scholarly journals FUS/TLS suppresses enterovirus replication and promotes antiviral innate immune responses

2021 ◽  
Author(s):  
Yuan Chao Xue ◽  
Chen Seng Ng ◽  
Yasir Mohamud ◽  
Gabriel Fung ◽  
Huitao Liu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Rna Binding ◽  
Coxsackievirus B3 ◽  
Innate Immune ◽  
Viral Rna ◽  
Direct Inhibition ◽  
Rna Transcription ◽  
Cvb3 Infection ◽  
Antiviral Innate Immunity

During viral infection, the dynamic virus-host relationship is constantly in play. Many cellular proteins such as RNA-binding proteins (RBPs) have been shown to mediate antiviral responses during viral infection. Here we reported that the RBP, fused in sarcoma/translocated in liposarcoma (FUS/TLS), acts as a host restricting factor against the infection of coxsackievirus B3 (CVB3). Mechanistically, we found that deletion of FUS leads to increased viral RNA transcription and enhanced internal ribosome entry site (IRES)-driven translation, with no apparent impact on viral RNA stability. We further demonstrated that FUS physically interacts with viral genome, which may contribute to direct inhibition of viral RNA transcription/translation. Moreover, we identified a novel function for FUS in regulating host innate immune response. We showed that in the absence of FUS, gene expression of type I interferons and proinflammatory cytokines elicited by viral or bacterial infection is significantly impaired. Emerging evidence suggests a role for stress granules (SGs) in antiviral innate immunity. We further uncovered that knockout of FUS abolishes the ability to form SGs upon CVB3 infection or polyinosinic:polycytidylic acid (polyIC) treatment. Finally, we showed that, to avoid FUS-mediated antiviral response and innate immunity, CVB3 infection results in cytoplasmic mislocalization and cleavage of FUS through the enzymatic activity of viral proteases. Together, our findings in this study identified FUS as a novel host antiviral factor, which restricts CVB3 replication through direct inhibition of viral RNA transcription and protein translation and by regulating host antiviral innate immunity. IMPORTANCE Enteroviruses are common human pathogens, including those that cause myocarditis (coxsackievirus B3, CVB3), poliomyelitis (poliovirus) and hand, foot and mouse disease (enterovirus 71). Understanding the virus-host interaction is crucial for finding the treatment and prevention of these pathogens. In this study, we explored the interplay between host RNA binding protein FUS/TLS and CVB3 and reported that FUS/TLS restricts CVB3 replication through direct inhibition of viral RNA transcription/translation and by regulation of cellular antiviral innate immunity. To impede the antiviral role of FUS, CVB3 targets FUS for mislocalization and cleavage. Findings from this study provide novel insights into interactions between CVB3 and the FUS, which may lead to novel therapeutic interventions against enterovirus-induced diseases.

scholarly journals When human guanylate-binding proteins meet viral infections

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Rongzhao Zhang ◽  
Zhixin Li ◽  
Yan-Dong Tang ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Downstream Signaling ◽  
Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

scholarly journals In VitroandIn VivoCharacterizations of Pichinde Viral Nucleoprotein Exoribonuclease Functions

2015 ◽  
Vol 89 (13) ◽  
pp. 6595-6607 ◽  
Author(s):  
Qinfeng Huang ◽  
Junjie Shao ◽  
Shuiyun Lan ◽  
Yanqin Zhou ◽  
Junji Xing ◽  
...  
Keyword(s):  
Viral Infection ◽  
Immune Suppression ◽  
Guinea Pigs ◽  
Hemorrhagic Fever ◽  
Rna Replication ◽  
Antiviral Drugs ◽  
Innate Immune ◽  
Viral Rna ◽  
Type I ◽  
Pichinde Virus

ABSTRACTArenaviruses cause severe hemorrhagic fever diseases in humans, and there are limited preventative and therapeutic measures against these diseases. Previous structural and functional analyses of arenavirus nucleoproteins (NPs) revealed a conserved DEDDH exoribonuclease (RNase) domain that is important for type I interferon (IFN) suppression, but the biological roles of the NP RNase in viral replication and host immune suppression have not been well characterized. Infection of guinea pigs with Pichinde virus (PICV), a prototype arenavirus, can serve as a surrogate small animal model for arenavirus hemorrhagic fevers. In this report, we show that mutation of each of the five RNase catalytic residues of PICV NP diminishes the IFN suppression activity and slightly reduces the viral RNA replication activity. Recombinant PICVs with RNase catalytic mutations can induce high levels of IFNs and barely grow in IFN-competent A549 cells, in sharp contrast to the wild-type (WT) virus, while in IFN-deficient Vero cells, both WT and mutant viruses can replicate at relatively high levels. Upon infection of guinea pigs, the RNase mutant viruses stimulate strong IFN responses, fail to replicate productively, and can become WT revertants. Serial passages of the RNase mutantsin vitrocan also generate WT revertants. Thus, the NP RNase function is essential for the innate immune suppression that allows the establishment of a productive early viral infection, and it may be partly involved in the process of viral RNA replication.IMPORTANCEArenaviruses, such as Lassa, Lujo, and Machupo viruses, can cause severe and deadly hemorrhagic fever diseases in humans, and there are limited preventative and treatment options against these diseases. Development of broad-spectrum antiviral drugs depends on a better mechanistic understanding of the conserved arenavirus proteins in viral infection. The nucleoprotein (NPs) of all arenaviruses carry a unique exoribonuclease (RNase) domain that has been shown to be critical for the suppression of type I interferons. However, the functional roles of the NP RNase in arenavirus replication and host immune suppression have not been characterized systematically. Using a prototype arenavirus, Pichinde virus (PICV), we characterized the viral growth and innate immune suppression of recombinant RNase-defective mutants in both cell culture and guinea pig models. Our study suggests that the NP RNase plays an essential role in the suppression of host innate immunity, and possibly in viral RNA replication, and that it can serve as a novel target for developing antiviral drugs against arenavirus pathogens.

scholarly journals Protease-Activated Receptor-2 Regulates the Innate Immune Response to Viral Infection in a Coxsackievirus B3–Induced Myocarditis

2013 ◽  
Vol 62 (19) ◽  
pp. 1737-1745 ◽  
Author(s):  
Alice Weithauser ◽  
Peter Bobbert ◽  
Silvio Antoniak ◽  
Andreas Böhm ◽  
Bernhard H. Rauch ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Coxsackievirus B3 ◽  
Innate Immune ◽  
Protease Activated Receptor 2

scholarly journals PATTERN-RECOGNIZING RECEPTORS AND THE INNATE IMMUNE RESPONSE TO VIRAL INFECTION

2018 ◽  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Infection ◽  
Innate Immune Response ◽  
English Literature ◽  
Innate Immune ◽  
Viral Pathogens ◽  
Antiviral Immune Response ◽  
Viral Antigens ◽  
Wide Range

The innate immune response to viral pathogens is crucial in mobilizing defensive reactions of an organism during the development of an acute viral infection. Cells of the innate immunity system detect viral antigens due to genetically programmed pattern-recognition receptors (PRRs), which are located either on the cell surface or inside the certain intracellular components. These image-recognizing receptors include Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors (RIG-I-like receptors), nucleotide oligomerization domain-like receptors (NOD-like receptors), also known as NACHT, LRR and PYD domains of the protein, and cytosolic DNA sensors. The trigger mechanisms for these receptors are viral proteins, and nucleic acids serve as activators. The presence of PRRs that are responsible for the determination of viral antigens in cellular components allows the cells of innate immunity to recognize a wide range of viral agents that replicate in various cellular structures, and develop an immune response to them. This article summarizes the disparate data presented in modern English literature on the role of PRRs and the associated signaling pathways. Understanding the recognition of viral pathogens required triggering a cascade of cytokine and interferon production provides insights into how viruses activate the signal paths of PRRs and the effect of the interaction of viral antigens and these receptors on the formation of the antiviral immune response.

scholarly journals MAVS Coordination of Antiviral Innate Immunity

2015 ◽  
Vol 89 (14) ◽  
pp. 6974-6977 ◽  
Author(s):  
Christine Vazquez ◽  
Stacy M. Horner
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Endoplasmic Reticulum ◽  
Retinoic Acid ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Antiviral Innate Immunity ◽  
Inducible Gene

RNA virus infection is sensed in the cytoplasm by the retinoic acid-inducible gene I (RIG-I)-like receptors. These proteins signal through the host adaptor protein MAVS to trigger the antiviral innate immune response. Here, we describe how MAVS subcellular localization impacts its function and the regulation underlying MAVS signaling. We propose a model to describe how the coordination of MAVS functions at the interface between the mitochondria and the mitochondrion-associated endoplasmic reticulum (ER) membrane programs antiviral signaling.

scholarly journals Double-Stranded RNA Sensors and Modulators in Innate Immunity

2019 ◽  
Vol 37 (1) ◽  
pp. 349-375 ◽  
Author(s):  
Sun Hur
Keyword(s):  
Innate Immunity ◽  
Immune Defense ◽  
Innate Immune ◽  
Protein Kinase R ◽  
Double Stranded Rna ◽  
Adenosine Deaminases ◽  
Binding Domains ◽  
Dsrna Binding ◽  
Rna Sensors ◽  
Antiviral Innate Immunity

Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms.

scholarly journals Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

2015 ◽  
Vol 35 (17) ◽  
pp. 3029-3043 ◽  
Author(s):  
Kashif Aziz Khan ◽  
Florence Dô ◽  
Alexandre Marineau ◽  
Priscilla Doyon ◽  
Jean-François Clément ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Glycogen Synthase ◽  
Es Cells ◽  
Interferon Regulatory Factor ◽  
Innate Immune ◽  
Regulatory Factor ◽  
Gsk 3Β ◽  
Antiviral Innate Immunity

Induction of an antiviral innate immune response relies on pattern recognition receptors, including retinoic acid-inducible gene 1-like receptors (RLR), to detect invading pathogens, resulting in the activation of multiple latent transcription factors, including interferon regulatory factor 3 (IRF3). Upon sensing of viral RNA and DNA, IRF3 is phosphorylated and recruits coactivators to induce type I interferons (IFNs) and selected sets of IRF3-regulated IFN-stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2). Here, we used wild-type, glycogen synthase kinase 3α knockout (GSK-3α−/−), GSK-3β−/−, and GSK-3α/β double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3β−/−mouse embryonic fibroblast cells in which GSK-3α was knocked down to demonstrate that both isoforms of GSK-3, GSK-3α and GSK-3β, are required for this antiviral immune response. Moreover, the use of two selective small-molecule GSK-3 inhibitors (CHIR99021 and BIO-acetoxime) or ES cells reconstituted with the catalytically inactive versions of GSK-3 isoforms showed that GSK-3 activity is required for optimal induction of antiviral innate immunity. Mechanistically, GSK-3 isoform activation following Sendai virus infection results in phosphorylation of β-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3-regulated ISGs. This study identifies the role of a GSK-3/β-catenin axis in antiviral innate immunity.

scholarly journals Towards a structural characterization of the IFIT antiviral complex

2014 ◽  
Vol 70 (a1) ◽  
pp. C246-C246
Author(s):  
Christina Dimech ◽  
Bhushan Nagar
Keyword(s):  
Innate Immunity ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Gel Filtration ◽  
Innate Immune ◽  
Limited Information ◽  
Virus Elimination ◽  
Tetratricopeptide Repeats ◽  
Immune Effector

Our first line of defense against viral pathogens is the innate immune system. Interferon-induced proteins with tetratricopeptide repeats (IFITs) are innate immune effector molecules that are thought to confer antiviral defense through the formation of the IFIT `Interactome', a multiprotein complex made up of IFIT1, IFIT2, IFIT3 and several other host factors1. Through IFIT1, this complex has the ability to distinguish self from non-self nucleic acids such as virus-derived RNA bearing 5´-triphosphate or viral mRNA lacking 2´-O methylation on the first two nucleotides1,2. We have limited information on the architecture of this complex, its role in innate immunity, and its activity downstream of RNA binding remain unclear. To better understand the mechanisms of Interactome formation, we are investigating the structure of its core, namely the IFIT1-IFIT2-IFIT3 complex. Since it is challenging to crystallize the complex as a whole, likely due to its size and heterogeneity, we are also targeting the structure of individual components and co-crystals of interacting domains. A crystal structure of human IFIT2 is available, and our lab has solved the structure of N-terminal human IFIT1 and, more recently, N-terminal IFIT3. In this study, we aim to characterize the interaction between IFIT1 and IFIT2, and between IFIT3 and IFIT2, through gel-filtration binding assays, in vitro pull-downs and deletion mutations. Preliminary results on the expression and purification of IFIT2-deletion mutants will be presented, as well as purification of IFIT subcomplexes. Understanding the molecular mechanisms behind IFIT-mediated virus elimination will help us unravel the complexities of these interactions and significantly advance our fundamental knowledge of innate immunity, paving the way for designing novel immunotherapeutics, which could potentially complement anti-cancer strategies that rely on oncolytic RNA viruses.

Evasion strategies of Zika virus antagonizing host innate immunity

2019 ◽  
Vol 14 (7) ◽  
pp. 465-471
Author(s):  
Chenxiao Huang ◽  
Xiujuan Wang ◽  
Shuyi Huang ◽  
Linlin Ou ◽  
Jianfeng Dai ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Zika Virus ◽  
Rna Virus ◽  
Innate Immune ◽  
Nonstructural Proteins ◽  
Neurodevelopmental Disease ◽  
Positive Strand Rna Virus ◽  
Positive Strand Rna ◽  
Antiviral Innate Immunity ◽  
Innate Immune Evasion

Zika virus is a small enveloped positive-strand RNA virus, which belongs to the Flaviviridae family. The RNA genome of all flaviviruses encodes three structural and seven nonstructural genes, together with 5′- and 3′-untranslated region genes flanking. Accompanying the explosive nature of the Zika outbreak in 2014, there was a devastating congenital neurodevelopmental disease in fetuses. Apart from viral RNA replication, polyprotein cleavage, Zika virus nonstructural proteins also play vital roles in the host's innate immune evasion. In this brief report, we summarize the evasion mechanisms of the viral nonstructural proteins antagonizing host antiviral innate immunity.

scholarly journals Innate immune responses in RNA viral infection

2020 ◽  
Author(s):  
Qian Xu ◽  
Yuting Tang ◽  
Gang Huang
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Viral Infection ◽  
Immune Cells ◽  
Innate Immune System ◽  
Viral Infections ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Past Century ◽  
Main Role

AbstractRNA viruses cause a multitude of human diseases, including several pandemic events in the past century. Upon viral invasion, the innate immune system responds rapidly and plays a key role in activating the adaptive immune system. In the innate immune system, the interactions between pathogen-associated molecular patterns and host pattern recognition receptors activate multiple signaling pathways in immune cells and induce the production of pro-inflammatory cytokines and interferons to elicit antiviral responses. Macrophages, dendritic cells, and natural killer cells are the principal innate immune components that exert antiviral activities. In this review, the current understanding of innate immunity contributing to the restriction of RNA viral infections was briefly summarized. Besides the main role of immune cells in combating viral infection, the intercellular transfer of pathogen and host-derived materials and their epigenetic and metabolic interactions associated with innate immunity was discussed. This knowledge provides an enhanced understanding of the innate immune response to RNA viral infections in general and aids in the preparation for the existing and next emerging viral infections.

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