scholarly journals Inhibition of Stress-Induced Viral Promoters by a Bovine Herpesvirus 1 Non-Coding RNA and the Cellular Transcription Factor, β-Catenin

2021 ◽  
Vol 22 (2) ◽  
pp. 519
Author(s):  
Jing Zhao ◽  
Nishani Wijesekera ◽  
Clinton Jones
Keyword(s):  
Transcriptional Activation ◽  
Bovine Herpesvirus ◽  
Transcription Unit ◽  
Productive Infection ◽  
Viral Gene ◽  
Gene Products ◽  
Rna Sequences ◽  
Bovine Herpesvirus 1 ◽  
Viral Promoters ◽  
Herpesvirus 1

The ability to establish, maintain, and reactivate from latency in sensory neurons within trigeminal ganglia (TG) is crucial for bovine herpesvirus 1 (BoHV-1) transmission. In contrast to lytic infection, the only viral gene abundantly expressed during latency is the latency-related (LR) gene. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency, in part because the glucocorticoid receptor (GR) transactivates viral promoters that drive expression of key viral transcriptional regulator proteins (bICP0 and bICP4). Within hours after dexamethasone treatment of latently infected calves, LR gene products and β-catenin are not readily detected in TG neurons. Hence, we hypothesized that LR gene products and/or β-catenin restrict GR-mediated transcriptional activation. A plasmid expressing LR RNA sequences that span open reading frame 2 (ORF2-Stop) inhibited GR-mediated transactivation of the BoHV-1 immediate early transcription unit 1 (IEtu1) and mouse mammary tumor virus (MMTV) promoter activity in mouse neuroblastoma cells (Neuro-2A). ORF2-Stop also reduced productive infection and GR steady-state protein levels in transfected Neuro-2A cells. Additional studies revealed that the constitutively active β-catenin mutant reduced the transactivation of the IEtu1 promoter by GR and dexamethasone. Collectively, these studies suggest ORF2 RNA sequences and Wnt/β-catenin signaling pathway actively promote maintenance of latency, in part, by impairing GR-mediated gene expression.

scholarly journals Two Pioneer Transcription Factors, Krüppel-Like Transcription Factor 4 and Glucocorticoid Receptor, Cooperatively Transactivate the Bovine Herpesvirus 1 ICP0 Early Promoter and Stimulate Productive Infection

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Fouad S. El-mayet ◽  
Laximan Sawant ◽  
Prasanth Thunuguntla ◽  
Jing Zhao ◽  
Clinton Jones
Keyword(s):  
Transcription Factors ◽  
Glucocorticoid Receptor ◽  
Viral Gene Expression ◽  
Bovine Herpesvirus ◽  
Transcription Unit ◽  
Productive Infection ◽  
Cell Protein ◽  
Viral Gene ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1

ABSTRACT An important site for bovine herpesvirus 1 (BoHV-1) latency is sensory neurons within trigeminal ganglia (TG). The synthetic corticosteroid dexamethasone consistently induces BoHV-1 reactivation from latency. Expression of four Krüppel-like transcription factors (KLF), i.e., KLF4, KLF6, PLZF (promyelocytic leukemia zinc finger), and KLF15, are induced in TG neurons early during dexamethasone-induced reactivation. The glucocorticoid receptor (GR) and KLF15 form a feed-forward transcription loop that cooperatively transactivates the BoHV-1 immediate early transcription unit 1 (IEtu1) promoter that drives bovine infected cell protein 0 (bICP0) and bICP4 expression. Since the bICP0 gene also contains a separate early (E) promoter, we tested the hypothesis that GR and KLF family members transactivate the bICP0 E promoter. GR and KLF4, both pioneer transcription factors, cooperated to stimulate bICP0 E promoter activity in a ligand-independent manner in mouse neuroblastoma cells (Neuro-2A). Furthermore, GR and KLF4 stimulated productive infection. Mutating both half GR binding sites did not significantly reduce GR- and KLF4-mediated transactivation of the bICP0 E promoter, suggesting that a novel mechanism exists for transactivation. GR and KLF15 cooperatively stimulated bICP0 activity less efficiently than GR and KL4: however, KLF6, PLZF, and GR had little effect on the bICP0 E promoter. GR, KLF4, and KLF15 occupied bICP0 E promoter sequences in transfected Neuro-2A cells. GR and KLF15, but not KLF4, occupied the bICP0 E promoter at late times during productive infection of bovine cells. Collectively, these studies suggest that cooperative transactivation of the bICP0 E promoter by two pioneer transcription factors (GR and KLF4) correlates with stimulating lytic cycle viral gene expression following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Reactivation from latency is consistently induced by the synthetic corticosteroid dexamethasone. We predict that increased corticosteroid levels activate the glucocorticoid receptor (GR). Consequently, viral gene expression is stimulated by the activated GR. The immediate early transcription unit 1 promoter (IEtu1) drives expression of two viral transcriptional regulatory proteins, bovine infected cell protein 0 (bICP0) and bICP4. Interestingly, a separate early promoter also drives bICP0 expression. Two pioneer transcription factors, GR and Krüppel-like transcription factor 4 (KLF4), cooperatively transactivate the bICP0 early (E) promoter. GR and KLF15 cooperate to stimulate bICP0 E promoter activity but significantly less than GR and KLF4. The bICP0 E promoter contains enhancer-like domains necessary for GR- and KLF4-mediated transactivation that are distinct from those for GR and KLF15. Stress-induced pioneer transcription factors are proposed to activate key viral promoters, including the bICP0 E promoter, during early stages of reactivation from latency.

scholarly journals Synergistic Activation of Bovine Herpesvirus 1 Productive Infection and Viral Regulatory Promoters by the Progesterone Receptor and Krüppel-Like Transcription Factor 15

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Fouad S. El-mayet ◽  
Ayman S. El-Habbaa ◽  
Jean D’Offay ◽  
Clinton Jones
Keyword(s):  
Transcription Factor ◽  
Progesterone Receptor ◽  
Bovine Herpesvirus ◽  
Transcriptional Regulators ◽  
Reproductive Failure ◽  
Productive Infection ◽  
Bovine Herpesvirus 1 ◽  
Live Vaccines ◽  
Viral Promoters ◽  
Herpesvirus 1

ABSTRACTBovine herpesvirus 1 (BoHV-1), including modified live vaccines, readily infects the fetus and ovaries, which can lead to reproductive failure. The BoHV-1 latency reactivation cycle in sensory neurons may further complicate reproductive failure in pregnant cows. The immediate early transcription unit 1 (IEtu1) promoter drives expression of important viral transcriptional regulators (bICP0 and bICP4). This promoter contains two functional glucocorticoid receptor (GR) response elements (GREs) that have the potential to stimulate productive infection following stressful stimuli. Since progesterone and the progesterone receptor (PR) can activate many GREs, we hypothesized that the PR and/or progesterone regulates productive infection and viral transcription. New studies demonstrated that progesterone stimulated productive infection. Additional studies revealed the PR and Krüppel-like transcription factor 15 (KLF15) cooperated to stimulate productive infection and IEtu1 promoter activity. IEtu1 promoter activation required both GREs, which correlated with the ability of the PR to interact with wild-type (wt) GREs but not mutant GREs. KLF15 also cooperated with the PR to transactivate the bICP0 early promoter, a promoter that maintains bICP0 protein expression during productive infection. Intergenic viral DNA fragments (less than 400 bp) containing two GREs and putative KLF binding sites present within genes encoding unique long 52 (UL-52; component of DNA primase/helicase complex), Circ, bICP4, and IEtu2 were stimulated by KLF15 and the PR more than 10-fold, suggesting that additional viral promoters are activated by these transcription factors. Collectively, these studies suggest progesterone and the PR promote BoHV-1 spread to reproductive tissues, thus increasing the incidence of reproductive failure.IMPORTANCEBovine herpesvirus 1 (BoHV-1) is the most frequently diagnosed cause of abortions in pregnant cows and can cause “abortion storms” in susceptible herds. Virulent field strains and even commercially available modified live vaccines can induce abortion, in part because BoHV-1 replicates efficiently in the ovary and corpus luteum. We now demonstrate that progesterone and the progesterone receptor (PR) stimulate productive infection. The BoHV-1 genome contains approximately 100 glucocorticoid receptor (GR) response elements (GREs). Interestingly, the PR can bind and activate many promoters that contain GREs. The PR and Krüppel-like transcription factor 15 (KLF15), which regulate key steps during embryo implantation, cooperate to stimulate productive infection and two viral promoters that drive expression of key viral transcriptional regulators. These studies suggest that the ability of progesterone and the PR to stimulate productive infection has the potential to promote virus spread in reproductive tissue and induce reproductive failure.

scholarly journals The Cellular Coactivator HCF-1 Is Required for Glucocorticoid Receptor-Mediated Transcription of Bovine Herpesvirus 1 Immediate Early Genes

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Laximan Sawant ◽  
Insun Kook ◽  
Jodi L. Vogel ◽  
Thomas M. Kristie ◽  
Clinton Jones
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Bovine Herpesvirus ◽  
Transcription Unit ◽  
Lytic Infection ◽  
Immediate Early ◽  
Productive Infection ◽  
Core Element ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1

ABSTRACTFollowing productive infection, bovine herpesvirus 1 (BoHV-1) establishes latency in sensory neurons. As in other alphaherpesviruses, expression of BoHV-1 immediate early (IE) genes is regulated by an enhancer complex containing the viral IE activator VP16, the cellular transcription factor Oct-1, and transcriptional coactivator HCF-1, which is assembled on an IE enhancer core element (TAATGARAT). Expression of the IE transcription unit that encodes the viral IE activators bICP0 and bICP4 may also be induced by the activated glucocorticoid receptor (GR) via two glucocorticoid response elements (GREs) located upstream of the enhancer core. Strikingly, lytic infection and reactivation from latency are consistently enhanced by glucocorticoid treatmentin vivo. As the coactivator HCF-1 is essential for IE gene expression of alphaherpesviruses and recruited by multiple transcription factors, we tested whether HCF-1 is required for glucocorticoid-induced IE gene expression. Depletion of HCF-1 reduced GR-mediated activation of the IE promoter in mouse neuroblastoma cells (Neuro-2A). More importantly, HCF-1-mediated GR activation of the promoter was dependent on the presence of GRE sites but independent of the TAATGARAT enhancer core element. HCF-1 was also recruited to the GRE region of a promoter lacking the enhancer core, consistent with a direct role of the coactivator in mediating GR-induced transcription. Similarly, during productive lytic infection, HCF-1 and GR occupied the IE region containing the GREs. These studies indicate HCF-1 is critical for GR activation of the viral IE genes and suggests that glucocorticoid induction of viral reactivation proceeds via an HCF-1–GR mechanism in the absence of the viral IE activator VP16.IMPORTANCEBoHV-1 transcription is rapidly activated during stress-induced reactivation from latency. The immediate early transcription unit 1 (IEtu1) promoter is regulated by the GR via two GREs. The IEtu1 promoter regulates expression of two viral transcriptional regulatory proteins, infected cell proteins 0 and 4 (bICP0 and bICP4), and thus must be stimulated during reactivation. This study demonstrates that activation of the IEtu1 promoter by the synthetic corticosteroid dexamethasone requires HCF-1. Interestingly, the GRE sites, but not the IE enhancer core element (TAATGARAT), were required for HCF-1-mediated GR promoter activation. The GR and HCF-1 were recruited to the IEtu1 promoter in transfected and infected cells. Collectively, these studies indicate that HCF-1 is critical for GR activation of the viral IE genes and suggest that an HCF-1–GR complex can stimulate the IEtu1 promoter in the absence of the viral IE activator VP16.

scholarly journals The bovine herpesvirus 1 gene encoding infected cell protein 0 (bICP0) can inhibit interferon-dependent transcription in the absence of other viral genes

2005 ◽  
Vol 86 (10) ◽  
pp. 2697-2702 ◽  
Author(s):  
Gail Henderson ◽  
Yange Zhang ◽  
Clinton Jones
Keyword(s):  
Gene Expression ◽  
Ring Finger ◽  
Viral Gene Expression ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Cell Protein ◽  
Viral Gene ◽  
Bovine Herpesvirus 1 ◽  
Infected Cell Protein ◽  
Herpesvirus 1

The infected cell protein 0 (bICP0) encoded by Bovine herpesvirus 1 (BHV-1) stimulates viral gene expression and productive infection. As bICP0 is expressed constitutively during productive infection, it is considered to be the major viral regulatory protein. Like other alphaherpesvirus ICP0 homologues, bICP0 contains a zinc RING finger near its N terminus that activates transcription and regulates subcellular localization. In this study, evidence is provided that bICP0 represses the human beta interferon (IFN-β) promoter and a simple promoter with consensus IFN-stimulated response elements following stimulation with double-stranded RNA (polyinosinic–polycytidylic acid), IFN regulatory factor 3 (IRF3) or IRF7. bICP0 also inhibits the ability of two protein kinases (TBK1 and IKKε) to activate IFN-β promoter activity. The zinc RING finger is necessary for inhibiting IFN-dependent transcription in certain cell types. Collectively, these studies suggest that bICP0 activates productive infection by stimulating viral gene expression and inhibiting IFN-dependent transcription.

scholarly journals The Latency-Related Gene of Bovine Herpesvirus 1 Inhibits Programmed Cell Death

1999 ◽  
Vol 73 (12) ◽  
pp. 9734-9740 ◽  
Author(s):  
Janice Ciacci-Zanella ◽  
Melissa Stone ◽  
Gail Henderson ◽  
Clinton Jones
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Acute Infection ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Gene Products ◽  
Bovine Herpesvirus 1 ◽  
Transfected Cells ◽  
Herpesvirus 1

ABSTRACT Although viral gene expression occurs in the peripheral nervous system during acute infection, bovine herpesvirus 1 (BHV-1) gene expression is extinguished, many neurons survive, and latency ensues. The only abundant viral transcript expressed during latency is the latency-related (LR) RNA, which is alternatively spliced in trigeminal ganglia during acute infection (L. Devireddy and C. Jones, J. Virol. 72:7294–7301, 1998). A subset of neurons express a protein encoded by the LR gene and the LR protein (LRP) is associated with cyclin-dependent kinase 2 (Cdk2)/cyclin complexes during productive infection (Y. Jiang, A. Hossain, M. T. Winkler, T. Holt, A. Doster, and C. Jones, J. Virol. 72:8133–8142, 1998). LR gene products inhibit cell cycle progression, perhaps as a result of LRP interacting with Cdk2/cyclin complexes. During acute infection, expression of cyclin A occurs in trigeminal ganglionic neurons (L. M. Schang, A. Hossain, and C. Jones, J. Virol. 70:3807–3814, 1996). Inappropriate expression of G1- and S-phase cyclins can initiate programmed cell death (PCD), apoptosis, in neurons, suggesting that LR gene products inhibit PCD. To test this hypothesis, we modified an assay to measure PCD frequency in transiently transfected cells. C6-ceramide, fumonisin B1(FB1), or etoposide was used to initiate PCD following transfection of cells with plasmids expressing LR gene products and the β-galactosidase gene. Transfected cells that survived were quantified by counting β-galactosidase-positive cells. Plasmids that expressed LR gene products promoted survival of monkey kidney (CV-1), human lung (IMR-90), or mouse neuroblastoma (neuro-2A) cells after induction of PCD. Plasmids with termination codons at the beginning of LR open reading frames or deletion of sequences that mediate splicing of LR RNA did not promote cell survival following PCD induction. We hypothesize that LR gene products play a role in promoting survival of postmitotic neurons during acute infection or reactivation.

scholarly journals Combinatorial Effects of the Glucocorticoid Receptor and Krüppel-Like Transcription Factor 15 on Bovine Herpesvirus 1 Transcription and Productive Infection

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Fouad S. El-mayet ◽  
Laximan Sawant ◽  
Prasanth Thunuguntla ◽  
Clinton Jones
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Glucocorticoid Receptor ◽  
Sensory Neurons ◽  
Viral Gene Expression ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Viral Gene ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1

ABSTRACT Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes lifelong latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bovine ICP0 (bICP0) and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency, and they stimulate certain viral promoters and productive infection. In this study, we demonstrate that the GR and KLF15 were frequently expressed in the same trigeminal ganglion (TG) neuron during reactivation and cooperatively stimulated productive infection and IEtu1 GREs in mouse neuroblastoma cells (Neuro-2A). We further hypothesized that additional regions in the BoHV-1 genome are transactivated by the GR or stress-induced transcription factors. To test this hypothesis, BoHV-1 DNA fragments (less than 400 bp) containing potential GR and KLF binding sites were identified and examined for transcriptional activation by stress-induced transcription factors. Intergenic regions within the unique long 52 gene (UL52; a component of the DNA primase/helicase complex), bICP4, IEtu2, and the unique short region were stimulated by KLF15 and the GR. Chromatin immunoprecipitation studies revealed that the GR and KLF15 interacted with sequences within IEtu1 GREs and the UL52 fragment. Coimmunoprecipitation studies demonstrated that KLF15 and the GR were associated with each other in transfected cells. Since the GR stimulates KLF15 expression, we suggest that these two transcription factors form a feed-forward loop that stimulates viral gene expression and productive infection following stressful stimuli. IMPORTANCE Bovine herpesvirus 1 (BoHV-1) is an important viral pathogen that causes respiratory disease and suppresses immune responses in cattle; consequently, life-threatening bacterial pneumonia can occur. Following acute infection, BoHV-1 establishes lifelong latency in sensory neurons. Reactivation from latency is initiated by the synthetic corticosteroid dexamethasone. Dexamethasone stimulates lytic cycle viral gene expression in sensory neurons of calves latently infected with BoHV-1, culminating in virus shedding and transmission. Two stress-induced cellular transcription factors, Krüppel-like transcription factor 15 (KLF15) and the glucocorticoid receptor (GR), cooperate to stimulate productive infection and viral transcription. Additional studies demonstrated that KLF15 and the GR form a stable complex and that these stress-induced transcription factors bind to viral DNA sequences, which correlates with transcriptional activation. The ability of the GR and KLF15 to synergistically stimulate viral gene expression and productive infection may be critical for the ability of BoHV-1 to reactivate from latency following stressful stimuli.

scholarly journals The latency-related gene of bovine herpesvirus-1 can inhibit the ability of bICP0 to activate productive infection

2002 ◽  
Vol 83 (12) ◽  
pp. 2965-2971 ◽  
Author(s):  
Vicki Geiser ◽  
Melissa Inman ◽  
Yange Zhang ◽  
Clinton Jones
Keyword(s):  
Protein Expression ◽  
Viral Gene Expression ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Viral Gene ◽  
Bovine Herpesvirus 1 ◽  
Dose Dependent Fashion ◽  
Herpesvirus 1 ◽  
Low Levels ◽  
Dose Dependent

Transfection of bovine cells with bovine herpesvirus-1 genomic DNA yields low levels of infectious virus. Cotransfection with the bICP0 gene enhances productive infection and virus yield because bICP0 can activate viral gene expression. Since the latency-related (LR) gene overlaps and is antisense to bICP0, the effects of LR gene products on productive infection were tested. The intact LR gene inhibited productive infection in a dose-dependent fashion but LR protein expression was not required. Further studies indicated that LR gene sequences near the 3′ terminus of the LR RNA are necessary for inhibiting productive infection. When cotransfected with the bICP0 gene, the LR gene inhibited bICP0 RNA and protein expression in transiently transfected cells. Taken together, these results suggest that abundant LR RNA expression in sensory neurons is one factor that has the potential to inhibit productive infection and consequently promote the establishment and maintenance of latency.

scholarly journals The Infected Cell Protein 0 Encoded by Bovine Herpesvirus 1 (bICP0) Associates with Interferon Regulatory Factor 7 and Consequently Inhibits Beta Interferon Promoter Activity

2009 ◽  
Vol 83 (8) ◽  
pp. 3977-3981 ◽  
Author(s):  
Kazima Saira ◽  
You Zhou ◽  
Clinton Jones
Keyword(s):  
Promoter Activity ◽  
Viral Gene Expression ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Cell Protein ◽  
Viral Gene ◽  
Regulatory Factor ◽  
Bovine Herpesvirus 1 ◽  
Protein Levels ◽  
Herpesvirus 1

ABSTRACT The bICP0 protein encoded by bovine herpesvirus 1 stimulates productive infection and viral gene expression but inhibits interferon (IFN)-dependent transcription. bICP0 inhibits beta IFN (IFN-β) promoter activity and induces degradation of IFN regulatory factor 3 (IRF3). Although bICP0 inhibits the trans-activation activity of IRF7, IRF7 protein levels are not reduced. In this study, we demonstrate that bICP0 is associated with IRF7. Furthermore, bICP0 inhibits the ability of IRF7 to trans-activate the IFN-β promoter in the absence of IRF3 expression. The interaction between bICP0 and IRF7 correlates with reduced trans-activation of the IFN-β promoter by IRF7.

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