Interferons (IFNs) encode a family of secreted
proteins that provide the front-line defense against
viral infections. Their diverse biological actions are thought to be mediated by the products of specific but usually overlapping sets of cellular genes induced in the target cells. We have recently isolated a new human IFN-induced gene that we have termed ISG20, which codes for a 3' to
5' exonuclease with specificity for single-stranded
RNA and, to a lesser extent, for
DNA. In this report, we demonstrate that ISG20 is involved in the
antiviral functions of IFN. In the absence of IFN treatment, ISG20-overexpressing HeLa cells showed resistance to
infections by
vesicular stomatitis virus (VSV), influenza virus, and encephalomyocarditis virus (three
RNA genomic viruses) but not to the
DNA genomic adenovirus. ISG20 specifically interfered with VSV
mRNA synthesis and
protein production while leaving the expression of cellular control genes unaffected. No
antiviral effect was observed in cells overexpressing a mutated ISG20
protein defective in
exonuclease activity, demonstrating that the
antiviral effects were due to the
exonuclease activity of ISG20. In addition, the inactive mutant ISG20
protein, which is able to inhibit ISG20
exonuclease activity in vitro, significantly reduced the ability of IFN to block VSV development. Taken together, these data suggested that the
antiviral activity of IFN against VSV is partly mediated by ISG20. We thus show that, besides
RNase L, ISG20 has an
antiviral activity, supporting the idea that it might represent a novel
antiviral pathway in the mechanism of IFN action.