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

Abstract

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.

All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes

“…Multiple studies have shown that ISG20 overexpression inhibits viral replication in an exonuclease-dependent manner, and several have observed a corresponding decrease in viral RNA ( 38 , 111 – 113 , 120 ). Moreover, most studies on ISG20 have utilized the catalytically inactive mutant D94G ( 110 ) to support the hypothesis that ISG20 exonuclease activity is required for antiviral activity ( 38 , 111 – 113 , 116 , 120 , 121 ). This invariant residue is crucial to ISG20 structure as it helps coordinate an Mn 2+ ion in the active site ( 122 ).…”

“…Recently, two groups have independently found that ISG20 mediates antiviral activity through translation inhibition and not RNA degradation, but propose two divergent mechanisms ( 121 , 123 ). One group proposes that ISG20-mediated translation inhibition is indirect, mediated through ISG20-dependent upregulation of other ISGs ( 123 ).…”

Montelukast, an Anti-asthmatic Drug, Inhibits Zika Virus Infection by Disrupting Viral Integrity

“…Yunwen Hu and Zhigang Song at the Shanghai Public Health Clinical Center; and YFV strain 17D obtained from Beijing Tiantan Biological Products, Ltd., were all propagated in C6/36 cells as described previously (Yu et al, 2017). The replication-competent vesicular stomatitis virus (VSV) containing an additional viral transcriptional unit coding green fluorescent protein (VSV-GFP) was kindly provided by Dr. Nannan Wu (Wu et al, 2019) and propagated in Vero E6 cells. The enterovirus 71 (EV71) was kindly provided by Dr. Shuye Zhang (Yuan et al, 2018) and propagated in RD cells.…”

West Nile Virus Restriction in Mosquito and Human Cells: A Virus under Confinement

“…For instance, Weiss C. M. et al reported that its antiviral activity was at least partly due to the positive regulation of the IFN response, thus increasing the expression of other antiviral ISGs [184]. More recently, using VSV as a model RNA virus, Wu N. et al proposed that ISG20 acts by decreasing protein translation from exogenous RNA in the absence of RNA degradation [185].…”

“…Viperin has also been reported to prevent viral replication and assembly in the endoplasmic reticulum [ 137 , 140 , 142 ]. However, viral protein synthesis seems to constitute a favored step for restriction, since the translation of viral RNA is inhibited by several antiviral effectors, such as PKR [ 135 , 137 ], IFITs [ 190 , 192 , 199 , 200 , 201 ], ISG20 [ 184 , 185 ], or SFLN11 [ 215 ]. Given that the precise antiviral mechanism of IFI27l2a, TRIM6/VAMP8, IFI6, DDX24, IFI44L, IFRD1, IL13RA1, MAFK, PAK3, SAMD9L, SC4MOL, and RIPK3 is still unclear, they are not represented in this diagram but are indicated in Table 1 .…”