Early Growth Response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression

Bedadala, Gautam R; Pinnoji, Rajeswara C; Hsia, Victor

doi:10.1038/cr.2007.44

Cited by 27 publications

(29 citation statements)

References 24 publications

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“…Given the fact that PC-12 cells and DRG neurons under NGF influence are frequently used as models for HSV-1 latency study, it would suggest that NGF-mediated HSV-1 gene silencing and quiescent state may result from, at least in part, by Egr-1 triggered inhibition on viral gene expression. This hypothesis was further supported by observation that over-expression of Egr-1 was sufficient to repress HSV-1 ICP4 and ICP22 in chromatin context in vitro[14]. We therefore hypothesized that Egr-1 may exhibit positive or negative regulatory effects on HSV-1 gene expression and replication depending upon distinct specific conditions and cellular environment.…”

Section: Discussionmentioning

confidence: 85%

“…For example, Nab2 (NGFI-A-binding protein 2 or Egr-1-binding protein 2) was a nuclear protein found to inhibit transcription induced by EGR particularly in chromatin context via nucleosomal remodeling [32]. This hypothesis was encouraged and supported by a previous study using a stably transformed nucleosome-associated plasmids in which HSV-1 ICP4 and ICP22 were repressed by Egr-1 and Nab2 was recruited to the regulatory sequence of ICP22 intron[14]. 5.…”

Section: Discussionmentioning

confidence: 99%

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Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Hsia

Graham

Bedadala

et al. 2013

BMRJ

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Aims To understand the mechanisms of Early Growth Response Protein 1 (Egr-1) induction upon HSV-1 lytic infection and its roles in regulating viral gene expression and replication. Study Design Rabbit corneal cell line SIRC and other cell lines were infected by HSV-1 to investigate the Egr-1 induction and its occupancy on the viral genome in different conditions. UV-inactivated HSV-1 and a recombinant virus over-expressing Egr-1 were generated to evaluate the regulatory effects on viral gene expression and replication during the infection. Methodology Egr-1 induction triggered by viral infection was determined by Western Blot analyses and immune-fluorescent microscopy. Real-time RT-PCR and a novel Cignal™ Reporter Assay were used for quantitative measurement of Egr-1 expression. Chromatin Immuno-precipitation (ChIP) was performed to address the Egr-1 occupancy to the viral regulatory sequences and the influence on viral replication was assessed by plaque assays. Results Our results indicated that Egr-1 expression requires viral gene expression since the UV-inactivated HSV-1 failed to produce Egr-1 protein. Blockade of viral replication did not block the Egr-1 protein synthesis, supporting the hypothesis that HSV-1 replication was not essential for Egr-1 production. Chromatin immune-precipitation (ChIP) and RT-PCR assays demonstrated that induced Egr-1 was able to interact with key regulatory elements near HSV-1 immediate-early (IE) genes and promote viral gene expression. Recombinant virus overexpressing Egr-1 revealed that Egr-1 enhanced the viral replication and the release of infectious virus. Conclusion Together these results concluded that HSV-1 triggers the expression of an important host transcription factor Egr-1 via a unique mechanism and benefit the viral gene expression and replication.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Hsia

Graham

Bedadala

et al. 2013

BMRJ

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“…To generate plasmid pgI-Luc, minigene gI-Pro that contains the VZV glycoprotein I (gI) promoter region located at bp Ϫ360 to Ϫ1 relative to the first ATG of the open reading frame (VZV pOka strain) was synthesized and cloned into the BglII and HindIII sites of pGL3-basic (Promega). Plasmid pICP22-SEAP has been described previously (40).…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of the Serine-Rich Tract of Varicella-Zoster Virus IE62

Kim

Shakya

Kim

et al. 2016

J Virol

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The immediate early 62 protein (IE62) of varicella-zoster virus (VZV), a major viral trans-activator, initiates the virus life cycle and is a key component of pathogenesis. The IE62 possesses several domains essential for trans-activation, including an acidic trans-activation domain (TAD), a serine-rich tract (SRT), and binding domains for USF, TFIIB, and TATA box binding protein (TBP). Transient-transfection assays showed that the VZV IE62 lacking the SRT trans-activated the early VZV ORF61 promoter at only 16% of the level of the full-length IE62. When the SRT of IE62 was replaced with the SRT of equine herpesvirus 1 (EHV-1) IEP, its trans-activation activity was completely restored. Herpes simplex virus 1 (HSV-1) ICP4 that lacks a TAD very weakly (1.5-fold) trans-activated the ORF61 promoter. An IE62 TAD-ICP4 chimeric protein exhibited trans-activation ability (10.2-fold), indicating that the IE62 TAD functions with the SRT of HSV-1 ICP4 to trans-activate viral promoters. When the serine and acidic residues of the SRT were replaced with Ala, Leu, and Gly, trans-activation activities of the modified IE62 proteins IE62-SRT⌬Se and IE62-SRT⌬Ac were reduced to 46% and 29% of wild-type activity, respectively. Bimolecular complementation assays showed that the TAD of IE62, EHV-1 IEP, and HSV-1 VP16 interacted with Mediator 25 in human melanoma MeWo cells. The SRT of IE62 interacted with the nucleolar-ribosomal protein EAP, which resulted in the formation of globular structures within the nucleus. These results suggest that the SRT plays an important role in VZV viral gene expression and replication. V aricella-zoster virus (VZV), a member of the Alphaherpesvirinae, is a ubiquitous human pathogen that causes varicella (chicken pox) in primary lytic infection and zoster (shingles) during reactivation from latent infection (1). VZV has a linear DNA genome of approximately 125 kbp that encodes at least 70 open reading frames (ORFs) (1). Herpesviruses with genomes of group D, such as equine herpesvirus 1 (EHV-1), bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and varicella-zoster virus (VZV), have a fixed long region (UL) covalently linked to a short (S) genomic region comprised of a pair of inverted repeat sequences that bracket a unique short segment (US) (2-4). Two alphaherpesviruses, VZV and EHV-1, are members of genus Varicellovirus and have very similar genomic structures (2, 4). The VZV immediate early 62 protein (IE62) of 1,310 amino acids (aa) is the major viral trans-activator and is essential for viral growth (1, 5, 6). IE62 is encoded by duplicated ORFs 62 and 71 and, as a tegument protein, is delivered to newly infected cell nuclei, where it initiates VZV replication by transactivating viral immediate early, early, and late genes (7,8). IE62 binds several viral proteins, such as ORF4 (9), ORF9 (10), ORF47 (11), and ORF63 (12), and cellular transcription factors, including upstream stimulatory factor (USF), TATA-binding protein (TBP), TFIIB,. IMPORTANCE The immediate early 62 protein (IE62) o...

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“…The results were presented as the fold induction of the reporter plasmid in the presence or absence of T3 (100 nM). The SEAP (Secreted Alkaline Phosphtase) assay was used as an internal control [23]. All experiments were performed with triplicate and repeated at least twice.…”

Section: Reporter Assaysmentioning

confidence: 99%

“…In addition to TH effects, roles of repressive chromatin/chromosome condensation on latent HSV-1 genome raised significant interest during the past decade [20][21][22][23][24][25][26]. The present investigation focused on the interaction of T3, TRs, and chromosome condensation during HSV-1 gene regulation in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

A Novel Thyroid Hormone Mediated Regulation of HSV-1 Gene Expression and Replication is Specific to Neuronal Cells and Associated with Disruption of Chromatin Condensation

Chen

Palem

Balish

et al. 2013

SOJPPS

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Previously we showed that thyroid hormone (T3) regulated the Herpes Simplex Virus Type -1 (HSV-1) gene expression and replication through its nuclear receptor TR via histone modification and chromatin remodeling in a neuroblastoma cell line neuro-2a cells (N2a). This observation suggested that T3 regulation may be neuron-specific and have implication in HSV-1 latency and reactivation. In this study, our in vitro latency/reactivation model demonstrated that removal of T3 can de-repress the HSV-1 replication and favor reactivation. Transfection studies and infection assays indicated that HSV-1 thymidine kinase (TK), a key viral gene during reactivation, was repressed by TR/T3 in cells with neuronal origin but not in non-neuronal cells. Additional studies showed that RCC1 (Regulator of Chromosome Condensation 1) was sequestered but efficiently detected upon viral infection in N2a cells. Western blot analyses indicated that addition of T3 repressed the RCC1 expression upon infection. It is likely that diminution of RCC1 upon infection in neuronal cells under the influence of TR/T3 may lead to repression of viral replication/gene expression thus promote latency. Together these results demonstrated that TR/T3 mediated regulation is specific to neuronal cells and differential chromosome condensation may play a critical role in this process.

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Early Growth Response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression

Cited by 27 publications

References 24 publications

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Functional Characterization of the Serine-Rich Tract of Varicella-Zoster Virus IE62

A Novel Thyroid Hormone Mediated Regulation of HSV-1 Gene Expression and Replication is Specific to Neuronal Cells and Associated with Disruption of Chromatin Condensation

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