scholarly journals Inhibition of Antiviral Innate Immunity by Avibirnavirus VP3 via Blocking TBK1-TRAF3 Complex Formation and IRF3 Activation

mSystems ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Tingjuan Deng ◽  
Boli Hu ◽  
Xingbo Wang ◽  
Lulu Lin ◽  
Jianwei Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Virus Infection ◽  
Complex Formation ◽  
Rna Virus ◽  
Critical Role ◽  
Type I ◽  
Antiviral Immune Response ◽  
Critical Residue ◽  
Irf3 Activation

ABSTRACT The host innate immune system develops various strategies to antagonize virus infection, and the pathogen subverts or evades host innate immunity for self-replication. In the present study, we discovered that Avibirnavirus infectious bursal disease virus (IBDV) VP3 protein significantly inhibits MDA5-induced beta interferon (IFN-β) expression by blocking IRF3 activation. Binding domain mapping showed that the CC1 domain of VP3 and the residue lysine-155 of tumor necrosis factor receptor-associated factor 3 (TRAF3) are essential for the interaction. Furthermore, we found that the CC1 domain was required for VP3 to downregulate MDA5-mediated IFN-β production. A ubiquitination assay showed that lysine-155 of TRAF3 was the critical residue for K33-linked polyubiquitination, which contributes to the formation of a TRAF3-TBK1 complex. Subsequently, we revealed that VP3 blocked TRAF3-TBK1 complex formation through reducing K33-linked polyubiquitination of lysine-155 on TRAF3. Taken together, our data reveal that VP3 inhibits MDA5-dependent IRF3-mediated signaling via blocking TRAF3-TBK1 complex formation, which improves our understanding of the interplay between RNA virus infection and the innate host antiviral immune response. IMPORTANCE Type I interferon plays a critical role in the host response against virus infection, including Avibirnavirus. However, many viruses have developed multiple strategies to antagonize the innate host antiviral immune response during coevolution with the host. In this study, we first identified that K33-linked polyubiquitination of lysine-155 of TRAF3 enhances the interaction with TBK1, which positively regulates the host IFN immune response. Meanwhile, we discovered that the interaction of the CC1 domain of the Avibirnavirus VP3 protein and the residue lysine-155 of TRAF3 reduced the K33-linked polyubiquitination of TRAF3 and blocked the formation of the TRAF3-TBK1 complex, which contributed to the downregulation of host IFN signaling, supporting viral replication.

scholarly journals Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Dandan Qi ◽  
Lei Hu ◽  
Tong Jiao ◽  
Tinghong Zhang ◽  
Xiaomei Tong ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Phosphatase Activity ◽  
Signaling Pathway ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Luciferase Assay ◽  
Dna Virus ◽  
Antiviral Immune Response

ABSTRACT The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-β) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-β stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-β. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-β reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity. IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

scholarly journals Gastrodin Inhibits Virus Infection by Promoting the Production of Type I Interferon

2021 ◽  
Vol 11 ◽  
Author(s):  
Yunlian Zhou ◽  
Mengyao Li ◽  
Tingyi Lv ◽  
Meixia Huang ◽  
Beilei Cheng ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Critical Role ◽  
Protective Role ◽  
Control Group ◽  
Type I ◽  
Effective Strategy ◽  
Herpes Simplex Virus 1 ◽  
Antiviral Immune Response ◽  
Hsv 1

Type I interferon (IFN-I) plays a critical role in the antiviral immune response. However, viruses have developed different strategies to suppress the production of IFN-I for its own escape and amplification. Therefore, promoting the production of IFN-I is an effective strategy against virus infection. Gastrodin (GTD), a phenolic glucoside extracted from Gastrodia elata Blume, has been reported to play a protective role in some central nervous system -related diseases and is beneficial for the recovery of diseases by inhibiting inflammation. However, the effect of GTD on virus infection is largely unknown. Here we found GTD treatment increased the survival rate of mice infected with vesicular stomatitis virus (VSV) or herpes simplex virus-1 (HSV-1). The production of IFN-I was increased in GTD-treated mice or macrophages compared to the control group, during virus infection. Furthermore, the activation of interferon regulatory factor 3 (IRF3) was promoted by GTD in macrophages upon VSV and HSV-1 infection. Our results demonstrated that GTD could inhibit the VSV and HSV-1 infection by promoting the production of IFN-I in macrophages and might provide an effective strategy against virus infection.

scholarly journals Myeloid neddylation targets IRF7 and promotes host innate immunity against RNA viruses

2021 ◽  
Vol 17 (9) ◽  
pp. e1009901
Author(s):  
Min Zhao ◽  
Yaolin Zhang ◽  
Xiqin Yang ◽  
Jiayang Jin ◽  
Zhuo Shen ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Nuclear Translocation ◽  
Rna Viruses ◽  
Rna Virus ◽  
Innate Immune ◽  
Type I ◽  
Gene Promoters ◽  
Post Translational Modification

Neddylation, an important type of post-translational modification, has been implicated in innate and adapted immunity. But the role of neddylation in innate immune response against RNA viruses remains elusive. Here we report that neddylation promotes RNA virus-induced type I IFN production, especially IFN-α. More importantly, myeloid deficiency of UBA3 or NEDD8 renders mice less resistant to RNA virus infection. Neddylation is essential for RNA virus-triggered activation of Ifna gene promoters. Further exploration has revealed that mammalian IRF7undergoes neddylation, which is enhanced after RNA virus infection. Even though neddylation blockade does not hinder RNA virus-triggered IRF7 expression, IRF7 mutant defective in neddylation exhibits reduced ability to activate Ifna gene promoters. Neddylation blockade impedes RNA virus-induced IRF7 nuclear translocation without hindering its phosphorylation and dimerization with IRF3. By contrast, IRF7 mutant defective in neddylation shows enhanced dimerization with IRF5, an Ifna repressor when interacting with IRF7. In conclusion, our data demonstrate that myeloid neddylation contributes to host anti-viral innate immunity through targeting IRF7 and promoting its transcriptional activity.

scholarly journals DNA-PK is a DNA sensor for IRF-3-dependent innate immunity

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Brian J Ferguson ◽  
Daniel S Mansur ◽  
Nicholas E Peters ◽  
Hongwei Ren ◽  
Geoffrey L Smith
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Vaccine Development ◽  
Rna Virus ◽  
Severe Combined Immunodeficiency ◽  
Type I ◽  
Dna Sensor ◽  
Dna Viruses ◽  
Cytoplasmic Dna ◽  
Dependent Protein

Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity.

scholarly journals Control of antiviral innate immune response by protein geranylgeranylation

2019 ◽  
Vol 5 (5) ◽  
pp. eaav7999 ◽  
Author(s):  
Shigao Yang ◽  
Alfred T. Harding ◽  
Catherine Sweeney ◽  
David Miao ◽  
Gregory Swan ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Influenza A ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Junction Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Destructive Inflammation

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

scholarly journals A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus

2020 ◽  
Author(s):  
Tingting Geng ◽  
Tao Lin ◽  
Duomeng Yang ◽  
Andrew G Harrison ◽  
Anthony T Vella ◽  
...  
Keyword(s):  
Virus Infection ◽  
Chikungunya Virus ◽  
Immune Cell ◽  
Rna Virus ◽  
Critical Role ◽  
Joint Damage ◽  
Interferon Γ ◽  
Type I ◽  
Dna And Rna ◽  
Sting Pathway

Abstract The stimulator of interferon gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Stinggt/gt) had elevated viremia throughout the viremic stage and viral burden in feet transiently, with a normal type I IFN response. Stinggt/gt mice presented much greater foot swelling, joint damage, and immune cell infiltration than wild-type mice. Intriguingly, expression of interferon-γ and Cxcl10 was continuously upregulated by approximately 7 to 10-fold and further elevated in Stinggt/gt mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7, and Cxcr2 was suppressed in Stinggt/gt joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.

scholarly journals MAPK Phosphatase 5 Expression Induced by Influenza and Other RNA Virus Infection Negatively Regulates IRF3 Activation and Type I Interferon Response

Cell Reports ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. 1722-1734 ◽  
Author(s):  
Sharmy J. James ◽  
Huipeng Jiao ◽  
Hong-Ying Teh ◽  
Hirotaka Takahashi ◽  
Chin Wen Png ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Rna Virus ◽  
Interferon Response ◽  
Type I ◽  
Mapk Phosphatase ◽  
Irf3 Activation

scholarly journals Functional modulation of plazmacytoid dendritic cells during viral infections

2018 ◽  
Vol 72 ◽  
pp. 264-277
Author(s):  
Lidia Szulc-Dąbrowska ◽  
Piotr Wojtyniak ◽  
Diana Papiernik ◽  
Justyna Struzik
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Dendritic Cells ◽  
Nucleic Acids ◽  
Viral Infections ◽  
Type I ◽  
Term Survival ◽  
Antiviral Immune Response ◽  
Type I Ifns ◽  
Immunodeficiency Virus

Plasmacytoid dendritic cells (pDCs), also known as interferon (IFN)-producing cells (IPCs), represent a unique cell population of innate immunity due to their ability to produce high amounts of type I IFNs in response to viral infections. The pDCs recognize viral nucleic acids via Toll-like receptor (TLR)7 and TLR9 localized in endosomal compartments. Type I IFNs, secreted by activated pDCs through the recognition of foreign nucleic acids, not only exhibit a direct antiviral activity but also activate NK cells, induce myeloid DC (mDC) maturation, promote T cell long-term survival and memory formation, polarization of Th1 cells, cytolytic activity of CD8+ T lymphocytes and IFN-γ production. Therefore, pDCs link innate and adaptive immunity to mount an effective antiviral immune response. The pDCs, which act as the main cells of innate immunity that produce type I IFNs, play an important role in controlling viral infections, including human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), lymphocytic choriomeningitis virus (LCMV), hepatitis C virus (HCV), hepatitis B virus (HBV), respiratory syncytial virus (RSV) and herpes simplex virus (HSV) infections. However, some of these viruses can infect and even replicate productively in pDCs, resulting in modulation and functional impairment of these cells. Thus, viruses evade host antiviral immune response to mediate a persistent infection.

scholarly journals Spatiotemporal dynamics of innate immune signaling via RIG-I–like receptors

2020 ◽  
Vol 117 (27) ◽  
pp. 15778-15788 ◽  
Author(s):  
Katharina Esser-Nobis ◽  
Lauren D. Hatfield ◽  
Michael Gale
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Rna Virus ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Resting Cells ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Irf3 Activation

RIG-I, MDA5, and LGP2 comprise the RIG-I–like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.

scholarly journals TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity

2016 ◽  
Vol 214 (2) ◽  
pp. 459-473 ◽  
Author(s):  
Xueting Lang ◽  
Tiantian Tang ◽  
Tengchuan Jin ◽  
Chen Ding ◽  
Rongbin Zhou ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Signaling Pathways ◽  
Type I Interferon ◽  
Critical Role ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Interferon Signaling ◽  
Antiviral Innate Immunity ◽  
Irf3 Activation

MDA5 plays a critical role in antiviral innate immunity by functioning as a cytoplasmic double-stranded RNA sensor that can activate type I interferon signaling pathways, but the mechanism for the activation of MDA5 is poorly understood. Here, we show that TRIM65 specifically interacts with MDA5 and promotes K63-linked ubiquitination of MDA5 at lysine 743, which is critical for MDA5 oligomerization and activation. Trim65 deficiency abolishes MDA5 agonist or encephalomyocarditis virus (EMCV)–induced interferon regulatory factor 3 (IRF3) activation and type I interferon production but has no effect on retinoic acid–inducible I (RIG-I), Toll-like receptor 3 (TLR3), or cyclic GMP-AMP synthase signaling pathways. Importantly, Trim65−/− mice are more susceptible to EMCV infection than controls and cannot produce type I interferon in vivo. Collectively, our results identify TRIM65 as an essential component for the MDA5 signaling pathway and provide physiological evidence showing that ubiquitination is important for MDA5 oligomerization and activation.

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