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.

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 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 Regulation of Krüppel-Like Factor 15 Expression by Herpes Simplex Virus Type 1 or Bovine Herpesvirus 1 Productive Infection

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1148
Author(s):  
Fouad S. El-mayet ◽  
Kelly S. Harrison ◽  
Clinton Jones
Keyword(s):  
Steady State ◽  
Promoter Activity ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Bovine Herpesvirus 1 ◽  
Protein Levels ◽  
Herpesvirus 1 ◽  
Simplex Virus ◽  
Hsv 1

Expression of Krüppel-like factor 15 (KLF15), a stress-induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed that KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1-immediate-early transcription unit 1 (IEtu1), herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoters. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 expression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection, and KLF15 steady-state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following infection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene, and to a lesser extent, bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 promoter activity. Collectively, these studies revealed that HSV-1 and BoHV-1 productive infection increased KLF15 steady-state protein levels, which correlated with increased virus production.

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 Regulation of Krüppel-like Factor 15 Expression by Herpes Simplex Virus Type 1 or Bovine Herpesvirus 1 Productive Infection

2021 ◽  
Author(s):  
Fouad S. El-Mayet ◽  
Kelly S. Harrison ◽  
Clinton Jones
Keyword(s):  
Steady State ◽  
Virus Type ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Cell Protein ◽  
Bovine Herpesvirus 1 ◽  
Protein Levels ◽  
Herpesvirus 1 ◽  
Hsv 1

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

scholarly journals The Infected Cell Protein 0 Encoded by Bovine Herpesvirus 1 (bICP0) Induces Degradation of Interferon Response Factor 3 and, Consequently, Inhibits Beta Interferon Promoter Activity

2007 ◽  
Vol 81 (7) ◽  
pp. 3077-3086 ◽  
Author(s):  
Kazima Saira ◽  
You Zhou ◽  
Clinton Jones
Keyword(s):  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Interferon Response ◽  
Response Factor ◽  
Bovine Herpesvirus 1 ◽  
Protein Levels ◽  
Beta Interferon ◽  
C Terminus ◽  
Herpesvirus 1

ABSTRACT The ICP0 protein (bICP0) encoded by bovine herpesvirus 1 is the major viral regulatory protein because it stimulates all viral promoters and, consequently, productive infection. Like other ICP0 analogues encoded by Alphaherpesvirinae subfamily members, bICP0 contains a zinc RING finger near its amino terminus that is necessary for activating transcription, regulating subcellular localization, and inhibiting interferon-dependent transcription. In this study, we discovered that sequences near the C terminus, and the zinc RING finger, are necessary for inhibiting the human beta interferon (IFN-β) promoter. In contrast to herpes simplex virus type 1-encoded ICP0, bICP0 reduces interferon response factor 3 (IRF3), but not IRF7, protein levels in transiently transfected cells. The zinc RING finger and sequences near the C terminus are necessary for bICP0-induced degradation of IRF3. A proteasome inhibitor, lactacystin, interfered with bICP0-induced degradation of IRF3, suggesting that bICP0, directly or indirectly, targets IRF3 for proteasome-dependent degradation. IRF3, but not IRF7, is not readily detectable in the nuclei of productively infected bovine cells during the late stages of infection. In the context of productive infection, IRF3 and IRF7 are detected in the nucleus at early times after infection. At late times after infection, IRF7, but not IRF3, is still detectable in the nuclei of infected cells. Collectively, these studies suggest that the ability of bICP0 to reduce IRF3 protein levels is important with respect to disarming the IFN response during productive infection.

scholarly journals Bovine herpesvirus 5 encodes a unique pattern of microRNAs compared with bovine herpesvirus 1

2014 ◽  
Vol 95 (3) ◽  
pp. 671-678 ◽  
Author(s):  
Qi Tang ◽  
Yi-Quan Wu ◽  
Dong-Sheng Chen ◽  
Qing Zhou ◽  
Huan-Chun Chen ◽  
...  
Keyword(s):  
Bovine Herpesvirus ◽  
Mature Mirnas ◽  
Productive Infection ◽  
Reference Sequence ◽  
Cell Protein ◽  
Bovine Herpesvirus 1 ◽  
Stem Loop ◽  
Herpesvirus Type ◽  
Mirna Genes ◽  
Herpesvirus 1

Bovine herpesvirus type 5 (BoHV-5) and bovine herpesvirus 1 (BoHV-1) are two closely related viruses. However, BoHV-5 is responsible for fatal meningitis in calves, while BoHV-1 is associated with infectious rhinotracheitis in cattle, and the mechanism by which the two viruses cause different symptoms is not well understood. In this study, we identified 11 microRNA (miRNA) genes, encoded by the BoHV-5 genome, that were processed into 16 detectable mature miRNAs in productive infection as determined by deep sequencing. We found that 6 out of 16 miRNA genes were present as two copies in the internal repeat and terminal repeat regions, resulting in a total of 17 miRNA-encoding loci distributed in both DNA strands. Surprisingly, BoHV-5 shared only one conservative miRNA with BoHV-1, which was located upstream of the origin of replication. Furthermore, in contrast to BoHV-1, no miRNAs were detected in the unique short region and locus within or near the bovine infected-cell protein 0 and latency-related genes. Variations in both the 5′ and 3′ ends of the reference sequence were observed, resulting in more than one isoform for each miRNA. All of the 16 miRNAs were detectable by stem–loop reverse transcriptase-PCR. The miRNAs with high read numbers were subjected to Northern blot analysis, and all pre-miRNAs and one mature miRNA were detected. Collectively, the data suggest that BoHV-5 encodes a different pattern of miRNAs, which may regulate the life cycle of BoHV-5 and might account for the different pathogenesis of this virus compared with BoHV-1.

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.

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