Regulation of arginase II by interferon regulatory factor 3 and the involvement of polyamines in the antiviral response.
The innate antiviral response requires the induction of genes and proteins with activities that limit virus replication. Among these, the well-characterized interferon beta (IFNB) gene is regulated through the cooperation of AP-1, NF-kappaB and interferon regulatory factor 3 (IRF-3) transcription factors. Using a constitutively active form of IRF-3, IRF-3 5D, we showed previously that IRF-3 also regulates an IFN-independent antiviral response through the direct induction of IFN-stimulated genes. In this study, we report that the arginase II gene (ArgII) as well as ArgII protein concentrations and enzymatic activity are induced in IRF-3 5D-expressing and Sendai virus-infected Jurkat cells in an IFN-independent manner. ArgII is a critical enzyme in the polyamine-biosynthetic pathway. Of the natural polyamines, spermine possesses antiviral activity and mediates apoptosis at physiological concentrations. Measurement of intracellular polyamine content revealed that expression of IRF-3 5D induces polyamine production, but that Sendai virus and vesicular stomatitis virus infections do not. These results show for the first time that the ArgII gene is an early IRF-3-regulated gene, which participates in the IFN-independent antiviral response through polyamine production and induction of apoptosis.
Grandvaux
Nathalie
N
Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Canada.
Gaboriau
François
F
Harris
Jennifer
J
tenOever
Benjamin R
BR
Lin
Rongtuan
R
Hiscott
John
J
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001119:Arginase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000821:virology; D010253:Respirovirus Infections / Q000235:genetics; D029082:Sendai virus / Q000472:pathogenicity; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D014157:Transcription Factors; D013096:Spermine; C477631:ARG2 protein, human; D001119:Arginase