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Pseudorabies virus infection results in a broad inhibition of host gene transcription

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Abstract
Pseudorabies virus (PRV) is a porcine alphaherpesvirus that belongs to the Herpesviridae family. We showed earlier that infection of porcine epithelial cells with PRV triggers activation of the nuclear factor kappa B (NF-kappa B) pathway, a pivotal signaling axis in the early immune response. However, PRV-induced NF-kappa B activation does not lead to NF-kappa B-dependent gene expression. Here, using electrophoretic mobility shift assays (EMSAs), we show that PRV does not disrupt the ability of NF-kappa B to interact with its kappa B target sites. Assessing basal cellular transcriptional activity in PRV-infected cells by quantitation of prespliced transcripts of constitutively expressed genes uncovered a broad suppression of cellular transcription by PRV, which also affects the inducible expression of NF-kappa B target genes. Host cell transcription inhibition was rescued when viral genome replication was blocked using phosphonoacetic acid (PAA). Remarkably, we found that host gene expression shutoff in PRV-infected cells correlated with a substantial retention of the NF-kappa B subunit p65, the TATA box binding protein, and RNA polymerase II-essential factors required for (NF-kappa B-dependent) gene transcription-in expanding PRV replication centers in the nucleus and thereby away from the host chromatin. This study reveals a potent mechanism used by the alphaherpesvirus PRV to steer the protein production capacity of infected cells to viral proteins by preventing expression of host genes, including inducible genes involved in mounting antiviral responses. IMPORTANCE Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections. We reported earlier that a DNA damage response in epithelial cells infected with the alphaherpesvirus pseudorabies virus (PRV) results in activation of the hallmark proinflammatory NF-kappa B signaling axis but, remarkably, that this activation does not lead to NF-kappa B-induced (proinflammatory) gene expression. Here, we report that PRV-mediated inhibition of host gene expression stretches beyond NF-kappa B-dependent gene expression and in fact reflects a broad inhibition of host gene transcription, which correlates with a substantial recruitment of essential host transcription factors in viral replication compartments in the nucleus, away from the host chromatin. These data uncover a potent alphaherpesvirus mechanism to interfere with production of host proteins, including proteins involved in antiviral responses. Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections.
Keywords
NF-KAPPA-B, RNA-POLYMERASE-II, TATA-BINDING PROTEIN, HERPES-SIMPLEX, IN-VITRO, MEDIATED TRANSCRIPTION, MAJOR TRANSACTIVATOR, REGULATORY, PROTEIN, ACTIVATION DOMAIN, COMPLEX-FORMATION, herpesvirus, host gene expression, pseudorabies virus, shutoff

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MLA
Romero Rata, Nicolás, et al. “Pseudorabies Virus Infection Results in a Broad Inhibition of Host Gene Transcription.” JOURNAL OF VIROLOGY, vol. 96, no. 13, 2022, doi:10.1128/jvi.00714-22.
APA
Romero Rata, N., Wuerzberger-Davis, S. M., Van Waesberghe, C., Jansens, R. J., Tishchenko Khoruzh, A., Verhamme, R., … Favoreel, H. (2022). Pseudorabies virus infection results in a broad inhibition of host gene transcription. JOURNAL OF VIROLOGY, 96(13). https://doi.org/10.1128/jvi.00714-22
Chicago author-date
Romero Rata, Nicolás, Shelly M. Wuerzberger-Davis, Cliff Van Waesberghe, Robert J. Jansens, Alexander Tishchenko Khoruzh, Ruth Verhamme, Shigeki Miyamoto, and Herman Favoreel. 2022. “Pseudorabies Virus Infection Results in a Broad Inhibition of Host Gene Transcription.” JOURNAL OF VIROLOGY 96 (13). https://doi.org/10.1128/jvi.00714-22.
Chicago author-date (all authors)
Romero Rata, Nicolás, Shelly M. Wuerzberger-Davis, Cliff Van Waesberghe, Robert J. Jansens, Alexander Tishchenko Khoruzh, Ruth Verhamme, Shigeki Miyamoto, and Herman Favoreel. 2022. “Pseudorabies Virus Infection Results in a Broad Inhibition of Host Gene Transcription.” JOURNAL OF VIROLOGY 96 (13). doi:10.1128/jvi.00714-22.
Vancouver
1.
Romero Rata N, Wuerzberger-Davis SM, Van Waesberghe C, Jansens RJ, Tishchenko Khoruzh A, Verhamme R, et al. Pseudorabies virus infection results in a broad inhibition of host gene transcription. JOURNAL OF VIROLOGY. 2022;96(13).
IEEE
[1]
N. Romero Rata et al., “Pseudorabies virus infection results in a broad inhibition of host gene transcription,” JOURNAL OF VIROLOGY, vol. 96, no. 13, 2022.
@article{8762653,
  abstract     = {{Pseudorabies virus (PRV) is a porcine alphaherpesvirus that belongs to the Herpesviridae family. We showed earlier that infection of porcine epithelial cells with PRV triggers activation of the nuclear factor kappa B (NF-kappa B) pathway, a pivotal signaling axis in the early immune response. However, PRV-induced NF-kappa B activation does not lead to NF-kappa B-dependent gene expression. Here, using electrophoretic mobility shift assays (EMSAs), we show that PRV does not disrupt the ability of NF-kappa B to interact with its kappa B target sites. Assessing basal cellular transcriptional activity in PRV-infected cells by quantitation of prespliced transcripts of constitutively expressed genes uncovered a broad suppression of cellular transcription by PRV, which also affects the inducible expression of NF-kappa B target genes. Host cell transcription inhibition was rescued when viral genome replication was blocked using phosphonoacetic acid (PAA). Remarkably, we found that host gene expression shutoff in PRV-infected cells correlated with a substantial retention of the NF-kappa B subunit p65, the TATA box binding protein, and RNA polymerase II-essential factors required for (NF-kappa B-dependent) gene transcription-in expanding PRV replication centers in the nucleus and thereby away from the host chromatin. This study reveals a potent mechanism used by the alphaherpesvirus PRV to steer the protein production capacity of infected cells to viral proteins by preventing expression of host genes, including inducible genes involved in mounting antiviral responses. IMPORTANCE Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections. We reported earlier that a DNA damage response in epithelial cells infected with the alphaherpesvirus pseudorabies virus (PRV) results in activation of the hallmark proinflammatory NF-kappa B signaling axis but, remarkably, that this activation does not lead to NF-kappa B-induced (proinflammatory) gene expression. Here, we report that PRV-mediated inhibition of host gene expression stretches beyond NF-kappa B-dependent gene expression and in fact reflects a broad inhibition of host gene transcription, which correlates with a substantial recruitment of essential host transcription factors in viral replication compartments in the nucleus, away from the host chromatin. These data uncover a potent alphaherpesvirus mechanism to interfere with production of host proteins, including proteins involved in antiviral responses. Herpesviruses are highly successful pathogens that cause lifelong persistent infections of their host. Modulation of the intracellular environment of infected cells is imperative for the success of virus infections.}},
  articleno    = {{e00714-22}},
  author       = {{Romero Rata, Nicolás and Wuerzberger-Davis, Shelly M. and Van Waesberghe, Cliff and Jansens, Robert J. and Tishchenko Khoruzh, Alexander and Verhamme, Ruth and Miyamoto, Shigeki and Favoreel, Herman}},
  issn         = {{0022-538X}},
  journal      = {{JOURNAL OF VIROLOGY}},
  keywords     = {{NF-KAPPA-B,RNA-POLYMERASE-II,TATA-BINDING PROTEIN,HERPES-SIMPLEX,IN-VITRO,MEDIATED TRANSCRIPTION,MAJOR TRANSACTIVATOR,REGULATORY,PROTEIN,ACTIVATION DOMAIN,COMPLEX-FORMATION,herpesvirus,host gene expression,pseudorabies virus,shutoff}},
  language     = {{eng}},
  number       = {{13}},
  pages        = {{20}},
  title        = {{Pseudorabies virus infection results in a broad inhibition of host gene transcription}},
  url          = {{http://dx.doi.org/10.1128/jvi.00714-22}},
  volume       = {{96}},
  year         = {{2022}},
}

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