Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells

Amy C. Sims, Susan C. Tilton, Vineet Menachery, Lisa E. Gralinski, Alexandra Schäfer, Melissa M. Matzke, Bobbie Jo M Webb-Robertson, Jean Chang, Maria L. Luna, Casey E. Long, Anil K. Shukla, Armand R. Bankhead, Susan E. Burkett, Gregory Zornetzer, Chien-Te Tseng, Thomas O. Metz, Raymond Pickles, Shannon McWeeney, Richard D. Smith, Michael G. Katze & 2 others Katrina M. Waters, Ralph S. Barica

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The severe acute respiratory syndrome coronavirus accessory protein ORF6 antagonizes interferon signaling by blocking karyopherin-mediated nuclear import processes. Viral nuclear import antagonists, expressed by several highly pathogenic RNA viruses, likely mediate pleiotropic effects on host gene expression, presumably interfering with transcription factors, cytokines, hormones, and/or signaling cascades that occur in response to infection. By bioinformatic and systems biology approaches, we evaluated the impact of nuclear import antagonism on host expression networks by using human lung epithelial cells infected with either wild-type virus or a mutant that does not express ORF6 protein. Microarray analysis revealed significant changes in differential gene expression,with approximately twice as many upregulated genes in the mutant virus samples by 48 h postinfection, despite identical viral titers. Our data demonstrated that ORF6 protein expression attenuates the activity of numerous karyopherin-dependent host transcription factors (VDR, CREB1, SMAD4, p53,EpasI, and Oct3/4) that are critical for establishing antiviral responses and regulating key host responses during virus infection. Results were confirmed by proteomic and chromatin immunoprecipitation assay analyses and in parallel microarray studies using infected primary human airway epithelial cell cultures. The data strongly support the hypothesis that viral antagonists of nuclear import actively manipulate host responses in specific hierarchical patterns, contributing to the viral pathogenic potential in vivo. Importantly, these studies and modeling approaches not only provide templates for evaluating virus antagonism of nuclear import processes but also can reveal candidate cellular genes and pathways that may significantly influence disease outcomes following severeacute respiratory syndrome coronavirus infection in vivo

Original languageEnglish (US)
Pages (from-to)3885-3902
Number of pages18
JournalJournal of Virology
Volume87
Issue number7
DOIs
StatePublished - Apr 2013

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Severe Acute Respiratory Syndrome
Coronavirus
Cell Nucleus Active Transport
imports
transcription (genetics)
lungs
karyopherins
Lung
Karyopherins
viruses
Viruses
cells
antagonists
epithelial cells
Transcription Factors
transcription factors
Epithelial Cells
Coronavirus Infections
infection
Gene Expression

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells. / Sims, Amy C.; Tilton, Susan C.; Menachery, Vineet; Gralinski, Lisa E.; Schäfer, Alexandra; Matzke, Melissa M.; Webb-Robertson, Bobbie Jo M; Chang, Jean; Luna, Maria L.; Long, Casey E.; Shukla, Anil K.; Bankhead, Armand R.; Burkett, Susan E.; Zornetzer, Gregory; Tseng, Chien-Te; Metz, Thomas O.; Pickles, Raymond; McWeeney, Shannon; Smith, Richard D.; Katze, Michael G.; Waters, Katrina M.; Barica, Ralph S.

In: Journal of Virology, Vol. 87, No. 7, 04.2013, p. 3885-3902.

Research output: Contribution to journalArticle

Sims, AC, Tilton, SC, Menachery, V, Gralinski, LE, Schäfer, A, Matzke, MM, Webb-Robertson, BJM, Chang, J, Luna, ML, Long, CE, Shukla, AK, Bankhead, AR, Burkett, SE, Zornetzer, G, Tseng, C-T, Metz, TO, Pickles, R, McWeeney, S, Smith, RD, Katze, MG, Waters, KM & Barica, RS 2013, 'Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells', Journal of Virology, vol. 87, no. 7, pp. 3885-3902. https://doi.org/10.1128/JVI.02520-12
Sims, Amy C. ; Tilton, Susan C. ; Menachery, Vineet ; Gralinski, Lisa E. ; Schäfer, Alexandra ; Matzke, Melissa M. ; Webb-Robertson, Bobbie Jo M ; Chang, Jean ; Luna, Maria L. ; Long, Casey E. ; Shukla, Anil K. ; Bankhead, Armand R. ; Burkett, Susan E. ; Zornetzer, Gregory ; Tseng, Chien-Te ; Metz, Thomas O. ; Pickles, Raymond ; McWeeney, Shannon ; Smith, Richard D. ; Katze, Michael G. ; Waters, Katrina M. ; Barica, Ralph S. / Release of severe acute respiratory syndrome coronavirus nuclear import block enhances host transcription in human lung cells. In: Journal of Virology. 2013 ; Vol. 87, No. 7. pp. 3885-3902.
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abstract = "The severe acute respiratory syndrome coronavirus accessory protein ORF6 antagonizes interferon signaling by blocking karyopherin-mediated nuclear import processes. Viral nuclear import antagonists, expressed by several highly pathogenic RNA viruses, likely mediate pleiotropic effects on host gene expression, presumably interfering with transcription factors, cytokines, hormones, and/or signaling cascades that occur in response to infection. By bioinformatic and systems biology approaches, we evaluated the impact of nuclear import antagonism on host expression networks by using human lung epithelial cells infected with either wild-type virus or a mutant that does not express ORF6 protein. Microarray analysis revealed significant changes in differential gene expression,with approximately twice as many upregulated genes in the mutant virus samples by 48 h postinfection, despite identical viral titers. Our data demonstrated that ORF6 protein expression attenuates the activity of numerous karyopherin-dependent host transcription factors (VDR, CREB1, SMAD4, p53,EpasI, and Oct3/4) that are critical for establishing antiviral responses and regulating key host responses during virus infection. Results were confirmed by proteomic and chromatin immunoprecipitation assay analyses and in parallel microarray studies using infected primary human airway epithelial cell cultures. The data strongly support the hypothesis that viral antagonists of nuclear import actively manipulate host responses in specific hierarchical patterns, contributing to the viral pathogenic potential in vivo. Importantly, these studies and modeling approaches not only provide templates for evaluating virus antagonism of nuclear import processes but also can reveal candidate cellular genes and pathways that may significantly influence disease outcomes following severeacute respiratory syndrome coronavirus infection in vivo",
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AU - Schäfer, Alexandra

AU - Matzke, Melissa M.

AU - Webb-Robertson, Bobbie Jo M

AU - Chang, Jean

AU - Luna, Maria L.

AU - Long, Casey E.

AU - Shukla, Anil K.

AU - Bankhead, Armand R.

AU - Burkett, Susan E.

AU - Zornetzer, Gregory

AU - Tseng, Chien-Te

AU - Metz, Thomas O.

AU - Pickles, Raymond

AU - McWeeney, Shannon

AU - Smith, Richard D.

AU - Katze, Michael G.

AU - Waters, Katrina M.

AU - Barica, Ralph S.

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