scholarly journals Cellular Genes Involved in Redox Regulation Are Altered by Inhibitors of Epstein‐Barr Virus Lytic Gene Expression

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Kelly Gorres ◽  
George Miller
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Redox Regulation ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Cellular Genes ◽  
Epstein Barr

scholarly journals New Noncoding Lytic Transcripts Derived from the Epstein-Barr Virus Latency Origin of Replication,oriP, Are Hyperedited, Bind the Paraspeckle Protein, NONO/p54nrb, and Support Viral Lytic Transcription

2015 ◽  
Vol 89 (14) ◽  
pp. 7120-7132 ◽  
Author(s):  
Subing Cao ◽  
Walter Moss ◽  
Tina O'Grady ◽  
Monica Concha ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Noncoding Rnas ◽  
Lytic Replication ◽  
Long Noncoding Rnas ◽  
Origin Of Replication ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Epstein Barr

ABSTRACTWe have previously shown that the Epstein-Barr virus (EBV) likely encodes hundreds of viral long noncoding RNAs (vlncRNAs) that are expressed during reactivation. Here we show that the EBV latency origin of replication (oriP) is transcribed bi-directionally during reactivation and that both leftward (oriPtLs) and rightward (oriPtRs) transcripts are largely localized in the nucleus. While the oriPtLs are most likely noncoding, at least some of the oriPtRs contain the BCRF1/vIL10 open reading frame. Nonetheless, oriPtR transcripts with long 5′ untranslated regions may partially serve noncoding functions. Both oriPtL and oriPtR transcripts are expressed with late kinetics, and their expression is inhibited by phosphonoacetic acid. RNA sequencing (RNA-seq) analysis showed that oriPtLs and oriPtRs exhibited extensive “hyperediting” at their Family of Repeat (FR) regions. RNA secondary structure prediction revealed that the FR region of both oriPtLs and oriPtRs may form large evolutionarily conserved and thermodynamically stable hairpins. The double-stranded RNA-binding protein and RNA-editing enzyme ADAR was found to bind to oriPtLs, likely facilitating editing of the FR hairpin. Further, the multifunctional paraspeckle protein, NONO, was found to bind to oriPt transcripts, suggesting that oriPts interact with the paraspeckle-based innate antiviral immune pathway. Knockdown and ectopic expression of oriPtLs showed that it contributes to global viral lytic gene expression and viral DNA replication. Together, these results show that these new vlncRNAs interact with cellular innate immune pathways and that they help facilitate progression of the viral lytic cascade.IMPORTANCERecent studies have revealed that the complexity of lytic herpesviral transcriptomes is significantly greater than previously appreciated with hundreds of viral long noncoding RNAs (vlncRNAs) being recently discovered. Work on cellular lncRNAs over the past several years has just begun to give us an initial appreciation for the array of functions they play in complex formation and regulatory processes in the cell. The newly identified herpesvirus lncRNAs are similarly likely to play a variety of different functions, although these functions are likely tailored to specific needs of the viral infection cycles. Here we describe novel transcripts derived from the EBV latency origin of replication. We show that they are hyperedited, that they interact with a relatively newly appreciated antiviral pathway, and that they play a role in facilitating viral lytic gene expression. These investigations are a starting point to unraveling the complex arena of vlncRNA function in herpesvirus lytic replication.

scholarly journals Pharmacologic Activation of Lytic Epstein-Barr Virus Gene Expression without Virion Production

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Jaeyeun Lee ◽  
John G. Kosowicz ◽  
S. Diane Hayward ◽  
Prashant Desai ◽  
Jennifer Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Viral Proteins ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Virion Production ◽  
Epstein Barr

ABSTRACT Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth. We investigated the effects of clofoctol on an EBV-positive Burkitt lymphoma cell line and confirmed the upregulation of all three branches of the UPR and activation of EBV lytic gene expression. While immediate early, early, and late EBV RNAs were all upregulated, immediate early and early viral proteins but not late viral proteins were expressed. Furthermore, infectious virions were not produced. The use of clofoctol in combination with a protein kinase R-like endoplasmic reticulum kinase inhibitor led to expression of late viral proteins. The effects of clofoctol on EBV lytic protein upregulation were not limited to lymphoid tumor cell lines but also occurred in naturally infected epithelial gastric cancer and nasopharyngeal cancer cell lines. An agent that upregulates lytic viral protein expression but that does not lead to the production of infectious virions may have particular value for lytic induction strategies in the clinical setting. IMPORTANCE Epstein-Barr virus is associated with many different cancers. In these cancers the viral genome is predominantly latent; i.e., most viral genes are not expressed, most viral proteins are not synthesized, and new virions are not produced. Some strategies for treating these cancers involve activation of lytic viral gene expression. We identify an antibacterial antibiotic, clofoctol, that is an activator of EBV lytic RNA and protein expression but that does not lead to virion production.

scholarly journals Contribution of C/EBP Proteins to Epstein-Barr Virus Lytic Gene Expression and Replication in Epithelial Cells

2006 ◽  
Vol 80 (3) ◽  
pp. 1098-1109 ◽  
Author(s):  
Jian Huang ◽  
Gangling Liao ◽  
Honglin Chen ◽  
Frederick Y. Wu ◽  
Lindsey Hutt-Fletcher ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Epstein Barr Virus ◽  
Gastric Cancer Cell Line ◽  
Lytic Cycle ◽  
Ags Cells ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Epstein Barr

ABSTRACT The contribution of C/EBP proteins to Epstein-Barr virus (EBV) lytic gene expression and replication in epithelial cells was examined. Nasopharyngeal carcinoma cell lines constitutively expressed C/EBPβ and had limited C/EBPα expression, while the AGS gastric cancer cell line expressed significant levels of both C/EBPα and C/EBPβ. Induction of the lytic cycle in EBV-positive AGS/BX1 cells with phorbol ester and sodium butyrate treatment led to a transient stimulation of C/EBPβ expression and a prolonged increase in C/EBPα expression. In AGS/BX1 cells, endogenous C/EBPα and C/EBPβ proteins were detected associated with the ZTA and oriLyt promoters but not the RTA promoter. Electrophoretic mobility shift assays confirmed binding of C/EBP proteins to multiple sites in the ZTA and oriLyt promoters. The response of these promoters in reporter assays to transfected C/EBPα and C/EBPβ proteins was consistent with the promoter binding assays and emphasized the relative importance of C/EBPs for activation of the ZTA promoter. Mutation of the oriLyt promoter proximal C/EBP site had little effect on ZTA activation of the promoter in a reporter assay. However, this mutation impaired oriLyt DNA replication, suggesting a separate replication-specific contribution for C/EBP proteins. Finally, the overall importance of C/EBP proteins for lytic gene expression was demonstrated using CHOP10 to antagonize C/EBP DNA binding activity. Introduction of CHOP10 significantly impaired induction of the ZTA, RTA, and BMRF1 proteins in chemically treated AGS/BX1 cells. Thus, C/EBPβ and C/EBPα expression are associated with lytic induction in AGS cells, and expression of C/EBP proteins in epithelial cells may contribute to the tendency of these cells to exhibit constitutive low-level ZTA promoter activity.

scholarly journals Viral Genome Methylation Differentially Affects the Ability of BZLF1 versus BRLF1 To Activate Epstein-Barr Virus Lytic Gene Expression and Viral Replication

2012 ◽  
Vol 87 (2) ◽  
pp. 935-950 ◽  
Author(s):  
C. K. Wille ◽  
D. M. Nawandar ◽  
A. R. Panfil ◽  
M. M. Ko ◽  
S. R. Hagemeier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Replication ◽  
Viral Genome ◽  
Epstein Barr Virus ◽  
Lytic Gene ◽  
Barr Virus ◽  
Lytic Gene Expression ◽  
Genome Methylation ◽  
Epstein Barr

scholarly journals Cellular MicroRNAs 200b and 429 Regulate the Epstein-Barr Virus Switch between Latency and Lytic Replication

2010 ◽  
Vol 84 (19) ◽  
pp. 10329-10343 ◽  
Author(s):  
Amy L. Ellis-Connell ◽  
Tawin Iempridee ◽  
Iris Xu ◽  
Janet E. Mertz
Keyword(s):  
Gene Expression ◽  
Epstein Barr Virus ◽  
Family Members ◽  
Lytic Replication ◽  
Dependent Manner ◽  
Lytic Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lytic Gene Expression ◽  
Epstein Barr

ABSTRACT We previously showed that the cellular proteins ZEB1 and ZEB2/SIP1 both play key roles in regulating the latent-lytic switch of Epstein-Barr Virus (EBV) by repressing BZLF1 gene expression. We investigated here the effects of cellular microRNA (miRNA) 200 (miR200) family members on the EBV infection status of cells. We show that miR200b and miR429, but not miR200a, can induce EBV-positive cells into lytic replication by downregulating expression of ZEB1 and ZEB2, leading to production of infectious virus. The levels of miR200 family members in EBV-infected cells strongly negatively correlated with the levels of the ZEBs (e.g., −0.89 [P < 0.001] for miR429 versus ZEB1) and positively correlated with the degree of EBV lytic gene expression (e.g., 0.73 [P < 0.01] for miR429 versus BZLF1). The addition of either miR200b or miR429 to EBV-positive cells led to EBV lytic reactivation in a ZEB-dependent manner; inhibition of these miRNAs led to decreased EBV lytic gene expression. The degree of latent infection by an EBV mutant defective in the primary ZEB-binding site of the EBV BZLF1 promoter was not affected by the addition of these miRNAs. Furthermore, EBV infection of primary blood B cells led to downregulation of these miRNAs and upregulation of ZEB levels. Thus, we conclude that miRNAs 200b and 429 are key regulators via their effects on expression of ZEB1 and ZEB2 of the switch between latent and lytic infection by EBV and, therefore, potential targets for development of new lytic induction therapeutics with which to treat patients with EBV-associated malignancies.

scholarly journals B cells infected with Type 2 Epstein-Barr virus (EBV) have increased NFATc1/NFATc2 activity and enhanced lytic gene expression in comparison to Type 1 EBV infection

2020 ◽  
Vol 16 (2) ◽  
pp. e1008365 ◽  
Author(s):  
James C. Romero-Masters ◽  
Shane M. Huebner ◽  
Makoto Ohashi ◽  
Jillian A. Bristol ◽  
Bayleigh E. Benner ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Epstein Barr Virus ◽  
Lytic Gene ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lytic Gene Expression ◽  
Epstein Barr
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