Abstract
The serine proteinase inhibitor (serpin) plasminogen activator inhibitor type 2 (PAI-2) is well characterized as an inhibitor of extracellular urokinase-type plasminogen activator. Here we show that intracellular, but not extracellular, PAI-2 protected cells from the rapid cytopathic effects of alphavirus infection. This protection did not appear to be related to an effect on apoptosis but was associated with a PAI-2-mediated induction of constitutive low-level interferon (IFN)-alpha/beta production and IFN-stimulated gene factor 3 (ISGF3) activation, which primed the cells for rapid induction of antiviral genes. This primed phenotype was associated with a rapid development of resistance to infection by the PAI-2 transfected cells and the establishment of a persistent productive infection. PAI-2 was also induced in macrophages in response to viral RNA suggesting that PAI-2 is a virus response gene. These observations, together with the recently demonstrated PAI-2-mediated inhibition of tumor necrosis factor-alpha induced apoptosis, (a) illustrate that PAI-2 has an additional and distinct function as an intracellular regulator of signal transduction pathway(s) and (b) demonstrate a novel activity for a eukaryotic serpin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / immunology
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Alphavirus / immunology*
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Antiviral Agents
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Apoptosis
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Cytopathogenic Effect, Viral / drug effects
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation / drug effects
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HeLa Cells
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Humans
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Influenza A virus / immunology
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Interferon-Stimulated Gene Factor 3
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interferon-alpha / genetics*
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Interferon-alpha / immunology
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Interferon-beta / genetics*
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Interferon-beta / immunology
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Plasminogen Activator Inhibitor 2 / genetics
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Plasminogen Activator Inhibitor 2 / pharmacology*
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Poly I-C / immunology
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Polymerase Chain Reaction
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Proteins / metabolism
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RNA, Messenger
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Ross River virus / immunology
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Serine Proteinase Inhibitors / genetics
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Serine Proteinase Inhibitors / pharmacology*
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Sindbis Virus / immunology
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Transcription Factors / metabolism
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Viral Proteins / metabolism
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Virus Latency
Substances
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Antiviral Agents
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DNA-Binding Proteins
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IRF9 protein, human
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Interferon-Stimulated Gene Factor 3
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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Interferon-alpha
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Plasminogen Activator Inhibitor 2
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Proteins
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RNA, Messenger
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Serine Proteinase Inhibitors
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Transcription Factors
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Viral Proteins
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Interferon-beta
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Poly I-C