scholarly journals The Viral Macrodomain Counters Host Antiviral ADP-Ribosylation

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 384 ◽  
Author(s):  
Yousef M. O. Alhammad ◽  
Anthony R. Fehr
Keyword(s):  
Immune Responses ◽  
Protein Interactions ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Protein Protein Interactions ◽  
Granule Formation ◽  
Inflammatory Cytokine Production ◽  
Adp Ribosylation ◽  
Antiviral Responses ◽  
Host Defense Response

Macrodomains, enzymes that remove ADP-ribose from proteins, are encoded by several families of RNA viruses and have recently been shown to counter innate immune responses to virus infection. ADP-ribose is covalently attached to target proteins by poly-ADP-ribose polymerases (PARPs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. This modification can have a wide variety of effects on proteins including alteration of enzyme activity, protein–protein interactions, and protein stability. Several PARPs are induced by interferon (IFN) and are known to have antiviral properties, implicating ADP-ribosylation in the host defense response and suggesting that viral macrodomains may counter this response. Recent studies have demonstrated that viral macrodomains do counter the innate immune response by interfering with PARP-mediated antiviral defenses, stress granule formation, and pro-inflammatory cytokine production. Here, we will describe the known functions of the viral macrodomains and review recent literature demonstrating their roles in countering PARP-mediated antiviral responses.

scholarly journals Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Bin Zhou ◽  
Fei Qi ◽  
Fangyi Wu ◽  
Hongbo Nie ◽  
Yifan Song ◽  
...  
Keyword(s):  
Immune Responses ◽  
Transcriptome Analysis ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Innate Immune ◽  
Endogenous Retroviruses ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Positive Regulator ◽  
Deficient Mice

ABSTRACT Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this “enemy within” may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela. Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

scholarly journals ADAR1 limits stress granule formation through both translation-dependent and translation-independent mechanisms

2021 ◽  
Author(s):  
Giulia A. Corbet ◽  
James M. Burke ◽  
Roy Parker
Keyword(s):  
Immune Response ◽  
Stress Response ◽  
Protein Interactions ◽  
Binding Activity ◽  
Innate Immune ◽  
Protein Protein Interactions ◽  
Granule Formation ◽  
Translation Inhibition ◽  
Translation Repression ◽  
Dsrna Binding

Stress granules (SGs) are cytoplasmic assemblies of RNA and protein that form when translation is repressed during the integrated stress response (ISR). SGs assemble from the combination of RNA-RNA, RNA-protein, and protein-protein interactions between mRNPs. The protein Adenosine deaminase acting on RNA 1 (ADAR1) recognizes and modifies dsRNAs within cells to prevent an aberrant innate immune response. ADAR1 localizes to SGs, and since RNA-RNA interactions contribute to SG assembly and dsRNA induces SGs, we examined how ADAR1 affects SG formation. First, we demonstrate that ADAR1 depletion triggers SGs by allowing endogenous dsRNA to activate the ISR through PKR activation and translation repression. However, we also show that ADAR1 limits SG formation independently of translation inhibition. ADAR1 repression of SGs is independent of deaminase activity, but dependent on dsRNA-binding activity, suggesting a model where ADAR1 binding limits RNA-RNA and/or RNA-protein interactions necessary for recruitment to SGs. Given that ADAR1 expression is induced during viral infection, these findings have implications for ADAR1's role in the antiviral response.

scholarly journals The Critical Role of PARPs in Regulating Innate Immune Responses

2021 ◽  
Vol 12 ◽  
Author(s):  
Huifang Zhu ◽  
Yan-Dong Tang ◽  
Guoqing Zhan ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Immune Responses ◽  
Critical Role ◽  
Molecular Targets ◽  
Adenosine Diphosphate ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Adp Ribosylation

Poly (adenosine diphosphate-ribose) polymerases (PARPs) are a family of proteins responsible for transferring ADP-ribose groups to target proteins to initiate the ADP-ribosylation, a highly conserved and fundamental post-translational modification in all organisms. PARPs play important roles in various cellular functions, including regulating chromatin structure, transcription, replication, recombination, and DNA repair. Several studies have recently converged on the widespread involvement of PARPs and ADP-Ribosylation reaction in mammalian innate immunity. Here, we provide an overview of the emerging roles of PARPs family and ADP-ribosylation in regulating the host’s innate immune responses involved in cancers, pathogenic infections, and inflammations, which will help discover and design new molecular targets for cancers, pathogenic infections, and inflammations.

scholarly journals Human Hemoglobin Subunit Beta Functions as a Pleiotropic Regulator of RIG-I/MDA5-Mediated Antiviral Innate Immune Responses

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Qian Yang ◽  
Si-Yu Bai ◽  
Lian-Feng Li ◽  
Su Li ◽  
Yuexiu Zhang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Redox State ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Signaling ◽  
Antiviral Responses ◽  
Antiviral Innate Immunity ◽  
Pleiotropic Regulator

ABSTRACT Hemoglobin is an important oxygen-carrying protein and plays crucial roles in establishing host resistance against pathogens and in regulating innate immune responses. The hemoglobin subunit beta (HB) is an essential component of hemoglobin, and we have previously demonstrated that the antiviral role of the porcine HB (pHB) is mediated by promoting type I interferon pathways. Thus, considering the high homology between human HB (hHB) and pHB, we hypothesized that hHB also plays an important role in the antiviral innate immunity. In this study, we characterized hHB as a regulatory factor for the replication of RNA viruses by differentially regulating the RIG-I- and MDA5-mediated antiviral signaling pathways. Furthermore, we showed that hHB directly inhibited MDA5-mediated signaling by reducing the MDA5–double-stranded RNA (dsRNA) interaction. Additionally, hHB required hHB-induced reactive oxygen species (ROS) to promote RIG-I-mediated signaling through enhancement of K63-linked RIG-I ubiquitination. Taken together, our findings suggest that hHB is a pleiotropic regulator of RIG-I/MDA5-mediated antiviral responses and further highlight the importance of the intercellular microenvironment, including the redox state, in regulating antiviral innate immune responses. IMPORTANCE Hemoglobin, the most important oxygen-carrying protein, is involved in the regulation of innate immune responses. We have previously reported that the porcine hemoglobin subunit beta (HB) exerts antiviral activity through regulation of type I interferon production. However, the antiviral activities and the underlying mechanisms of HBs originating from other animals have been poorly understood. Here, we identified human HB (hHB) as a pleiotropic regulator of the replication of RNA viruses through regulation of RIG-I/MDA5-mediated signaling pathways. hHB enhances RIG-I-mediated antiviral responses by promoting RIG-I ubiquitination depending on the hHB-induced reactive oxygen species (ROS), while it blocks MDA5-mediated antiviral signaling by suppressing the MDA5-dsRNA interaction. Our results contribute to an understanding of the crucial roles of hHB in the regulation of the RIG-I/MDA5-mediated signaling pathways. We also provide novel insight into the correlation of the intercellular redox state with the regulation of antiviral innate immunity.

scholarly journals Negative Regulation of RNF90 on RNA Virus-Triggered Antiviral Immune Responses Targeting MAVS

2021 ◽  
Vol 12 ◽  
Author(s):  
Bo Yang ◽  
Ge Zhang ◽  
Xiao Qin ◽  
Yulu Huang ◽  
Xiaowen Ren ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Rna Virus ◽  
Ring Finger ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Antiviral Signaling ◽  
Antiviral Responses ◽  
Mitochondrial Antiviral Signaling ◽  
Antiviral Innate Immunity

The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity.

scholarly journals Zika Virus Non-Structural Protein NS5 Inhibits the RIG-I Pathway and Interferon Lambda 1 Promoter Activation by Targeting IKK Epsilon

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1024 ◽  
Author(s):  
Lundberg ◽  
Melén ◽  
Westenius ◽  
Jiang ◽  
Österlund ◽  
...  
Keyword(s):  
Immune Responses ◽  
Zika Virus ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Regulatory Factor ◽  
Promoter Activation ◽  
Antiviral Responses ◽  
Pathogenic Viruses ◽  
Epithelial Barriers

The Zika virus (ZIKV) is a member of the Flaviviridae family and an important human pathogen. Most pathogenic viruses encode proteins that interfere with the activation of host innate immune responses. Like other flaviviruses, ZIKV interferes with the expression of interferon (IFN) genes and inhibits IFN-induced antiviral responses. ZIKV infects through epithelial barriers where IFN-λ1 is an important antiviral molecule. In this study, we analyzed the effects of ZIKV proteins on the activation of IFN-λ1 promoter. All ZIKV proteins were cloned and transiently expressed. ZIKV NS5, but no other ZIKV protein, was able to interfere with the RIG-I signaling pathway. This inhibition took place upstream of interferon regulatory factor 3 (IRF3) resulting in reduced phosphorylation of IRF3 and reduced activation of IFN-λ1 promoter. Furthermore, we showed that ZIKV NS5 interacts with the protein kinase IKKε, which is likely critical to the observed inhibition of phosphorylation of IRF3.

scholarly journals Differential induction of innate memory in porcine monocytes by β-glucan or bacillus Calmette-Guerin

2020 ◽  
pp. 175342592095160
Author(s):  
Kristen A Byrne ◽  
Christopher K Tuggle ◽  
Crystal L Loving
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Immune Responses ◽  
Tolerance Induction ◽  
Innate Immune ◽  
Bacillus Calmette Guerin ◽  
Innate Immune Responses ◽  
Inflammatory Cytokine Production ◽  
Tnf Α ◽  
Microbial Products

Innate immunomodulation via induction of innate memory is one mechanism to alter the host’s innate immune response to reduce or prevent disease. Microbial products modulate innate responses with immediate and lasting effects. Innate memory is characterized by enhanced (training) or depressed (tolerance) innate immune responses, including pro-inflammatory cytokine production, to secondary exposure following a priming event. To investigate the ability of β-glucans and bacillus Calmette-Guerin to induce innate training or tolerance in pig cells, porcine monocytes were cultured with priming agonist (β-glucans or bacillus Calmette-Guerin) then re-stimulated 5 d later with a heterologous microbial agonist to determine induction of innate memory. Priming with β-glucan from Saccharomyces cerevisiae depressed IL-1β and TNF-α cytokine responses to re-stimulation with LPS, indicative of a tolerized state. However, bacillus Calmette-Guerin priming induced a trained state in porcine monocytes, as LPS re-stimulation enhanced IL-1β and TNF-α gene expression and protein production. We present the first evidence of innate memory in pig monocytes, with bacillus Calmette-Guerin (training) or Saccharomyces cerevisiae β-glucan (tolerance). Induction of a trained or tolerized state in vitro is a first step to identify agonists to alter the innate immune system at the animal level with the intent of enhancing disease resistance.

scholarly journals Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 182
Author(s):  
Cindy Chiang ◽  
Guanqun Liu ◽  
Michaela U. Gack
Keyword(s):  
Immune Responses ◽  
Current Knowledge ◽  
Innate Immune ◽  
Type I ◽  
Innate Immune Responses ◽  
Deubiquitinating Enzymes ◽  
Viral Pathogens ◽  
Dna Viruses ◽  
E3 Ligases ◽  
Antiviral Responses

Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.

Oral Immune Activation by Disgust and Disease-Related Pictures

2015 ◽  
Vol 29 (3) ◽  
pp. 119-129 ◽  
Author(s):  
Richard J. Stevenson ◽  
Deborah Hodgson ◽  
Megan J. Oaten ◽  
Luba Sominsky ◽  
Mehmet Mahmut ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Negative Control ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Markers ◽  
Before And After ◽  
Secondary Analyses ◽  
Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

Innate immune responses and type 1 diabetes: A role for a long non-coding RNA?

2014 ◽  
Vol 9 (S 01) ◽  
Author(s):  
MP Ashton ◽  
I Tan ◽  
L Mackin ◽  
C Elso ◽  
E Chu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Non Coding Rna ◽  
Long Non Coding Rna
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