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Interferon-Stimulated Genes As Enhancers of Antiviral Innate Immune Signaling

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Interferon-Stimulated Genes As Enhancers of Antiviral Innate Immune Signaling Review Journal of Innate J Innate Immun 2018;10:85–93 Received: August 29, 2017 DOI: 10.1159/000484258 Accepted after revision: October 14, 2017 Immunity Published online: November 30, 2017 Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling a a b a Keaton M. Crosse Ebony A. Monson Michael R. Beard Karla J. Helbig a Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, and b Department of Molecular and Cellular Biology, Research Centre for Infectious Diseases, University of Adelaide, Adelaide, SA, Australia Keywords Introduction Interferon-stimulated genes · Interferon · Innate immunity · Virus Viral infection constitutes a significant portion of hu- man morbidity and mortality, which has led to extensive investigation into the countermeasures employed by the Abstract host to combat such infection. The mammalian immune The ability of a host to curb a viral infection is heavily reliant system acts to eradicate viral infection through disrupting on the effectiveness of an initial antiviral innate immune re- pathways and functions imperative to the pathogen’s life- sponse, resulting in the upregulation of interferon (IFN) and, cycle, and it is the innate immune system that carries a subsequently, IFN-stimulated genes (ISGs). ISGs serve to substantial burden of the defense against viral pathogens. mount an antiviral state within a host cell, and although the Our innate immune system has evolved a range of recep- specific antiviral function of a number of ISGs has been char- tors to detect viral pathogens, termed pattern recognition acterized, the function of many of these ISGs remains to be receptors (PRRs), which recognize viral proteins and nu- determined. Recent research has uncovered a novel role for cleic acid in the process of non-self-recognition. Once ac- a handful of ISGs, some of them directly induced by IFN reg- tivated, PRRs initiate a series of signaling cascades that ulatory factor 3 in the absence of IFN itself. These ISGs, most result in the production of the well-known antiviral cyto- with potent antiviral activity, are also able to augment vary- kine, interferon (IFN). IFN is able to act in both an auto- ing arms of the innate immune response to viral infection, crine and paracrine manner to activate the Janus kinase thereby strengthening this response. This new understand- signal transducer and activator of transcription (JAK- ing of the role of ISGs may, in turn, help the recent advance- STAT) signaling pathway, resulting in the subsequent ment of novel therapeutics aiming to augment innate sig- downstream expression of hundreds of antiviral host ef- naling pathways in an attempt to control viral infection and fector proteins, called IFN-stimulated genes (ISGs) which pathogenesis. © 2017 The Author(s) control viral infection in the infected cell and help neigh- Published by S. Karger AG, Basel boring cells to resist infection [1]. Much research has fo- cused on the host receptors and proteins involved in the recognition of viral pathogens and the production of IFN, © 2017 The Author(s) Dr. Karla J. Helbig Published by S. Karger AG, Basel Department of Physiology, Anatomy and Microbiology La Trobe University, 1 Kingsbury Drive E-Mail [email protected] Bundoora, VIC 3083 (Australia) www.karger.com/jin This article is licensed under the Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International License (CC BY- E-Mail k.helbig @ latrobe.edu.au NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any dis- tribution of modified material requires written permission. Table 1. Interferon-stimulated genes that have specific antiviral targets as well as immune modulatory functions ISG Virus families shown to be susceptible Ref. Genome group Component of innate Upregulated of susceptible immune system independently viral family augmented by ISG of type I IFN PKR Poxviridae (vaccinia virus) 15, 16 dsDNA MDA5, TLR3, MAVS, no, but present Picornavirdae (encephalomyocarditis virus) ssRNA(+) TRAF2, TRAF6 at high basal Togaviridae (Semliki Forest virus) levels ZAP Togaviridae (Sindbis virus) 20, 21 ssRNA(+) RIG-I yes Filoviridae (Ebolavirus, Marburg virus) ssRNA(–) Paramyxoviridae (Newcastle disease virus) Orthomyxoviridae (influenza A virus) Retroviridae (murine leukemia virus) TRIM21 Picornaviridae (human rhinovirus) 30, 36 ssRNA(+) cGAS, RIG-I, NF-κB, no Adenovirdae (human adenovirus type 5) dsDNA AP-1, IRF3/5/7 TRIM56 Orthomyxoviridae (influenza A and B viruses) 31 – 33 ssRNA(+) STING, TLR3/TRIF no Flaviviridae (HCV, bovine viral diarrhea virus, ssRNA(–) yellow fever, DENV serotype 2) Rhabdoviridae (VSV) Coronaviridae (human coronavirus OC43) Viperin Flaviviridae (DENV, HCV, West Nile virus, 2 ssRNA(+) TLR7/9 (IRAK1/TRAF6) yes tick-borne encephalitis virus) ssRNA(–) NF-κB1/p50, AP-1 Herpesviridae (human Cytomegalovirus) dsDNA Paramyxoviridae (respiratory syncytial virus) Togaviridae (Chikungunya virus, Sindbis virus) Orthomyxoviridae (influenza A virus) Retroviridae (human immunodeficiency virus) Bunyaviridae (Bunyamwera virus) Picornaviridae (rhinovirus) Rhabdoviridae (VSV) DDX60 Rhabdoviridae (VSV) 46 ssRNA(–) RIG-I, MDA5, LGP2 no Flaviviridae (HCV) ssRNA(+) ISG, interferon-stimulated gene; Ref., reference; HCV, hepatitis C virus; VSV, vesicular stomatitis virus; DENV, Dengue virus; ssDNA, single-stranded DNA; dsDNA, double-stranded DNA. but the research into the ability of the ISGs themselves to rectly by IFN regulatory factor 3 (IRF3) very early (once control viral infection of host cells is limited. a virus has been detected in a host cell), independently of Work aimed at elucidating the function of some of IFN, offering a positive reinforcement of the initial viral these ISGs has revealed a broad scope of very specific an- detection pathways. This review will briefly discuss the tiviral mechanisms able to target viruses at varying stages detection of viral pathogens and the production of ISGs, of their life-cycle, with some ISGs having a broader spec- and then focus specifically on this new family of ISGs with trum of viral targets, such as cholesterol-25-hydroxylase its dual roles in combating viral infection. and the IFN-induced transmembrane (IFITM) proteins which inhibit the entry of many viruses. MX1 inhibits the early viral replication of multiple viral families and vi- Innate Immune Recognition of Pathogens and ISG perin has been shown to inhibit both viral egress and the Production replication of multiple viruses [2, 3]. However, increasing evidence in recent years has pointed to a role for a small The first PRRs to be described were the Toll-like recep- handful of these host ISGs in specific mechanisms of viral tors (TLRs) in Drosophila, and we now know that both restriction as well as in positive augmentation of the ear- cell surface and cytosolic PRRs exists in all metazoan an- ly innate pattern-recognition pathways that upregulate imals. PRRs recognize the pathogen-activated molecular the ISGs themselves (Table 1; Fig. 1). Some of these ISGs patterns (PAMPS) present in invading pathogenic organ- are present at high basal levels, or can be regulated di- isms, such as nucleic acids (double-stranded [ds]RNA, 86 J Innate Immun 2018;10:85–93 Crosse/Monson/Beard/Helbig DOI: 10.1159/000484258 Fig. 1. When a virus enters a cell, viral PAMPS are recognized by the antibody bound to nonenveloped viruses entering the cytosol pattern recognition receptors, and activate a number of signaling and catalyzes the synthesis of K63-linked polyubiquinated (K63 cascades that result in the production of type I and III interferon Ub) chains to activate IRFs and NF-κB, and induce a type I IFN (IFN) and inflammatory cytokines to induce an antiviral state. response independently of RIG-I and cGAS; (2) it recruits the pro- These pathways are augmented and enhanced by a number of IFN- teasome instigating premature virion uncoating, exposing PAMPS stimulated genes (ISGs). Protein kinase R (PKR) is a double- to RIG-I and cGAS. TRIM56 acts as a scaffold protein promoting stranded RNA receptor pivotal in the activation of MAVS (both IRF3 activation by enhancing the efficient interaction of STING following MDA5 activation and independently of MDA5 and and TBK1 and via an interaction with TRIF. Viperin enhances the RIG-I activation). Zinc-finger antiviral protein S (ZAP-S) enhanc- K63-linked ubiquitination of IRAK1 by promoting an interaction es RIG-I ATPase activity. Tripartite motif 21 (TRIM21) enhances between IRAK1 and TRAF6. DDX60 can bind dsRNA, and it as- innate immune signaling in 2 ways: (1) it detects the Fc portion of sociates with both RIG-I and MDA5 to enhance their activation. single-stranded [ss]RNA, dsDNA, and 5 triphosphate Viral pathogens can trigger the activation of cell-sur- RNA) and proteins, with the early innate response detec- face or endosomal TLRs, cytoplasmic PRRs such as RIG- tion of PAMPS being characterized best in mouse′ models I-like receptors (RLRs), including RIG-I and MDA-5 of infection and also in humans. Once a PRR recognizes which detect viral RNA, and dsDNA sensors such as a PAMP, a series of signaling pathways is set in motion, cGAS, DAI, and IFI16 which all activate primary signal- involving a number of conserved adaptor molecules, and ing adaptors, followed by the activation of IRFs, and cul- this results in the production of type I IFN (IFN-β and/or minating in the production of IFN. The ability of these IFN-α), and sometimes type III IFN (IFN-λ), all of which PRRs to detect viral RNA and DNA in comparison to host are critical mediators of innate immunity (Fig. 1; re- nucleic acid species is governed mainly by the localization viewed in [1]). of these receptors, the local concentration of nucleic acid, ISG Enhancement of Innate Immune J Innate Immun 2018;10:85–93 87 Signaling DOI: 10.1159/000484258 and the structure of the nucleic acids able to bind to each teins (ZAPs), IFN-regulated members of the tripartite PRR (reviewed in [4]). motif (TRIM)-containing family, viperin, and the Type I IFNs are produced by most cells, while type III DExD/H box helicase (DDX60) (Fig.
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