Plasma Cell-Specific Transcription Factor XBP-1s Binds to and Transactivates the Epstein-Barr Virus BZLF1 Promoter

Sun, Chia Chi; Thorley‐Lawson, David A.

doi:10.1128/jvi.01055-07

Cited by 108 publications

(109 citation statements)

References 53 publications

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“…5), indicating that XBP-1 is important for the up-regulation of LMP1 therein. On the other hand, it has been reported that XBP-1 can induce EBV lytic gene expression in some cell types (31,32), but in our study, treatment with ER stress inducers or ectopic expression of XBP-1s did not increase EBV lytic proteins ( Fig. 1C; data not shown).…”

Section: Resultscontrasting

confidence: 48%

Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Hsiao

Chang²,

Chen

et al. 2009

Cancer Research

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Endoplasmic reticulum (ER) stress-activated unfolded protein response (UPR) plays multiple roles in cancer development, but its specific roles for virus-associated cancers have not been fully understood. It is still unknown whether ER stress/ UPR occurs in and contributes to nasopharyngeal carcinoma (NPC), an epithelial malignancy closely associated with EBV. Here, we report that UPR proteins are frequently detected in NPC biopsies. In addition, we reveal that, in EBV-infected NPC cells, ER stress inducers up-regulate a potent EBV oncoprotein latent membrane protein 1 (LMP1), and the ER stress-induced LMP1 enhances production of interleukin-8. ER stress triggers LMP1 expression at a transcriptional level, activating a distal LMP1 promoter TR-L1. TR-L1 contains an ER stressresponsive element, which is targeted by an UPR protein XBP-1. Ectopic expression of XBP-1 induces LMP1 expression, and knockdown of XBP-1 blocks ER stress-triggered upregulation of LMP1 in NPC cells. Furthermore, XBP-1 significantly correlates with LMP1 expression in NPC tumor biopsies. Therefore, this study not only provides a novel clue linking ER stress/UPR to EBV-associated NPC but also suggests that ER stress/UPR can promote virus-associated cancer in a unique way by driving expression of a viral oncogene.

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Section: Resultscontrasting

confidence: 48%

Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Hsiao

Chang²,

Chen

et al. 2009

Cancer Research

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“…However, the priming factor for EBV reactivation in vivo is poorly understood. The plasma cell differentiation factor X-box binding protein-1 (XBP-1) binds and transactivates Zp in a plasma cell line and in lymphoid cell lines but not in epithelial cell lines (52). XBP-1 also induces BZLF1 transcription and is involved in B cell differentiation into plasma cells.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor-Mediated Induction of EBV Reactivation as a Risk Factor for Sjögren’s Syndrome

Inoue

Mishima

Yamamoto-Yoshida

et al. 2012

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates a variety of biological effects by binding to environmental pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). Although numerous animal studies have demonstrated the harmful effects of dioxins, it remains controversial whether dioxins pose a risk to human health. Enhanced lytic replication of EBV is a risk factor for the development of autoimmune diseases and cancers. This study evaluated the possibility that ligand-activated AhR reactivates EBV. EBV reactivation and AhR transactivation were evaluated with luciferase assays. Saliva samples were collected from 19 patients with primary Sjögren’s syndrome (SS). Control saliva samples were obtained from 10 healthy individuals and nine patients with severe dry mouth. TCDD enhanced BZLF1 transcription, which mediates the switch from the latent to the lytic form of EBV infection in EBV-positive B cell lines and in a salivary gland epithelial cell line. Moreover, TCDD-induced increases in BZLF1 mRNA and EBV genomic DNA levels were confirmed in the B cell lines. Saliva from SS patients activated the transcription of both CYP1A1 and BZLF1. Additionally, there was a positive correlation between CYP1A1 and BZLF1 promoter activities. AhR ligands elicited the reactivation of EBV in activated B cells and salivary epithelial cells, and these ligands are involved in SS. Our findings reveal novel aspects of the biological effects of dioxin and the AhR-dependent pathogenesis of autoimmune diseases.

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“…More recently, several other molecules, such as bortezomib (BZ) and thapsigargin (TG), have been reported to induce the EBV lytic cycle in Burkitt cell lines (6). X-box-binding protein 1 (XPB1 form), activated during the unfolded protein response (UPR), also has been shown to induce the switch from latent to lytic cycle by triggering the immediate-early transactivator proteins ZTA and RTA (7). These proteins can, in turn, activate the entire set of EBV lytic gene promoters, controlling the switch from latency to lytic replication (8).…”

mentioning

confidence: 99%

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

Granato

Santarelli

Farina

et al. 2014

J Virol

132

129

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Autophagy is a catabolic pathway that helps cells to survive under stressful conditions. Cells also use autophagy to clear microbiological infections, but microbes have learned how to manipulate the autophagic pathway for their own benefit. The experimental evidence obtained in this study suggests that the autophagic flux is blocked at the final steps during the reactivation of Epstein-Barr virus (EBV) from latency. This is indicated by the level of the lipidated form of LC3 that does not increase in the presence of bafilomycin and by the lack of colocalization of autophagosomes with lysosomes, which correlates with reduced Rab7 expression. Since the inhibition of the early phases of autophagy impaired EBV replication and viral particles were observed in autophagic vesicles in the cytoplasm of producing cells, we suggest that EBV exploits the autophagic machinery for its transportation in order to enhance viral production. The autophagic block was not mediated by ZEBRA, an immediate-early EBV lytic gene, whose transfection in Ramos, Akata, and 293 cells promoted a complete autophagic flux. The block occurred only when the complete set of EBV lytic genes was expressed. We suggest that the inhibition of the early autophagic steps or finding strategies to overcome the autophagic block, allowing viral degradation into the lysosomes, can be exploited to manipulate EBV replication. IMPORTANCEThis study shows, for the first time, that autophagy is blocked at the final degradative steps during EBV replication in several cell types. Through this block, EBV hijacks the autophagic vesicles for its intracellular transportation and enhances viral production. A better understanding of virus-host interactions could help in the design of new therapeutic approaches against EBV-associated malignancies.

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Plasma Cell-Specific Transcription Factor XBP-1s Binds to and Transactivates the Epstein-Barr Virus BZLF1 Promoter

Cited by 108 publications

References 53 publications

Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Endoplasmic Reticulum Stress Triggers XBP-1–Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma

Aryl Hydrocarbon Receptor-Mediated Induction of EBV Reactivation as a Risk Factor for Sjögren’s Syndrome

Epstein-Barr Virus Blocks the Autophagic Flux and Appropriates the Autophagic Machinery To Enhance Viral Replication

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