The interferon stimulated gene 20 protein (ISG20) is an innate defense antiviral factor that discriminates self versus non-self translation

ISG20 is a broad spectrum antiviral protein thought to directly degrade viral RNA. However, this mechanism of inhibition remains controversial. Using the Vesicular Stomatitis Virus (VSV) as a model RNA virus, we show here that ISG20 interferes with viral replication by decreasing protein synthesis in the absence of RNA degradation. Importantly, we demonstrate that ISG20 exerts a translational control over a large panel of non-self RNA substrates including those originating from transfected DNA, while sparing endogenous transcripts. This activity correlates with the protein's ability to localize in cytoplasmic processing bodies. Finally, these functions are conserved in the ISG20 murine ortholog, whose genetic ablation results in mice with increased susceptibility to viral infection. Overall, our results posit ISG20 as an important defense factor able to discriminate the self/non-self origins of the RNA through translation modulation. Author summary The interferon-induced protein 20 (ISG20) is an RNA exonuclease endowed with broad antiviral properties. The prevailing mechanism of inhibition described for ISG20 indicates that this enzyme is capable of directly degrading viral RNA in the absence of apparent sequence specificity. This mode of action has been however challenged by recent studies that revealed that ISG20 could target specific structures on the hepatitis B virus, as well as by others that suggested inhibition in the absence of viral RNA degradation. We now demonstrate that ISG20 interferes with viral replication not by degrading viral RNA, but by impairing its translation. This mechanism of translational control targets all RNAs originated from ectopically introduced genetic material (through viral infection or transient transfection) that we define here collectively as non-self, independently from their viral/non-viral origins. However, ISG20 bears no effect on the translation of endogenous mRNAs transcripts, suggesting that ISG20 can discriminate between the cell's own genetic material (self) and foreign one. By taking profit of their mode of replication through integration, or EBV-like episomal maintenance certain pathogens seemingly escape ISG20 by what can be defined as self-mimicry. Lastly, this mechanism of action is conserved in the ISG20 murine ortholog, whose genetic ablation results in mice with increased susceptibility to viral infection. Overall, our study reveals a novel role of ISG20 as a translational modulator of foreign genetic material playing important functions during viral infection in vivo.