ectopic expression of IRF-7 could enhance the induction. In Akata BL cells, in which LMP-1 could not induce IRF-7, LMP-1 could not induce Tap-2. Addition of IRF-7, which complements the defect in Akata cells, could stimulate the expression of Tap-2. Furthermore, LMP-1 and IRF-7A but not other IRF-7 splicing variants could activate endogenous Tap-2. A Tap-2 promoter reporter construct could be activated by the overexpression of IRF-7A. The activation could be specifically enhanced by LMP-1 and was dependent on an intact interferon-stimulated response element (ISRE) present in the Tap-2 promoter. Also, IRF-7 can bind to the Tap-2 promoter under physiological conditions in vivo, as shown by formaldehyde cross-linking, as well as to the Tap-2 ISRE in vitro, as shown by gel mobility shift assays. Furthermore, LMP-1 facilitates the phosphorylation and nuclear translocation of IRF-7. These data point to the role of IRF-7 as a secondary mediator of LMP-1-activated signal transduction for Tap-2 as follows: LMP-1 stimulates the expression of IRF-7 and facilitates its phosphorylation and nuclear translocation, and then the activated IRF-7 mediates the activation of the cellular Tap-2 gene. The induction of Tap-2 by IRF-7 and LMP-1 may have an important implication for the immune response to EBV and its persistence in vivo.

scholarly journals Interferon Regulatory Factor 7 Regulates Expression of Epstein-Barr Virus Latent Membrane Protein 1: a Regulatory Circuit

2003 ◽  
Vol 77 (17) ◽  
pp. 9359-9368 ◽  
Author(s):  
Shunbin Ning ◽  
Angela M. Hahn ◽  
Leslie E. Huye ◽  
Joseph S. Pagano
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 1 ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Regulatory Circuit ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr

ABSTRACT We have shown previously that interferon regulatory factor 7 (IRF7), a multifunctional protein intimately involved in latent Epstein-Barr virus (EBV) infection, is induced as well as activated by EBV latent membrane protein 1 (LMP1), the principal EBV oncoprotein. Since the LMP1 promoter (LMP1p) contains an interferon-stimulated response element (ISRE), we hypothesized that IRF7 might be able to regulate LMP1 expression and thus participate in a regulatory circuit between these two genes. In this study, IRF7 was shown first to activate LMP1p in transient transfection assays. Compared with EBV nuclear antigen 2 (EBNA2), the most potent viral transactivator of LMP1p, IRF7 has a lesser effect (approximately 10% that of EBNA2) on induction of LMP1p. Study with IRF7 deletion mutants showed that IRF7 functional domains have similar effects on both the beta interferon (IFN-β) and LMP1 promoters in BJAB and 293 cells, and study with IRF7 phosphomimetic mutants showed that IRF7 phosphorylation may be involved in the activation of these two promoters. Further, the ISRE in LMP1p responds to IRF7 induction and IRF7 binds to this element. In the EBV-positive cell line P3HR1, which lacks the complete EBNA2 and EBV-encoded leader protein genes and hence expresses low-level LMP1, IRF7 alone can notably increase the endogenous LMP1 mRNA and protein levels. These results indicate that LMP1 is regulated by this host cell gene in addition to the viral factor, EBNA2, and may help to explain how LMP1 is expressed in type II latency in the absence of EBNA2. Moreover, IRF7 can regulate a viral gene in addition to a host cellular gene such as the IFN-β gene. Together with the previous data that LMP1 can induce IRF7 expression and facilitate IRF7 phosphorylation and nuclear translocation, these results suggest a positive regulatory circuit between IRF7 and LMP1.

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

2005 ◽  
Vol 79 (15) ◽  
pp. 10040-10052 ◽  
Author(s):  
Angela M. Hahn ◽  
Leslie E. Huye ◽  
Shunbin Ning ◽  
Jennifer Webster-Cyriaque ◽  
Joseph S. Pagano
Keyword(s):  
Viral Replication ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Lytic Replication ◽  
Immediate Early ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Antiviral Responses ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr

ABSTRACT Virus infection stimulates potent antiviral responses; specifically, Epstein-Barr virus (EBV) infection induces and activates interferon regulatory factor 7 (IRF-7), which is essential for production of alpha/beta interferons (IFN-α/β) and upregulates expression of Tap-2. Here we present evidence that during cytolytic viral replication the immediate-early EBV protein BZLF-1 counteracts effects of IRF-7 that are central to host antiviral responses. We initiated these studies by examining IRF-7 protein expression in vivo in lesions of hairy leukoplakia (HLP) in which there is abundant EBV replication but the expected inflammatory infiltrate is absent. This absence might predict that factors involved in the antiviral response are absent or inactive. First, we detected significant levels of IRF-7 in the nucleus, as well as in the cytoplasm, of cells in HLP lesions. IRF-7 activity in cell lines during cytolytic viral replication was examined by assay of the IRF-7-responsive promoters, IFN-α4, IFN-β, and Tap-2, as well as of an IFN-stimulated response element (ISRE)-containing reporter construct. These reporter constructs showed consistent reduction of activity during lytic replication. Both endogenous and transiently expressed IRF-7 and EBV BZLF-1 proteins physically associate in cell culture, although BZLF-1 had no effect on the nuclear localization of IRF-7. However, IRF-7-dependent activity of the IFN-α4, IFN-β, and Tap-2 promoters, as well as an ISRE promoter construct, was inhibited by BZLF-1. This inhibition occurred in the absence of other EBV proteins and was independent of IFN signaling. Expression of BZLF-1 also inhibited activation of IRF-7 by double-stranded RNA, as well as the activity of a constitutively active mutant form of IRF-7. Negative regulation of IRF-7 by BZLF-1 required the activation domain but not the DNA-binding domain of BZLF-1. Thus, EBV may subvert cellular antiviral responses and immune detection by blocking the activation of IFN-α4, IFN-β, and Tap-2 by IRF-7 through the medium of BZLF-1 as a negative regulator.

scholarly journals Interferon Regulatory Factor 4 Is Involved in Epstein-Barr Virus-Mediated Transformation of Human B Lymphocytes

2008 ◽  
Vol 82 (13) ◽  
pp. 6251-6258 ◽  
Author(s):  
Dongsheng Xu ◽  
Lingjun Zhao ◽  
Luis Del Valle ◽  
Judith Miklossy ◽  
Luwen Zhang
Keyword(s):  
B Lymphocytes ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Ebv Transformation ◽  
Epstein Barr ◽  
Cns Lymphomas ◽  
Interferon Regulatory Factor 4

ABSTRACT Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. EBV latent membrane protein 1 (LMP-1) is required for EBV transformation processes. Interferon regulatory factor 4 (IRF-4) is a transcription factor and has oncogenic potential. We find that high levels of IRF-4 are associated with EBV transformation of human primary B cells in vitro and with EBV type III latency in which LMP-1 is expressed. We show that EBV LMP-1 stimulates IRF-4 expression in B lymphocytes. The stimulation of IRF-4 by LMP-1 requires signaling from LMP-1 and involves cellular NF-κB. The growth of EBV-transformed cells is inhibited when IRF-4 is specifically down-regulated. We further demonstrate that IRF-4 knockdown cells have lower proliferation but higher apoptotic rates than control cells. Finally, IRF-4 is expressed in significant numbers of specimens of primary central nervous system (CNS) lymphomas (12/27 [44.4%]), an EBV-associated malignancy. The association between the expression levels of LMP-1 and IRF-4 is statistically significant (P = 0.011) in these CNS lymphomas. Our data suggest that IRF-4 may be a critical factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia.

scholarly journals Intracellular Signaling Molecules Activated by Epstein-Barr Virus for Induction of Interferon Regulatory Factor 7

2001 ◽  
Vol 75 (24) ◽  
pp. 12393-12401 ◽  
Author(s):  
Luwen Zhang ◽  
Lihong Wu ◽  
Ke Hong ◽  
Joseph S. Pagano
Keyword(s):  
Membrane Protein ◽  
Intracellular Signaling ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Interferon Regulatory Factor ◽  
Dominant Negative ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Interferon Regulatory Factor 7 ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) is the principal oncogenic protein in the EBV transformation process. LMP-1 induces the expression of interferon regulatory factor 7 (IRF-7) and activates IRF-7 protein by phosphorylation and nuclear translocation. LMP-1 is an integral membrane protein with two regions in its C terminus that initiate signaling processes, the C-terminal activator regions 1 (CTAR-1) and CTAR-2. Here, genetic analysis of LMP-1 has determined that the PXQXT motif that governs the interaction between LMP-1 CTAR-1 and tumor necrosis factor receptor-associated factors (TRAFs) is needed to induce the expression of IRF-7. Mutations in the PXQXT motif in CTAR-1 that disrupt the interaction between LMP-1 and TRAFs abolished the induction of IRF-7. Also, dominant-negative mutants of TRAFs inhibited the induction of IRF-7 by CTAR-1. The last three amino acids (YYD) of CTAR-2 are also important for the induction of IRF-7. When both PXQXT and YYD were mutated (LMP-DM), the LMP-1 mutant failed to induce IRF-7. Also, LMP-DM blocked the induction of IRF-7 by wild-type LMP-1. These data strongly suggest that both CTAR-1 and CTAR-2 of LMP-1 independently induce the expression of IRF-7. In addition, NF-κB is involved in the induction of IRF-7. A superrepressor of IκB (sr-IκB) could block the induction of IRF-7 by LMP-1, and overexpression of NF-κB (p65 plus p50) could induce the expression of IRF-7. In addition, we have found that human IRF-7 is a stable protein, and sodium butyrate, a modifier of chromatin structure, induces IRF-7.

scholarly journals Interferon Regulatory Factor 5 Represses Expression of the Epstein-Barr Virus Oncoprotein LMP1: Braking of the IRF7/LMP1 Regulatory Circuit

2005 ◽  
Vol 79 (18) ◽  
pp. 11671-11676 ◽  
Author(s):  
Shunbin Ning ◽  
Leslie E. Huye ◽  
Joseph S. Pagano
Keyword(s):  
Transient Expression ◽  
Epstein Barr Virus ◽  
Interferon Regulatory Factor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
Regulatory Factor ◽  
Barr Virus ◽  
Regulatory Circuit ◽  
Epstein Barr

ABSTRACT We have reported evidence for a positive regulatory circuit between interferon regulatory factor 7 (IRF7) and the Epstein-Barr virus (EBV) oncoprotein 1 (LMP1) (S. Ning, A. M. Hahn, and J. S. Pagano, J. Virol. 77:9359-9368, 2003). To explore a possible braking mechanism for this circuit, several type II EBV-infected cell lines that express different levels of LMP1 and IRF7 proteins and therefore are convenient for studying modulation of expression of LMP1 were analyzed. Endogenous levels of IRF7 and LMP1 were directly correlated. Transient expression of an IRF7 dominant-negative mutant decreased LMP1 levels. Endogenous IRF5 and IRF7 proteins were shown to physically associate in EBV-positive cells. Transient expression of IRF5 decreased activation of the LMP1 promoter by IRF7 in a dose-dependent manner. Finally, transfection of either an IRF5 dominant-negative construct or IRF5 small interfering RNA in these cells resulted in increases in endogenous levels of LMP1. These results indicate that IRF5 can downregulate IRF7's induction of expression of LMP1 most likely by interacting with IRF7 and provide a means of modulating a regulatory circuit between IRF7 and LMP1.

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