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

Abstract

Interferon (IFN) signaling induces the expression of a wide array of genes, collectively referred to as IFN-stimulated genes (ISGs) that generally function to inhibit viral replication. RNA viruses are frequently targeted by ISGs through recognition of viral replicative intermediates and molecular features associated with viral genomes, or the lack of molecular features associated with host mRNAs. The ISGs reviewed here primarily inhibit viral replication in an RNA-centric manner, working to sense, degrade, or repress expression of viral RNA. This review focuses on dissecting how these ISGs exhibit multiple antiviral mechanisms, often through use of varied co-factors, highlighting the complexity of the type I IFN response. Specifically, these ISGs can mediate antiviral effects through viral RNA degradation, viral translation inhibition, or both. While the OAS/RNase L pathway globally degrades RNA and arrests translation, ISG20 and ZAP employ targeted RNA degradation and translation inhibition to block viral replication. Meanwhile, SHFL targets translation by inhibiting -1 ribosomal frameshifting, which is required by many RNA viruses. Finally, a number of E3 ligases inhibit viral transcription, an attractive antiviral target during the lifecycle of negative-sense RNA viruses which must transcribe their genome prior to translation. Through this review, we aim to provide an updated perspective on how these ISGs work together to form a complex network of antiviral arsenals targeting viral RNA processes.

Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells

“…Remarkably, vitamin C upregulated the expression of the viral-sensing receptors RIG-1 and MDA-5 in both humans and mice (Figure 3A-C). Furthermore, vitamin C also led to the upregulation of several other ISGs, including OAS1, 2, and 3, which sense RNA and lead to the synthesis of RNase, which can degrade viral RNA [27,40]. Furthermore, IFITMs that have been reported to be highly expressed in barrier cells such as epithelial cells were also upregulated.…”

“…The xenobiotic response via the aryl hydrocarbon receptor (AHR) pathway was upregulated, and aldehyde dehydrogenase 3B (ALDH3B)-the molecule in the network-is an integral part of this pathway. Several tripartite motif proteins (TRIMs) are also upregulated in the network, and TRIM29 is reported to be involved in macrophage activation in response to respiratory infections [27].…”

“…To investigate the role of vitamin C in antiviral responses, we aimed to determine whether there were changes in interferon-stimulated genes (ISGs) after vitamin C treatment, using the Interferome database [18,19]. ISGs are thought to be induced by type I interferons and play a significant role in inhibiting viral replication [27]. Recent advances indicate that the ISGs can be expressed at the basal level, and may be upregulated independently of interferon signaling.…”

Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors

“…HEM45: HeLa estrogen-modulated, band 45) is an RNA exonuclease that has been studied to have a broad antiviral activity. Expression of ISG20 can be regulated by both type I and II interferons (IFNs) and it plays a role in mediating interferon’s antiviral activities 25 , 45 , 46 . Pentecost group, showed that ISG20 mediates estrogen controlled cellular proliferation and differentiation 47 .…”

The Recognition of and Reactions to Nucleic Acid Nanoparticles by Human Immune Cells

“…The main effector functions of ISGs are to target pathways and functions required during the pathogens’ life cycle as well as to enhance innate immune signaling. In addition, ISGs encode proapoptotic proteins that lead cells to apoptosis under specific conditions [ 32 , 33 ].…”