Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta

Almohammed, Rajaei; Osborn, Kay; Ramasubramanyan, Sharada; Perez-Fernandez, Ijiel B. Naranjo; Godfrey, Anja; Mancini, Erika J.; Sinclair, Alison J.

doi:10.1099/jgv.0.001056

Cited by 8 publications

(4 citation statements)

References 62 publications

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“…We therefore tested whether exogenous expression of IRF4 in DG75 cells can activate miR-155HG transcription via upstream enhancers. Because IRF4 activates the control plasmid (pRL-TK), firefly reporter activity was normalized to actin expression as a previously described alternative in these assays ( 36 ). Consistent with previously reported data, we found that the exogenous expression of IRF4 resulted in a 4-fold increase in miR-155HG promoter activity ( 28 ).…”

Section: Resultsmentioning

confidence: 99%

Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Wood

Carvell

Gunnell

et al. 2018

J Virol

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MicroRNA miR-155 is expressed at high levels in many human cancers, particularly lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development of numerous lymphomas. Two genes carried by EBV (LMP1 and EBNA2) upregulate miR-155 expression, and miR-155 expression is required for the growth of EBV-infected B cells. We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression through enhancer-mediated activation of IRF4. IRF4 then activates both the miR-155HG promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore identify enhancer-mediated activation of miR-155HG as a critical step in promoting B cell growth and a likely contributor to lymphoma development.

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Section: Resultsmentioning

confidence: 99%

Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Wood

Carvell

Gunnell

et al. 2018

J Virol

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“…We therefore tested whether exogenous expression of IRF4 in DG75 cells can activate miR-155HG transcription via upstream enhancers. Because IRF4 activates the control plasmid (pRL-TK), Firefly reporter activity was normalized to actin expression as a previously described alternative in these assays (35). Consistent with published data, we found that exogenous expression of IRF4 resulted in a 4-fold increase in miR-155HG promoter activity (29).…”

Section: Resultsmentioning

confidence: 99%

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

Wood

Carvell

Gunnell

et al. 2018

Preprint

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16The oncogenic microRNA-155 (miR-155) is the most frequently upregulated miRNA in 17 Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-18 viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription 19 factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host 20 cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates 21IRF4 transcription indicating that EBV may upregulate miR-155 through direct and 22 indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-23 155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can 24 activate IRF4 and miR-155HG expression through specific upstream enhancers that are 25 dependent on the Notch signaling transcription factor RBPJ, a known binding partner of 26 EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 27 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene 28 editing to remove the EBNA2-and IRF4-responsive miR-155HG enhancer located 60 kb 29 upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our 30 data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-31 miR-155 expression network and play a key role in the maintenance of miR-155 expression 32 in EBV-infected B cells. These findings provide important insights that will improve our 33 understanding of miR-155 control in B cell malignancies. 34 35 IMPORTANCE 36MicroRNA-155 (miR-155) is expressed at high level in many human cancers particularly 37 lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development 38. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/311886 doi: bioRxiv preprint first posted online May. 1, 2018; 3 of numerous lymphomas. Two EBV-encoded genes (LMP1 and EBNA2) upregulate miR-39 155 expression and miR-155 expression is required for the growth of EBV-infected B cells. 40We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by 41 activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which 42 miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression 43 through enhancer-mediated activation of IRF4. IRF4 then activates both the miR-155HG 44 promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove 45 the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore 46 identify enhancer-mediated activation of miR-155HG as a critical step in promoting B cell 47 growth and a likely driver of lymphoma development. 48 49. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in pe...

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“…For instance, BNLF2a is a vital EBV inhibitor of the transporter associated with antigen processing (TAP) protein complex. It can shut down peptide/HLA presentation through the blockage of peptides and ATP binding to the TAP complex [ 70 ]. The third evasion molecule is an EBV-encoding gene, BILF1, which encodes a constitutively active G-protein-coupled receptor (GPCR) that not only downregulates HLA I via endocytic and exocytic pathways, but also induces signalling-mediated tumourigenesis [ 71 ].…”

Section: Specific Immune Response To Ebvmentioning

confidence: 99%

Deciphering the Role of Epstein–Barr Virus Latent Membrane Protein 1 in Immune Modulation: A Multifaced Signalling Perspective

Šimičić,

Batović,

Stojanović Marković

et al. 2024

Viruses

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The disruption of antiviral sensors and the evasion of immune defences by various tactics are hallmarks of EBV infection. One of the EBV latent gene products, LMP1, was shown to induce the activation of signalling pathways, such as NF-κB, MAPK (JNK, ERK1/2, p38), JAK/STAT and PI3K/Akt, via three subdomains of its C-terminal domain, regulating the expression of several cytokines responsible for modulation of the immune response and therefore promoting viral persistence. The aim of this review is to summarise the current knowledge on the EBV-mediated induction of immunomodulatory molecules by the activation of signal transduction pathways with a particular focus on LMP1-mediated mechanisms. A more detailed understanding of the cytokine biology molecular landscape in EBV infections could contribute to the more complete understanding of diseases associated with this virus.

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Mechanism of activation of the BNLF2a immune evasion gene of Epstein-Barr virus by Zta

Cited by 8 publications

References 62 publications

Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Enhancer Control of MicroRNA miR-155 Expression in Epstein-Barr Virus-Infected B Cells

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

Deciphering the Role of Epstein–Barr Virus Latent Membrane Protein 1 in Immune Modulation: A Multifaced Signalling Perspective

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