Stimulation of bovine herpesvirus-1 productive infection by the adenovirus E1A gene and a cell cycle regulatory gene, E2F-4

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.

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

Journal of Virology ◽

10.1128/jvi.01519-18 ◽

2018 ◽

Vol 93 (1) ◽

Cited By ~ 2

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

Journal of Virology ◽

10.1128/jvi.00987-18 ◽

2018 ◽

Vol 92 (17) ◽

Cited By ~ 10

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.

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Identification of functional domains within the bICP0 protein encoded by bovine herpesvirus 1

Journal of General Virology ◽

10.1099/vir.0.80698-0 ◽

2005 ◽

Vol 86 (4) ◽

pp. 879-886 ◽

Cited By ~ 22

Author(s):

Yange Zhang ◽

Joe Zhou ◽

Clinton Jones

Keyword(s):

Nuclear Localization ◽

Nuclear Localization Signal ◽

Ring Finger ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Functional Domains ◽

Bovine Herpesvirus 1 ◽

Transposon Insertion ◽

Localization Signal ◽

Herpesvirus 1

It is believed that the bICP0 protein encoded by bovine herpesvirus 1 (BoHV-1) stimulates productive infection by activating viral gene expression. Like the other ICP0-like proteins encoded by alphaherpesvirinae subfamily members, bICP0 contains a zinc RING finger near its amino terminus. The zinc RING finger of bICP0 activates viral transcription, stimulates productive infection, and is toxic to certain cell types. Apart from the zinc RING finger, bICP0 possesses little similarity to the herpes simplex virus type 1 ICP0 protein making it difficult to predict what regions of bICP0 are important. To begin to identify bICP0 functional domains that are not part of the zinc RING finger, a panel of transposon insertion mutants that span bICP0 was developed. A large domain spanning aa 78–256, and a separate domain that is at or near aa 457 was necessary for efficient transactivation of a simple promoter. Transposon insertion at aa 91 impaired bICP0 protein stability in transfected cells. Insertion of transposons into the acidic domain of bICP0 had little or no effect on transactivation of a simple promoter or protein expression suggesting this region does not play a major role in activating gene expression. Sequences near the C terminus (aa 607–676) contain a functional nuclear localization signal. Collectively, these studies indicated that bICP0 contains several important functional domains: (i) the zinc RING finger, (ii) two separate domains that activate transcription, and (iii) a C-terminal nuclear localization signal that is also necessary for efficient transactivation.

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Progesterone increases the incidence of bovine herpesvirus 1 reactivation from latency and stimulates productive infection

Virus Research ◽

10.1016/j.virusres.2019.197803 ◽

2020 ◽

Vol 276 ◽

pp. 197803 ◽

Cited By ~ 2

Author(s):

Fouad S. El-mayet ◽

Laximan Sawant ◽

Nishani Wijesekera ◽

Clinton Jones

Keyword(s):

Bovine Herpesvirus ◽

Productive Infection ◽

Bovine Herpesvirus 1 ◽

Herpesvirus 1

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Cooperative activation of bovine herpesvirus 1 productive infection and viral regulatory promoters by androgen receptor and Krüppel-like transcription factors 4 and 15

Virology ◽

10.1016/j.virol.2020.08.015 ◽

2021 ◽

Vol 552 ◽

pp. 63-72

Author(s):

Laximan Sawant ◽

Prasanth Thunuguntla ◽

Clinton Jones

Keyword(s):

Transcription Factors ◽

Androgen Receptor ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Bovine Herpesvirus 1 ◽

Herpesvirus 1 ◽

Cooperative Activation

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The serum and glucocorticoid-regulated protein kinases (SGK) stimulate bovine herpesvirus 1 and herpes simplex virus 1 productive infection

Virus Research ◽

10.1016/j.virusres.2016.06.007 ◽

2016 ◽

Vol 222 ◽

pp. 106-112 ◽

Cited By ~ 6

Author(s):

Insun Kook ◽

Clinton Jones

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Protein Kinases ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Herpes Simplex Virus 1 ◽

Bovine Herpesvirus 1 ◽

Herpesvirus 1 ◽

Simplex Virus

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The Involvement of Histone H3 Acetylation in Bovine Herpesvirus 1 Replication in MDBK Cells

Viruses ◽

10.3390/v10100525 ◽

2018 ◽

Vol 10 (10) ◽

pp. 525 ◽

Cited By ~ 3

Author(s):

Liqian Zhu ◽

Xinyi Jiang ◽

Xiaotian Fu ◽

Yanhua Qi ◽

Guoqiang Zhu

Keyword(s):

Histone H3 ◽

Bovine Herpesvirus ◽

Productive Infection ◽

Histone H4 ◽

Bovine Herpesvirus 1 ◽

Amino Acid Synthesis ◽

Histone H4 Acetylation ◽

Histone H3 Acetylation ◽

Herpesvirus 1 ◽

H3 Acetylation

During bovine herpesvirus 1 (BoHV-1) productive infection in cell cultures, partial of intranuclear viral DNA is present in nucleosomes, and viral protein VP22 associates with histones and decreases histone H4 acetylation, indicating the involvement of histone H4 acetylation in virus replication. In this study, we demonstrated that BoHV-1 infection at the late stage (at 24 h after infection) dramatically decreased histone H3 acetylation [at residues K9 (H3K9ac) and K18 (H3K18ac)], which was supported by the pronounced depletion of histone acetyltransferases (HATs) including CBP/P300 (CREB binding protein and p300), GCN5L2 (general control of amino acid synthesis yeast homolog like 2) and PCAF (P300/CBP-associated factor). The depletion of GCN5L2 promoted by virus infection was partially mediated by ubiquitin-proteasome pathway. Interestingly, the viral replication was enhanced by HAT (histone acetyltransferase) activator CTPB [N-(4-Chloro-3-trifluoromethylphenyl)-2-ethoxy-6-pentadecylbenzamide], and vice versa, inhibited by HAT inhibitor Anacardic acid (AA), suggesting that BoHV-1 may take advantage of histone acetylation for efficient replication. Taken together, we proposed that the HAT-dependent histone H3 acetylation plays an important role in BoHV-1 replication in MDBK (Madin-Darby bovine kidney) cells.

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

Journal of General Virology ◽

10.1099/vir.0.81109-0 ◽

2005 ◽

Vol 86 (10) ◽

pp. 2697-2702 ◽

Cited By ~ 40

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.

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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

Journal of Virology ◽

10.1128/jvi.02064-06 ◽

2007 ◽

Vol 81 (7) ◽

pp. 3077-3086 ◽

Cited By ~ 77

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.

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