The B-Cell-Specific Transcription Factor and Master Regulator Pax5 Promotes Epstein-Barr Virus Latency by Negatively Regulating the Viral Immediate Early Protein BZLF1

Raver, Ryan M.; Panfil, Amanda R.; Hagemeier, Stacy R.; Kenney, Shannon C.

doi:10.1128/jvi.00546-13

Cited by 33 publications

(36 citation statements)

References 73 publications

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“…Given that the PAX5 and Oct-2 proteins inhibit Z activity (55,56) and that PAX5 represses synthesis of XBP-1 in lymphoid cells (57), one might expect that addition of BLIMP1 would induce EBV lytic gene expression in some EBV ϩ B-cell lines under some conditions; this hypothesis has been validated (58). Other investigators reported that while expression of EBV Z protein was restricted to BLIMP1-positive epithelial cells in oral hairy leukoplakia (OHL) tissue samples, this relationship did not hold in IM tonsillar B cells, suggesting that BLIMP1 may be necessary for induction of EBV lytic gene expression during differentiation of epithelial but not B cells (59).…”

Section: Importancementioning

confidence: 99%

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

Reusch

Nawandar

Wright

et al. 2015

J Virol

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Epstein-Barr virus (EBV) maintains a lifelong latent infection within a subset of its host IMPORTANCEThis study is the first one to show that the cellular transcription factor BLIMP1, a key player in both epithelial and B-cell differentiation, induces reactivation of the oncogenic herpesvirus Epstein-Barr virus (EBV) out of latency into lytic replication in a variety of cancerous epithelial cell types as well as in some, but not all, B-cell types that contain this virus in a dormant state. The mechanism by which BLIMP1 does so involves strongly turning on expression of both of the immediate early genes of the virus, probably by directly acting upon the promoters as part of protein complexes or indirectly by altering the expression or activities of some cellular transcription factors and signaling pathways. The fact that EBV ؉ cancers usually contain mostly undifferentiated cells may be due in part to these cells dying from lytic EBV infection when they differentiate and express wild-type BLIMP1.

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Section: Importancementioning

confidence: 99%

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

Reusch

Nawandar

Wright

et al. 2015

J Virol

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“…17 In addition, important B-cell transcription factors repressing plasma cell differentiation have been shown to repress also EBV replication. 36,37 Curiously most of post-transplant lymphoproliferative disorders exhibit plasma cell differentiation suggesting a connection between these two events in transplant recipients. It is of interest that, as in other aggressive lymphomas, XBP1 activation is related to aggressive disease.…”

Section: Discussionmentioning

confidence: 99%

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

et al. 2014

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Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell

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“…4C). The levels of Oct-2, Pax-5, ZEB1, and YY1, negative regulators of Z's activities or BZLF1 expression (14,15,62,75), also declined. Unexpectedly, the level of Ikaros RNA did not decline significantly.…”

Section: Ikaros Contributes To Maintenance Of Ebv Latency In B Cellsmentioning

confidence: 99%

“…EBV establishes long-term latency in B cells, undergoing reactivation when they differentiate into plasma cells (2). Some Bcell-specific factors (e.g., Oct-2 and Pax-5) promote EBV latency (14,15), while some plasma-cell-specific factors (e.g., XBP-1s and BLIMP-1) promote EBV lytic replication (6,7,70,71). To further understand how Ikaros contributes to EBV latency, we examined the effect of changing its level on the expression of some cellular factors known to play key roles in regulating EBV's latent-lytic switch or B-cell differentiation into plasma cells.…”

Section: Ikaros Contributes To Maintenance Of Ebv Latency In B Cellsmentioning

confidence: 99%

“…It binds AP-1-like sites called Z-responsive elements (ZREs), preferentially activating transcription from the methylated forms of its target promoters, including the methylated EBV genomes present in latently infected B cells (12,13). The cellular transcription factors Oct-2, Pax-5, p65 subunit of NF-B, and c-Myc promote EBV latency in part by interacting with Z, inhibiting its functional activities (14)(15)(16)(17).…”

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Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

Iempridee

Reusch

Riching

et al. 2014

J Virol

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Ikaros is a zinc finger DNA-binding protein that regulates chromatin remodeling and the expression of genes involved in the cell cycle, apoptosis, and Notch signaling. It is a master regulator of lymphocyte differentiation and functions as a tumor suppressor in acute lymphoblastic leukemia. Nevertheless, no previous reports described effects of Ikaros on the life cycle of any human lymphotropic virus. Here, we demonstrate that full-length Ikaros (IK-1) functions as a major factor in the maintenance of viral latency in Epstein

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The B-Cell-Specific Transcription Factor and Master Regulator Pax5 Promotes Epstein-Barr Virus Latency by Negatively Regulating the Viral Immediate Early Protein BZLF1

Abstract: The latent-to-lytic switch of Epstein-Barr virus (EBV) is mediated by the immediate early protein BZLF1 (Z).

Cited by 33 publications

References 73 publications

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

Epstein-Barr Virus Utilizes Ikaros in Regulating Its Latent-Lytic Switch in B Cells

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