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

2005 ◽  
Vol 86 (4) ◽  
pp. 879-886 ◽  
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.

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 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 The Zinc RING Finger of Bovine Herpesvirus 1-Encoded bICP0 Protein Is Crucial for Viral Replication and Virulence

2008 ◽  
Vol 82 (24) ◽  
pp. 12060-12068 ◽  
Author(s):  
Kazima Saira ◽  
Shafiqul Chowdhury ◽  
Natasha Gaudreault ◽  
Leticia da Silva ◽  
Gail Henderson ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Mutant Virus ◽  
Productive Infection ◽  
Single Amino Acid ◽  
Cell Protein ◽  
Bovine Herpesvirus 1 ◽  
Latently Infected ◽  
Herpesvirus 1

ABSTRACT Bovine herpesvirus 1 (BHV-1) infected cell protein 0 (bICP0) stimulates productive infection, in part by activating viral gene expression. The C3HC4 zinc RING finger of bICP0 is crucial for activating viral transcription and productive infection. In this study, we used a bacterial artificial chromosome containing a wild-type (wt) virulent BHV-1 strain to generate a single amino acid mutation in the C3HC4 zinc RING finger of bICP0. This virus (the 51g mutant) contains a cysteine-to-glycine mutation (51st amino acid) in the C3HC4 zinc RING finger of bICP0. A plasmid expressing the 51g mutant protein did not transactivate viral promoter activity as efficiently as wt bICP0. The 51g mutant virus expressed higher levels of the bICP0 protein than did the 51g rescued virus (51gR) but yielded reduced virus titers following infection of permissive bovine cells. The 51g mutant virus, but not the 51gR virus, grew poorly in bovine cells pretreated with imiquimod to stimulate interferon production. During acute infection of calves, levels of infectious virus were 2 to 3 logs lower in ocular or nasal swabs with 51g than with 51gR. Calves latently infected with the 51g mutant did not reactivate from latency because virus shedding did not occur in ocular or nasal cavities. As expected, calves latently infected with 51gR reactivated from latency following dexamethasone treatment. These studies demonstrate that mutation of a single well-conserved cysteine residue in the C3HC4 zinc RING finger of bICP0 has dramatic effects on the growth properties of BHV-1.

scholarly journals The Bovine Herpesvirus 1 Immediate-Early Protein (bICP0) Associates with Histone Deacetylase 1 To Activate Transcription

2001 ◽  
Vol 75 (20) ◽  
pp. 9571-9578 ◽  
Author(s):  
Yange Zhang ◽  
Clinton Jones
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Cell Protein ◽  
Bovine Herpesvirus 1 ◽  
Histone Deacetylase 1 ◽  
Early Protein ◽  
Herpesvirus 1

ABSTRACT Infected-cell protein 0 encoded by bovine herpesvirus 1 (BHV-1) (bICP0) is necessary for efficient productive infection, in large part, because it activates all 3 classes of BHV-1 genes (U. V. Wirth, C. Fraefel, B. Vogt, C. Vlcek, V. Paces, and M. Schwyzer, J. Virol. 66:2763–2772, 1992). Although bICP0 is believed to be a functional homologue of herpes simplex virus type 1-encoded ICP0, the only well-conserved domain between the proteins is a zinc ring finger located near the amino terminus of both proteins. Our previous studies demonstrated that bICP0 is toxic to transfected cells but does not appear to directly induce apoptosis (Inman, M., Y. Zhang, V. Geiser, and C. Jones, J. Gen. Virol. 82:483–492, 2001). C-terminal sequences in the last 320 amino acids of bICP0 mediate subcellular localization. Mutagenesis of the zinc ring finger within bICP0 revealed that this domain was important for transcriptional activation. In this study, we demonstrate that bICP0 interacts with histone deacetylase 1 (HDAC1), which results in activation of a simple promoter containing four consensus Myc-Max binding sites. The interaction between bICP0 and HDAC1 correlated with inhibition of Mad-dependent transcriptional repression. In resting CV-1 cells, bICP0 relieved HDAC1-mediated transcriptional repression. The zinc ring finger was required for relieving HDAC1-induced repression but not for interacting with HDAC1. In fetal bovine lung cells but not in a human epithelial cell line, bICP0 expression correlated with reduced steady-state levels of HDAC1 in crude cytoplasmic extracts. We hypothesize that the ability of bICP0 to overcome HDAC1-induced repression plays a role in promoting productive infection in highly differentiated cell types.

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 Analysis of a bovine herpesvirus 1 recombinant virus that does not express the bICP0 protein

2005 ◽  
Vol 86 (7) ◽  
pp. 1987-1996 ◽  
Author(s):  
V. Geiser ◽  
Y. Zhang ◽  
C. Jones
Keyword(s):  
Point Mutation ◽  
Recombinant Virus ◽  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Mutant Virus ◽  
Productive Infection ◽  
Cell Protein ◽  
Null Mutant ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1

Bovine herpesvirus 1 (BHV-1) infected-cell protein 0 (bICP0) stimulates productive infection by activating viral gene expression. In this study, an attempt was made to construct a recombinant virus with point mutations in the C3HC4 zinc RING finger of bICP0, as this domain is necessary for activating viral transcription and productive infection. A virus was identified in bovine cells that induced small clusters of infected cells resembling a small plaque. Instead of the expected mutations within the zinc RING finger, this virus contained a point mutation within the initiating ATG of bICP0, a point mutation two bases downstream from the ATG mutation and deletion of flanking plasmid sequences used for homologous recombination. The bICP0 mutant was rescued with wild-type (wt) bICP0 sequences and the bICP0-rescued virus produced wt plaques. The bICP0-rescued virus and wt BHV-1, but not the mutant, expressed the bICP0 protein during productive infection of bovine cells, suggesting that the mutant virus was a null mutant. Consequently, the mutant was designated the bICP0 null mutant. Infection of bovine cells with the bICP0 null mutant resulted in at least 100-fold lower virus titres, indicating that bICP0 protein expression is important, but not required, for virus production. When bovine cells infected with the bICP0 null mutant virus were subcultured, the cells continued to divide, but viral DNA could be detected after more than 35 passages, suggesting that the bICP0 null mutant induced a persistent-like infection in bovine cells and that it may be useful for generating additional bICP0 mutants.

scholarly journals The zinc ring finger in the bICP0 protein encoded by bovine herpesvirus-1 mediates toxicity and activates productive infection

2001 ◽  
Vol 82 (3) ◽  
pp. 483-492 ◽  
Author(s):  
Melissa Inman ◽  
Yange Zhang ◽  
Vicki Geiser ◽  
Clinton Jones
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Ring Finger ◽  
Bovine Herpesvirus ◽  
Productive Infection ◽  
Bovine Herpesvirus 1 ◽  
Herpesvirus 1 ◽  
Simplex Virus

The bICP0 protein encoded by bovine herpesvirus 1 (BHV-1) is believed to activate transcription and consequently productive infection. Expression of full-length bICP0 protein is toxic in transiently transfected mouse neuroblastoma cells (neuro-2A) in the absence of other viral genes. However, bICP0 does not appear to directly induce apoptosis. Although bICP0 is believed to be functionally similar to the herpes simplex virus type 1-encoded ICP0, the only protein domain that is well conserved is a C3HC4 zinc ring finger located near the N terminus of both proteins. Site-specific mutagenesis of the zinc ring finger of bICP0 demonstrated that it was important for inducing aggregated chromatin structures in transfected cells and toxicity. The zinc ring finger was also required for stimulating productive infection in bovine cells and for trans-activating the thymidine kinase (TK) promoter of herpes simplex virus type 1. Deletion of amino acids spanning 356–677 of bICP0 altered subcellular localization of bICP0 and prevented trans-activation of the TK promoter. However, this deletion did not prevent trans-activation of the viral genome. Taken together, these studies indicated that bICP0 has several functional domains, including the zinc ring finger, which stimulate productive infection and influence cell survival.

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