scholarly journals Bovine herpesvirus 1 productive infection and immediate early transcription unit 1 promoter are stimulated by the synthetic corticosteroid dexamethasone

Virology ◽  
2015 ◽  
Vol 484 ◽  
pp. 377-385 ◽  
Author(s):  
Insun Kook ◽  
Caitlin Henley ◽  
Florencia Meyer ◽  
Federico G. Hoffmann ◽  
Clinton Jones
Keyword(s):  
Bovine Herpesvirus ◽  
Transcription Unit ◽  
Immediate Early ◽  
Productive Infection ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1 ◽  
Early Transcription

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 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 Bovine herpesvirus 1 immediate-early protein (bICP0) interacts with the histone acetyltransferase p300, which stimulates productive infection and gC promoter activity

2006 ◽  
Vol 87 (7) ◽  
pp. 1843-1851 ◽  
Author(s):  
Yange Zhang ◽  
Yunquan Jiang ◽  
Vicki Geiser ◽  
Joe Zhou ◽  
Clinton Jones
Keyword(s):  
Histone Acetyltransferase ◽  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Immediate Early ◽  
Productive Infection ◽  
Dominant Negative Mutant ◽  
Bovine Herpesvirus 1 ◽  
Early Protein ◽  
Herpesvirus 1 ◽  
Acetyltransferase P300

The immediate-early protein, bICP0, of Bovine herpesvirus 1 (BHV-1) transactivates viral promoters and stimulates productive infection. bICP0 is expressed constitutively during productive infection, as its gene contains an immediate-early and an early promoter. Like other ICP0 homologues encoded by members of the subfamily Alphaherpesvirinae, bICP0 contains a zinc RING finger located near its N terminus. Mutations that disrupt the bICP0 zinc RING finger impair its ability to activate transcription, stimulate productive infection, inhibit interferon-dependent transcription in certain cell types and regulate subnuclear localization. bICP0 also interacts with a cellular chromatin-remodelling enzyme, histone deacetylase 1 (HDAC1), and can relieve HDAC1-mediated transcriptional repression, suggesting that bICP0 inhibits silencing of the viral genome. In this study, it was shown that bICP0 interacted with the histone acetyltransferase p300 during productive infection and in transiently transfected cells. In addition, p300 enhanced BHV-1 productive infection and transactivated a late viral promoter (gC). In contrast, a CH3-domain deletion mutant of p300, which is a dominant-negative mutant, did not activate the gC promoter. bICP0 and p300 cooperated to activate the gC promoter, suggesting that there is a synergistic effect on promoter activation. As p300 can activate certain antiviral signalling pathways (for example, interferon), it was hypothesized that interactions between p300 and bICP0 may dampen the antiviral response following infection.

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 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.

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