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 Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

Virus-associated activation of innate immunity induces rapid disruption of Peyer’s patches in mice

Blood ◽  
2013 ◽  
Vol 122 (15) ◽  
pp. 2591-2599 ◽  
Author(s):  
Simon Heidegger ◽  
David Anz ◽  
Nicolas Stephan ◽  
Bernadette Bohn ◽  
Tina Herbst ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Lymph Nodes ◽  
Immune Activation ◽  
Innate Immune ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Type I ◽  
Peripheral Lymph ◽  
Key Points

Key Points Systemic virus infection leads to rapid disruption of the Peyer’s patches but not of peripheral lymph nodes. Virus-associated innate immune activation and type I IFN release blocks trafficking of B cells to Peyer’s patches.

scholarly journals Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

2020 ◽  
Author(s):  
Richa Mishra ◽  
Sanjana Bhattacharya ◽  
Bhupendra S Rawat ◽  
Ashish Kumar ◽  
Akhilesh Kumar ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mouse Model ◽  
Immune Responses ◽  
Therapeutic Potential ◽  
Innate Immune ◽  
Locked Nucleic Acid ◽  
Type I ◽  
Innate Immune Responses ◽  
Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

scholarly journals Swine Acute Diarrhea Syndrome Coronavirus Nucleocapsid Protein Antagonizes Interferon-β Production via Blocking the Interaction Between TRAF3 and TBK1

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhihai Zhou ◽  
Yuan Sun ◽  
Jingya Xu ◽  
Xiaoyu Tang ◽  
Ling Zhou ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Acute Diarrhea ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Type I ◽  
Innate Immune Responses ◽  
N Protein ◽  
Antiviral Innate Immunity ◽  
Diarrhea Syndrome

Swine acute diarrhea syndrome coronavirus (SADS-CoV), first discovered in 2017, is a porcine enteric coronavirus that can cause acute diarrhea syndrome (SADS) in piglets. Here, we studied the role of SADS-CoV nucleocapsid (N) protein in innate immunity. Our results showed that SADS-CoV N protein could inhibit type I interferon (IFN) production mediated by Sendai virus (Sev) and could block the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3). Simultaneously, the IFN-β promoter activity mediated by TANK binding kinase 1 (TBK1) or its upstream molecules in the RLRs signal pathway was inhibited by SADS-CoV N protein. Further investigations revealed that SADS-CoV N protein could counteract interaction between TNF receptor-associated factor 3 (TRAF3) and TBK1, which led to reduced TBK1 activation and IFN-β production. Our study is the first report of the interaction between SADS-CoV N protein and the host antiviral innate immune responses, and the mechanism utilized by SADS-CoV N protein provides a new insight of coronaviruses evading host antiviral innate immunity.

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 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 Innate Immune Priming by cGAS as a Preparatory Countermeasure Against RNA Virus Infection

2018 ◽  
Author(s):  
Michael T. Parker ◽  
Smita Gopinath ◽  
Corey E. Perez ◽  
Melissa M. Linehan ◽  
Jason M. Crawford ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Virus Infection ◽  
Immune Activation ◽  
Rna Viruses ◽  
Rna Virus ◽  
Gene Knockout ◽  
Innate Immune ◽  
Dna Sensing ◽  
Low Level ◽  
Innate Immune Activation

AbstractThe detection of nucleic acids by pattern recognition receptors is an ancient and conserved component of the innate immune system. Notably, RNA virus genomes are sensed by mammalian cytosolic RIG-I–like receptors, thereby activating interferon-stimulated gene (ISG) expression to restrict viral replication. However, recent evidence indicates that the cGAS-STING DNA sensing pathway also protects against RNA viruses. So far, the mechanisms responsible for DNA sensing of RNA viruses, which replicate without known DNA intermediates, remain unclear. By using cGAS gene knockout and reconstitution in human and mouse cell cultures, we discovered that DNA sensing and cGAMP synthase activities are required for cGAS-mediated restriction of vesicular stomatitis virus and Sindbis virus. The level of cGAMP produced in response to RNA virus infection was below the threshold of detection, suggesting that only transient and/or low levels of cGAMP are produced during RNA virus infections. To clarify the DNA ligands that activate cGAS activity, we confirmed that cGAS binds mitochondrial DNA in the cytosol of both uninfected and infected cells; however, the amount of cGAS-associated mitochondrial DNA did not change in response to virus infection. Rather, a variety of pre-existing cytosolic DNAs, including mitochondrial DNA and endogenous cDNAs, may serve as stimuli for basal cGAS activation. Importantly, cGAS knockout and reconstitution experiments demonstrated that cGAS drives low-level ISG expression at steady state. We propose that cGAS-STING restricts RNA viruses by promoting a preparatory immune activation state within cells, likely primed by endogenous cellular DNA ligands.ImportanceMany medically important RNA viruses are restricted by the cGAS-STING DNA-sensing pathway of innate immune activation. Since these viruses replicate without DNA intermediates, it is unclear what DNA ligand(s) are responsible for triggering this pathway. We show here that cGAS’s DNA binding and signaling activities are required for RNA virus restriction, similar to the mechanisms by which it restricts DNA viruses. Furthermore, we confirmed that cGAS continuously binds host DNA, which was unaffected by RNA virus infection. Finally, cGAS expression correlated with the low-level expression of interferon-stimulated genes in uninfected cells, bothin vitroandin vivo. We propose that cGAS-mediated sensing of endogenous DNA ligands contributes to RNA virus restriction by establishing a baseline of innate immune activation.

scholarly journals Caspase-dependent cleavage of DDX21 suppresses host innate immunity

2021 ◽  
Author(s):  
Chan Ding ◽  
Yingjie Sun ◽  
Wei Wu ◽  
Yang Qu ◽  
Shengqing Yu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Virus Infection ◽  
Ribosomal Rna ◽  
Potential Role ◽  
Rna Virus ◽  
Rna Helicases ◽  
Immune Balance ◽  
Ribosomal Rna Processing ◽  
Antiviral Innate Immunity

DEAD (Glu-Asp-Ala-Glu)-box RNA helicases have been proven to contribute to antiviral innate immunity. DDX21 RNA helicase was identified as a nuclear protein involved in ribosomal RNA processing and RNA unwinding. DDX21 was also proved to be the scaffold protein in the complex of DDX1-DDX21-DHX36 which senses double strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleave DDX21 at D126 and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the IFN-β signaling pathway by suppressing the formation of DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immunity response towards virus.

scholarly journals ANXA2 enhances virus replication through negatively regulating cGAS-STING and RLRs-mediated signal pathway

2021 ◽  
Author(s):  
Mengdi Xue ◽  
Hongyang Liu ◽  
Zhaoxia Zhang ◽  
Chunying Feng ◽  
Kunli Zhang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Virus Replication ◽  
Nuclear Translocation ◽  
Ectopic Expression ◽  
Innate Immune ◽  
Encephalomyocarditis Virus ◽  
Negative Regulator ◽  
Signal Pathways ◽  
Type I ◽  
Type I Ifn

AbstractHost nucleic acid receptors can recognize the viral DNA or RNA upon virus infection, which further triggers multiple signal pathways to promote the translocation of the interferon regulatory factor 3 (IRF3) into nucleus and produce type I interferon (IFN), leading to the host antiviral response. Here, we report a novel negative regulator Annexin A2 (ANXA2) that regulates type I IFN production through multiple mechanisms. Ectopic expression of ANXA2 inhibited the production of type I IFN induced by DNA- and RNA viruses and enhanced virus replication, while knockout of ANXA2 expression enhanced the production of type I IFN and inhibited virus replication. Mechanistically, ANXA2 not only disrupted MDA5 recruiting MAVS, but also inhibited the interaction between MAVS and TRAF3 upon RNA virus infection. In addition, ANXA2 impacted the translocation of STING from endoplasmic reticulum to Golgi apparatus upon DNA virus infection. Interestingly, ANXA2 also inhibited IRF3 phosphorylation and nuclear translocation through competing with TANK-binds kinase 1 (TBK1) and inhibitor-κB kinase ε (IKKε) for binding to IRF3. Anxa2 deficiency in vivo increased the production of type I IFN, which resulted in suppression of encephalomyocarditis virus (EMCV) replication. Our findings reveal that ANXA2, as a negative regulator of type I IFN production, plays an important role in regulating the host antiviral responses.Author summaryAnnexin is a family of evolutionarily conserved multi-gene proteins, which are widely distributed in various tissues and cells of plants and animals. These proteins can reversibly bind to phospholipid membranes and to calcium ions (Ca2+). To date, several studies have confirmed that some members of the Annexin family regulate the antiviral innate immune response. Until now, regulation of the production of type I IFN by ANXA2 is not reported. In this study, ANXA2 were found to strongly inhibit the production of type I IFN, leading to increased virus replication while knockout of ANXA2 expression inhibited virus replication by increasing the amount of IFN. Compared with wild-type littermates, ANXA2 deficiency mice produced more type I IFN to inhibit virus replication. Our results provide methanistic insights into the novel role of ANXA2 in the antiviral innate immune responses.

scholarly journals Cellular nucleic acid–binding protein is essential for type I interferon–mediated immunity to RNA virus infection

2021 ◽  
Vol 118 (26) ◽  
pp. e2100383118
Author(s):  
Yongzhi Chen ◽  
Xuqiu Lei ◽  
Zhaozhao Jiang ◽  
Katherine A. Fitzgerald
Keyword(s):  
Gene Expression ◽  
Nucleic Acid ◽  
Virus Infection ◽  
Rna Virus ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Nucleic Acid Binding ◽  
Nucleic Acid Binding Protein ◽  
Acid Binding Protein

Type I interferons (IFNs) are innate immune cytokines required to establish cellular host defense. Precise control of IFN gene expression is crucial to maintaining immune homeostasis. Here, we demonstrated that cellular nucleic acid–binding protein (CNBP) was required for the production of type I IFNs in response to RNA virus infection. CNBP deficiency markedly impaired IFN production in macrophages and dendritic cells that were infected with a panel of RNA viruses or stimulated with synthetic double-stranded RNA. Furthermore, CNBP-deficient mice were more susceptible to influenza virus infection than were wild-type mice. Mechanistically, CNBP was phosphorylated and translocated to the nucleus, where it directly binds to the promoter of IFNb in response to RNA virus infection. Furthermore, CNBP controlled the recruitment of IFN regulatory factor (IRF) 3 and IRF7 to IFN promoters for the maximal induction of IFNb gene expression. These studies reveal a previously unrecognized role for CNBP as a transcriptional regulator of type I IFN genes engaged downstream of RNA virus–mediated innate immune signaling, which provides an additional layer of control for IRF3- and IRF7-dependent type I IFN gene expression and the antiviral innate immune response.

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