---
title: "Antiviral Roles of Interferon-Stimulated Genes and Viral Antagonists"
id: "frontiers-in-immunology-5-antiviral-functions-of-interferon-stimulated-genes-and-virus-mediated-antagonism"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-5-antiviral-functions-of-interferon-stimulated-genes-and-virus-mediated-antagonism"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961358"
published_at: "2026-10-23T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Antiviral Roles of Interferon-Stimulated Genes and Viral Antagonists
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-5-antiviral-functions-of-interferon-stimulated-genes-and-virus-mediated-antagonism
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961358)
- **Published At:** 2026-10-23T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Interferons (**IFNs**) activate the JAK/STAT pathway, driving transcription of several hundred **ISGs** that restrict viral replication and modulate immunity. Some ISGs are induced by type I, II, and III IFNs, with cell-type differences in expression magnitude and repertoire. - Key antiviral effector families reviewed include **ISG15**/ISGylation, **MX1**/MX2 GTPases, the OAS–**RNase L** system, **PKR**, the IFIT family, viperin, PML nuclear bodies, APOBEC3, IFITMs and tetherin. Each family blocks viral replication via distinct molecular mechanisms such as RNA degradation, translation arrest, inhibition of fusion, or virion tethering. - Viruses have evolved diverse antagonists that target ISG pathways; examples reported include viral de-ISGylases and proteases that impair ISG15 functions, as well as mechanisms that counteract MX proteins and RNase L activity. - Evidence includes genetic loss-of-function models and molecular interaction studies: ISG15-deficient mice show increased susceptibility to several viruses; mutation of viral de-ISGylation enzymes reduces viral growth in vitro; MX proteins trap viral ribonucleoproteins or interfere with polymerase function. - Functional heterogeneity and species differences are prominent: MX activity varies by host and even by polymorphism within species; ISG15 has intracellular and extracellular roles that differ between humans and mice; a limited set of ISG15-specific E3 ligases has been identified. - Unresolved points the authors note: incomplete mechanistic definitions for many ISGs, limited knowledge of ISG15 E3 ligases, species-specific differences (human vs. mouse vs. avian), and the need to clarify extracellular ISG15 signaling and its receptors in vivo. - The review organizes representative ISG effector mechanisms and pairs each with known or putative viral countermeasures, indicating an ongoing virus–host arms race that shapes both antiviral effector evolution and viral antagonists.
## Clinical Analysis & Structured Key Points
Frontiers | Antiviral functions of Interferon-stimulated genes and virus-mediated antagonism REVIEW article Front. Immunol. , 23 October 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1961358 Published in Frontiers in Immunology Molecular Innate Immunity 7 impact factor 11.3 citescore Editor & Reviewers Edited by S N Sébastien Nisole Reviewed by B N Béatrice Nal F R Ferdinand Roesch Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 ISG effector pathways and viral countermeasures. View in article REVIEW article Front. Immunol. , 23 October 2026 Sec. Molecular Innate Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1961358 Antiviral functions of Interferon-stimulated genes and virus-mediated antagonism Z Z Zhaobin Zhou Y N Yuchen Nan * C W Chunyan Wu * Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China Article metrics View details Abstract Interferons (IFNs) are cytokines that play crucial roles in antiviral activity, anti-proliferation, stimulation of cytotoxic T cells, and modulation of host immune responses. Like other cytokines, IFNs bind their receptors on the cell surface to activate intracellular signal transduction. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the transcriptional activation of interferon-stimulated genes (ISGs). More than 300 ISGs can be upregulated by IFNs. Among these ISGs are a myriad of antiviral effectors, including ISG15, myxovirus resistance 1 (MX1), ribonuclease L (RNase L), and protein kinase R (PKR). Given the potent antiviral responses elicited by IFN-activated JAK/STAT signaling, viruses have evolved diverse strategies to antagonize this pathway during infection. In this review, recent progress in understanding the functions of ISGs is summarized, with particular emphasis on viral antagonism of ISG-mediated antiviral responses. 1 IFN-mediated signaling as an antiviral pathway Interferons (IFNs) are a group of secreted cytokines that play key roles in host antiviral immunity, defined by their ability to inhibit virus replication. To date, three types of IFNs have been characterized ( 1 – 3 ). Type I IFNs, the largest IFN family, include IFN-α, IFN-β, IFN-ϵ, IFN-κ, and IFN-ω ( 4 ). All type I IFNs bind to a ubiquitously expressed heterodimeric receptor complex composed of IFN-α receptor 1 (IFNAR1) and IFNAR2 to activate the JAK/STAT pathway ( 5 ). Type II IFN consists solely of IFN-γ, which is classified separately from type I IFNs due to its distinct chromosomal localization and receptor usage ( 2 , 6 ). Signaling for IFN-γ is transduced through the broadly expressed IFN-γ receptor complex (IFNGR) ( 7 – 9 ). IFN-γ plays a central role in establishing cellular immunity but is capable of inducing expression of a subset of antiviral genes that respond to type I IFNs as well ( 10 , 11 ). Type III IFNs are the most recently identified family and comprise IFN-λ1 to IFN-λ4 ( 6 , 12 ). The IFN-λs signal through a heterodimeric receptor composed of IFNLR1 (or IL-28R) and IL-10R2, which differs from type I/II IFN receptors. Moreover, the genes encoding IFN-λs are located at a distinct chromosomal locus ( 4 , 6 , 13 ). However, IFN-λs activate the same JAK/STAT pathway and induce gene expression patterns similar to those of type I IFNs. Type I, type II and type III IFNs differ in the cells that produce them. Type I interferons (IFNs) are produced by most virus-infected cells, but plasmacytoid dendritic cells (pDCs) are the main producers of IFN-α in vivo ( 14 ). The type I interferon receptor is expressed on almost all cell types, which means type I IFNs can act throughout the body ( 1 , 3 ). Type II IFN is produced mainly by activated T cells and natural killer (NK) cells rather than by infected cells, whereas its receptor is also widely expressed ( 2 , 15 ). Type III IFNs are produced mainly by epithelial cells and their production is different between tissues. However, it is notable that the receptor of type III IFNs is expressed largely on epithelial cells ( 16 ). Therefore, type I and type II IFNs could act throughout the body whereas type III IFNs act only at mucosal surfaces and cause fewer systemic effects than type I IFNs ( 3 , 17 ). Like other cytokines, IFNs stimulate cells by binding to their corresponding receptors, thereby activating specific signaling pathways, principally the JAK/STAT pathway ( 18 ). Activation of JAK/STAT by IFNs triggers a cascade of events that ultimately leads to the induction of a broad set of IFN-stimulated genes (ISGs) ( 19 ) ( Figure 1 ), commonly estimated at several hundred genes, whereas the exact number detected varies substantially among cell types and species ( 20 , 21 ). These ISGs include antiviral effectors that restrict virus replication. In addition to the JAK/STAT pathway, activation of host pattern-recognition receptors (PRRs), including RIG-I-like receptors (RLRs) and Toll-like receptors (TLRs), also leads to ISG expression ( 22 , 23 ). To date, considerable progress has been made in characterizing the cellular responses and antiviral activities mediated by ISGs. Genetic loss-of-function studies have identified major effector pathways or families of the interferon-mediated antiviral response, such as the MX GTPase pathway, the 2’,5’-oligoadenylate synthetase (OAS)-directed RNase L pathway, the protein kinase R (PKR) pathway, the ISG15 ubiquitin-like pathway, the tripartite motif (TRIM) family, and interferon-induced transmembrane proteins (IFITMs). These pathways collectively block viral transcription, degrade viral RNA, inhibit translation, and modify protein function to control viral replication. Ongoing studies continue to reveal additional activities of these effector proteins and uncover unexpected functions of antiviral responses ( 24 ). In this review, the functions of representative ISGs and viral strategies for antagonizing ISG-mediated antiviral responses are discussed in detail. Figure 1 IFN signaling pathways that drive ISG expression. Binding of type I (IFN-α/β) and type III (IFN-λ) IFNs to their cognate receptor complexes (IFNAR1/IFNAR2 and IFNLR1/IL-10R2, respectively) activates JAK1/TYK2, leading to phosphorylation of STAT1 and STAT2, which associate with IRF9 to form the ISGF3 complex. Binding of type II IFN (IFN-γ) to IFNGR1/IFNGR2 activates JAK1/JAK2, leading to phosphorylation of STAT1 and formation of gamma-activated factor (GAF) homodimers. ISGF3 and GAF translocate to the nucleus, where they bind IFN-stimulated response elements (ISREs) and gamma-activated sequences (GAS), respectively, in the promoters of ISGs, thereby activating the transcription of hundreds of antiviral effector genes. 2 Functions of ISGs The binding of type I IFNs to their receptors on the cell surface initiates a signaling cascade that leads to the induction of more than 300 ISGs. Some of these ISGs can also be upregulated by type II and type III IFNs ( 25 , 26 ). The functional diversity of ISGs indicates that IFNs play multiple roles beyond their canonical antiviral or anti-tumor functions. Evidence from microarray studies has shown that ISG expression is cell type-specific, ranging from 50 to 1,000 genes, with 200 to 500 genes commonly expressed across cell types ( 25 ). This implies that IFNs can exert different functions in different cellular contexts. ISGs can be further classified into distinct categories according to their functions. Depending on the category, ISGs are involved in diverse pathways, including amino acid and lipid metabolism, antigen processing and presentation, host cell signaling, transcriptional regulation, ubiquitination, apoptosis, host defense, immune modulation, inflammation, and tumor suppression ( 26 ). The ISGs that play important roles in antiviral defense during infection can be broadly divided into at least two groups based on their functions. The first group comprises proteins directly involved in host defense, including those that possess intrinsic antiviral activity at the cellular level. The second group includes ISGs that participate in host cell signaling. Within this group are PRRs, such as TLRs and RLRs, which detect pathogens and initiate host innate immune signaling. Certain adaptor proteins for TLRs that mediate signaling, such as MyD88, can be upregulated as well to enhance PRR signaling ( 27 ). Transcription factors, including members of the IRF family, the STAT family, and NF-κB, form amplification loops, thereby leading to enhanced IFN production and ISG expression ( 24 , 26 , 27 ). Moreover, proteins involved in other pathways can be upregulated, such as ubiquitin-activating E1 and ubiquitin-conjugating E2 enzymes, as well as IL-1β-converting enzyme ( 27 ). Among ISGs induced by IFNs, those acting as direct antiviral effectors are especially relevant to the outcome of infection, such as ISG15, MX1, the OAS family, RNase L, PKR and IFIT1 ( Figure 2 ). Their prominence is supported by their participation in the virus-host arms race, as viruses have independently evolved antagonists against these ISGs, which indicates these effectors are important enough to shape viral evolution. In this section, each of these ISGs will be discussed. Figure 2 Antiviral effector mechanisms of the representative ISG families. Schematic illustration of the antiviral functions of the ten ISG families discussed in this review: ISG15 (ISGylation of viral and cellular proteins), MXA/MXB (dynamin-like GTPases that trap viral ribonucleoprotein complexes), the OAS/RNase L system (OAS1–3 synthesize 2’,5’-oligoadenylates (2-5A) that activate RNase L to degrade viral and host single-stranded RNA, with cleavage products amplifying MDA5/STING signaling and promoting apoptosis), the IFIT family (cap-dependent recognition and translational suppression of non-self RNA), PKR (double-stranded RNA-triggered translation arrest), viperin (a radical SAM enzyme that produces the chain-terminating nucleotide ddhCTP), PML nuclear bodies (nuclear scaffolds that sequester viral proteins and restrict virus replication), APOBEC3 proteins (cytidine deaminases that deaminate single-stranded viral DNA, leading to G-to-A hypermutation and degradation of the viral genome), IFITM proteins (intramembrane proteins that block fusion of enveloped viruses during cell entry), and tetherin (a GPI-anchored membrane protein that traps budding virions at the cell surface and prevents their release). 2.1 ISG15 and ISGylation system ISG15 was identified following the discovery of ubiquitin and characterized as a potential ubiquitin homolog ( 28 ). The mature human ISG15 protein is a shorter product derived from a precursor by removal of eight amino acids at the C-terminus, thus sharing the identical C-terminal Leu-Arg-Leu-Arg-Gly-Gly sequence with mature ubiquitin ( 29 ). Unlike other ubiquitin homologs such as SUMO and Nedd8, ISG15 is not present in yeast, insects, plants, or other non-vertebrate organisms, implying that ISG15 performs a highly specialized function in vertebrates ( 30 ). As a ubiquitin-like molecule, ISG15 can be conjugated to cellular substrates through a reversible process termed ISGylation, which involves E1-activating enzymes, E2-conjugating enzymes, and E3 ligases ( 28 , 31 ). Protein ISGylation does not cause degradation of substrates, unlike K48-linked protein ubiquitination, and no universal role has been defined for protein ISGylation. It remains unclear whether ISGylated proteins face a common consequence analogous to ubiquitination, or whether their fates vary depending on the individual ISGylated protein ( 24 , 32 ). However, evidence suggests that ISGylation triggers co-localization of multivesicular bodies (MVBs) with lysosomes and promotes the aggregation and degradation of MVB proteins in both HEK-293 cells and mouse primary macrophages ( 33 ). The strength of ISG induction by IFNs does not always correlate with the potency of restriction or a particularly important role in viral antagonism. There are numerous examples of ISGs being extremely potent despite low to moderate levels of induction by IFN. However, the expression of ISG15 is strongly upregulated upon IFN treatment. Direct evidence for its role in host innate immunity comes from ISG15-deficient mice, which exhibit increased susceptibility to influenza A and B viruses, Sindbis virus and HSV-1 ( 34 , 35 ). Conversely, mutation of the viral de-ISGylation machinery impairs viral replication; for instance, a point mutation impairing the protease activity of the ovarian tumor (OTU) domain in nsp2 of porcine reproductive and respiratory syndrome virus (PRRSV) results in reduced viral growth in vitro ( 36 ). ISG15 and ISGylation can target the budding of enveloped viruses (HIV-1, Ebola virus, Chikungunya virus) in a virus-specific manner ( 37 ). For example, ISG15 interacts with the ubiquitin E3 ligase Nedd4 and blocks Nedd4-mediated ubiquitination of Ebola virus VP40, resulting in reduced release of VP40 virus-like particles ( 38 ). However, a recent report also demonstrated that ISG15 deficiency restricts HIV-1 infection in vitro and it appeared that ISG15-deficient cells express elevated levels of other ISGs, consequently exhibiting broad-spectrum resistance to viral infection ( 39 ). Conversely, the interference of ISGylation with ubiquitination blocks protein-protein interactions, suggesting a unique perspective for its function ( 32 ). ISG15 has been reported to interfere with the ubiquitination cascade ( 40 ), and can also prevent virus-mediated degradation of IRF3 to enhance IFN-β expression ( 41 ). Furthermore, ISGylation has been shown to modulate enzyme function. For example, conjugation of ISG15 to protein phosphatase 1B (PPM1B) suppresses its activity and enhances NF-κB signaling ( 42 ). In humans, free ISG15 binds to USP18 intracellularly, increasing its stability and leading to inhibition of IFN-α/β signaling; however, this phenomenon is not observed in mice ( 43 ). In addition to its intracellular function as a protein modifier, a cytokine-like function of ISG15 has been proposed, as ISG15 can be secreted from human monocytes and lymphocytes and is detectable in both blood and urine ( 44 , 45 ). It has been demonstrated that ISG15 stimulates the proliferation of NK cells as well as IFN-γ induction from T cells in a dose-dependent manner ( 44 ). Meanwhile, ISG15 also functions as a neutrophil chemotactic factor ( 45 , 46 ). A recent study demonstrated that extracellular ISG15 activates PBMCs through the LFA-1 integrin receptor (CD11a) to enhance secretion of IFN-γ and IL-10 ( 47 ). Conversely, porcine ISG15 (pISG15) appears to exert antiviral activity in porcine alveolar macrophages (PAMs) against PRRSV infection when PAMs are pre-treated with recombinant pISG15 as a mimic for the extracellular form of ISG15 ( 48 ), although the underlying mechanism requires further investigation. In addition to its roles in viral infection, several reports have also demonstrated that aberrantly elevated or compromised ISG15 expression is observed in various human diseases, including multiple types of cancer, neurodegenerative disorders, inflammatory diseases, and bacterial infections ( 49 , 50 ). Recent studies have substantially expanded our understanding of ISG15 biology. A limited number of ISG15-specific E3 ligases have been described so far ( 51 – 53 ), which include HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) in humans, HERC6 (mouse), ARIH1 and TRIM25 ( 53 ). Both HERC5 and HERC6 are themselves ISGs, forming a positive-feedback amplification loop ( 54 , 55 ). The role of ISG15 during SARS-CoV-2 infection has also been actively investigated. ISGylation of the SARS-CoV-2 nucleocapsid (N) protein has been shown to impair its oligomerization and inhibit viral replication ( 56 ). Moreover, ISG15 has been demonstrated to directly activate MDA5 through ISGylation, enhancing the innate immune sensing of viral RNA independently of ubiquitin ( 57 ), representing a previously unappreciated mechanism of ISG15-mediated antiviral immunity. 2.2 The myxovirus resistance proteins 2.2.1 MXA protein encoded by MX1 IFNs induce the expression of several guanine-hydrolyzing proteins, including the myxovirus resistance (MX) proteins. Humans possess two distinct MX genes located on chromosome 21, MX1 (encoding MXA) and MX2 (encoding MXB) ( 58 ). MX1 and MX2 were first identified as antiviral proteins through the observation that mutations within the MX locus on chromosome 16 confer susceptibility to orthomyxovirus infection in mice ( 59 ). Mouse strains expressing the active MX1 gene (about 64% identity to human) are highly resistant to influenza virus infection ( 60 ). MX proteins have been classified as a subclass of the dynamin-like GTPase superfamily ( 61 ). Three domains have been identified from the N-terminus to the C-terminus of MX proteins: a GTPase domain, a central domain involved in protein-protein interaction, and the C-terminal effector domain with leucine zipper motifs ( 61 ). The primary roles of MXA in humans or MX1 proteins in other mammalian hosts remain incompletely defined. MX1 in mice and rats is a nuclear protein ( 62 ), and has been demonstrated to inhibit influenza virus or influenza-like viruses such as Thogoto virus, as these viruses replicate in the nucleus. However, MXA or MX1 proteins from humans and other hosts are cytoplasmic proteins with smooth endoplasmic reticulum localization and have demonstrated broader inhibition of not only influenza virus but also other viruses such as vesicular stomatitis virus (VSV), Semliki Forest virus, and measles virus ( 62 – 65 ). Furthermore, although MX1 in mammalian hosts has been considered an inhibitory factor for influenza virus, the function of avian MX proteins differs. Only one MX protein with no antiviral activity has been identified in ducks and chickens ( 66 , 67 ). However, later in vitro studies demonstrated that chicken MX protein is highly polymorphic, and the polymorphism at amino acid 631 is proposed to determine its antiviral activity ( 68 , 69 ). Furthermore, chicken MX protein is dispensable for IFN-mediated resistance to influenza virus and lacks GTPase activity, which may explain its lack of antiviral activity ( 70 ). Although the detailed functions of MX proteins have not been fully defined, several virus-specific mechanisms have been identified. MX proteins can target viral nucleocapsid-like structures of Thogoto virus ( 71 ). The interaction between MX proteins has been characterized, and the smooth endoplasmic reticulum localization of MXs allows them to monitor exocytic events and mediate vesicle trafficking to trap essential viral components, thereby preventing viral replication at early time points ( 72 ). Moreover, MX1 can associate with subunits of the influenza virus polymerase to block viral transcription ( 73 ). Besides negative-strand RNA viruses, a recent study indicated that porcine MX1 plays a dominant role in inhibiting the N-Nsp9 interaction by interacting with the PRRSV N protein to inhibit replication of PRRSV (a positive-strand RNA virus) ( 74 ). 2.2.2 MXB protein encoded by MX2 Unlike MX1, MX2 is localized in the nucleus due to a nuclear localization signal (NLS) within its N-terminus and is ineffective against influenza virus although MXB is highly homologous in sequence (63% identity) to MXA ( 75 – 77 ). Mouse lacks MX2 gene, instead, mouse MXB protein is a duplicate of mouse MX1 during evolution. Human MXB was shown to possess antiviral activity against HIV-1 by reducing the level of integrated viral DNA ( 78 ), with both nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed ( 76 , 79 ). It is notable that MXB mutants that are unable to b
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