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

Identifieur interne : 001871 ( Main/Exploration ); précédent : 001870; suivant : 001872

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

Auteurs : Amy C. Sims [États-Unis] ; Susan C. Tilton ; Vineet D. Menachery ; Lisa E. Gralinski ; Alexandra Sch Fer ; 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 Kent Tseng ; Thomas O. Metz ; Raymond Pickles ; Shannon Mcweeney ; Richard D. Smith ; Michael G. Katze ; Katrina M. Waters ; Ralph S. Baric

Source :

RBID : pubmed:23365422

Descripteurs français

English descriptors

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 severe acute respiratory syndrome coronavirus infection in vivo.

DOI: 10.1128/JVI.02520-12
PubMed: 23365422


Affiliations:


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Le document en format XML

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<term>Active Transport, Cell Nucleus (physiology)</term>
<term>Chromatin Immunoprecipitation</term>
<term>Computational Biology (methods)</term>
<term>DNA Primers (genetics)</term>
<term>Epithelial Cells (metabolism)</term>
<term>Epithelial Cells (virology)</term>
<term>Gene Regulatory Networks (physiology)</term>
<term>Humans</term>
<term>Lung (cytology)</term>
<term>Microarray Analysis</term>
<term>Proteomics</term>
<term>Real-Time Polymerase Chain Reaction</term>
<term>SARS Virus (metabolism)</term>
<term>Signal Transduction (physiology)</term>
<term>Systems Biology (methods)</term>
<term>Transcription, Genetic (physiology)</term>
<term>Viral Regulatory and Accessory Proteins (metabolism)</term>
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<term>Amorces ADN (génétique)</term>
<term>Analyse sur microréseau</term>
<term>Biologie des systèmes ()</term>
<term>Biologie informatique ()</term>
<term>Cellules épithéliales (métabolisme)</term>
<term>Cellules épithéliales (virologie)</term>
<term>Humains</term>
<term>Immunoprécipitation de la chromatine</term>
<term>Poumon (cytologie)</term>
<term>Protéines virales régulatrices ou accessoires (métabolisme)</term>
<term>Protéomique</term>
<term>Réaction de polymérisation en chaine en temps réel</term>
<term>Réseaux de régulation génique (physiologie)</term>
<term>Transcription génétique (physiologie)</term>
<term>Transduction du signal (physiologie)</term>
<term>Transport nucléaire actif (physiologie)</term>
<term>Virus du SRAS (métabolisme)</term>
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<term>DNA Primers</term>
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<term>SARS Virus</term>
<term>Viral Regulatory and Accessory Proteins</term>
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<term>Systems Biology</term>
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<term>Transduction du signal</term>
<term>Transport nucléaire actif</term>
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<term>Signal Transduction</term>
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<term>Immunoprécipitation de la chromatine</term>
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<front>
<div type="abstract" xml:lang="en">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 severe acute respiratory syndrome coronavirus infection in vivo.</div>
</front>
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