The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming.
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.
Antalis
T M
TM
Queensland Cancer Fund Experimental Oncology Unit, The Queensland Institute of Medical Research, Brisbane 4029, Australia. toniA@qimr.edu.au
La Linn
M
M
Donnan
K
K
Mateo
L
L
Gardner
J
J
Dickinson
J L
JL
Buttigieg
K
K
Suhrbier
A
A
D000260:Adenoviruses, Human / Q000276:immunology; D000524:Alphavirus / Q000276:immunology*; D000998:Antiviral Agents; D017209:Apoptosis; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000494:pharmacology*; D011070:Poly I-C / Q000276:immunology; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger; D012398:Ross River virus / Q000276:immunology; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000494:pharmacology*; D012845:Sindbis Virus / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D017735:Virus Latency
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; C494227:IRF9 protein, human; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D017396:Plasminogen Activator Inhibitor 2; D011506:Proteins; D012333:RNA, Messenger; D015842:Serine Proteinase Inhibitors; D014157:Transcription Factors; D014764:Viral Proteins; D016899:Interferon-beta; D011070:Poly I-C