scholarly journals Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity

2021 ◽  
Vol 218 (3) ◽  
Author(s):  
Zheng-jun Gao ◽  
Wen-ping Li ◽  
Xin-tao Mao ◽  
Tao Huang ◽  
Hao-li Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Innate Immunity ◽  
Viral Infections ◽  
Critical Role ◽  
Endogenous Retrovirus ◽  
Type I ◽  
Single Nucleotide ◽  
Antiviral Immune Response ◽  
Genome Bisulfite Sequencing ◽  
Antiviral Innate Immunity

Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.

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 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.

The transmembrane serine protease hepsin suppresses type I interferon induction by cleaving STING

2021 ◽  
Vol 14 (687) ◽  
pp. eabb4752
Author(s):  
Fu Hsin ◽  
Yu-Chen Hsu ◽  
Yu-Fei Tsai ◽  
Shu-Wha Lin ◽  
Helene Minyi Liu
Keyword(s):  
Innate Immunity ◽  
Viral Infections ◽  
Ectopic Expression ◽  
Type I ◽  
Adapter Proteins ◽  
Type I Ifn ◽  
Chronic Viral Infections ◽  
Viral Proteases ◽  
Transmembrane Serine Protease ◽  
Antiviral Innate Immunity

Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection–induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNβ during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.

scholarly journals KAT8 selectively inhibits antiviral immunity by acetylating IRF3

2019 ◽  
Vol 216 (4) ◽  
pp. 772-785 ◽  
Author(s):  
Wanwan Huai ◽  
Xingguang Liu ◽  
Chunmei Wang ◽  
Yunkai Zhang ◽  
Xi Chen ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Transcriptional Activity ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Gene Promoters ◽  
Innate Immune Responses ◽  
Antiviral Immune Response ◽  
Lysine Acetyltransferase ◽  
Antiviral Innate Immunity

The transcription factor interferon regulatory factor 3 (IRF3) is essential for virus infection–triggered induction of type I interferons (IFN-I) and innate immune responses. IRF3 activity is tightly regulated by conventional posttranslational modifications (PTMs) such as phosphorylation and ubiquitination. Here, we identify an unconventional PTM of IRF3 that directly inhibits its transcriptional activity and attenuates antiviral immune response. We performed an RNA interference screen and found that lysine acetyltransferase 8 (KAT8), which is ubiquitously expressed in immune cells (particularly in macrophages), selectively inhibits RNA and DNA virus–triggered IFN-I production in macrophages and dendritic cells. KAT8 deficiency protects mice from viral challenge by enhancing IFN-I production. Mechanistically, KAT8 directly interacts with IRF3 and mediates IRF3 acetylation at lysine 359 via its MYST domain. KAT8 inhibits IRF3 recruitment to IFN-I gene promoters and decreases the transcriptional activity of IRF3. Our study reveals a critical role for KAT8 and IRF3 lysine acetylation in the suppression of antiviral innate immunity.

scholarly journals N6-Methyladenosine modification of hepatitis B and C viral RNAs attenuates host innate immunity via RIG-I signaling

2020 ◽  
Vol 295 (37) ◽  
pp. 13123-13133 ◽  
Author(s):  
Geon-Woo Kim ◽  
Hasan Imam ◽  
Mohsin Khan ◽  
Aleem Siddiqui
Keyword(s):  
Innate Immunity ◽  
Hepatitis B ◽  
Viral Infections ◽  
Type I ◽  
Rna Recognition ◽  
Single Nucleotide ◽  
Viral Rnas ◽  
Dual Functional ◽  
Nucleotide Mutation ◽  
Host Innate Immunity

N6-Methyladenosine (m6A), the methylation of the adenosine base at the nitrogen 6 position, is the most common epitranscriptomic modification of mRNA that affects a wide variety of biological functions. We have previously reported that hepatitis B viral RNAs are m6A-modified, displaying a dual functional role in the viral life cycle. Here, we show that cellular m6A machinery regulates host innate immunity against hepatitis B and C viral infections by inducing m6A modification of viral transcripts. The depletion of the m6A writer enzymes (METTL3 and METTL14) leads to an increase in viral RNA recognition by retinoic acid–inducible gene I (RIG-I), thereby stimulating type I interferon production. This is reversed in cells in which m6A METTL3 and METTL14 are overexpressed. The m6A modification of viral RNAs renders RIG-I signaling less effective, whereas single nucleotide mutation of m6A consensus motif of viral RNAs enhances RIG-I sensing activity. Importantly, m6A reader proteins (YTHDF2 and YTHDF3) inhibit RIG-I–transduced signaling activated by viral RNAs by occupying m6A-modified RNAs and inhibiting RIG-I recognition. Collectively, our results provide new insights into the mechanism of immune evasion via m6A modification of viral RNAs.

scholarly journals Evasion of Antiviral Innate Immunity by Porcine Reproductive and Respiratory Syndrome Virus

2021 ◽  
Vol 12 ◽  
Author(s):  
Tong-Yun Wang ◽  
Ming-Xia Sun ◽  
Hong-Liang Zhang ◽  
Gang Wang ◽  
Guoqing Zhan ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Viral Infections ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Swine Industry ◽  
Interferon Stimulated Genes ◽  
Β Receptor ◽  
Underlying Mechanisms ◽  
Antiviral Innate Immunity

Innate immunity is the front line for antiviral immune responses and bridges adaptive immunity against viral infections. However, various viruses have evolved many strategies to evade host innate immunity. A typical virus is the porcine reproductive and respiratory syndrome virus (PRRSV), one of the most globally devastating viruses threatening the swine industry worldwide. PRRSV engages several strategies to evade the porcine innate immune responses. This review focus on the underlying mechanisms employed by PRRSV to evade pattern recognition receptors signaling pathways, type I interferon (IFN-α/β) receptor (IFNAR)-JAK-STAT signaling pathway, and interferon-stimulated genes. Deciphering the antiviral immune evasion mechanisms by PRRSV will enhance our understanding of PRRSV’s pathogenesis and help us to develop more effective methods to control and eliminate PRRSV.

scholarly journals Untangling the roles of RNA helicases in antiviral innate immunity

2021 ◽  
Vol 17 (12) ◽  
pp. e1010072
Author(s):  
Morgane Baldaccini ◽  
Sébastien Pfeffer
Keyword(s):  
Innate Immunity ◽  
Viral Infections ◽  
Current Knowledge ◽  
Rnai Pathway ◽  
Special Focus ◽  
Type I ◽  
Small Interfering Rnas ◽  
Rna Helicases ◽  
Viral Dsrna ◽  
Antiviral Innate Immunity

One of the first layers of protection that metazoans put in place to defend themselves against viruses rely on the use of proteins containing DExD/H-box helicase domains. These members of the duplex RNA–activated ATPase (DRA) family act as sensors of double-stranded RNA (dsRNA) molecules, a universal marker of viral infections. DRAs can be classified into 2 subgroups based on their mode of action: They can either act directly on the dsRNA, or they can trigger a signaling cascade. In the first group, the type III ribonuclease Dicer plays a key role to activate the antiviral RNA interference (RNAi) pathway by cleaving the viral dsRNA into small interfering RNAs (siRNAs). This represents the main innate antiviral immune mechanism in arthropods and nematodes. Even though Dicer is present and functional in mammals, the second group of DRAs, containing the RIG-I-like RNA helicases, appears to have functionally replaced RNAi and activate type I interferon (IFN) response upon dsRNA sensing. However, recent findings tend to blur the frontier between these 2 mechanisms, thereby highlighting the crucial and diverse roles played by RNA helicases in antiviral innate immunity. Here, we will review our current knowledge of the importance of these key proteins in viral infection, with a special focus on the interplay between the 2 main types of response that are activated by dsRNA.

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 Endogenous Retrovirus-Derived lnc-ALVE1-AS1 Exerts Antiviral Defense Against ALV-J Infection in Chicken Macrophages

2021 ◽  
Author(s):  
Huan Luo ◽  
Xuming Hu ◽  
Huixian Wu ◽  
Gul Zaib ◽  
Wenxian Chai ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Defense ◽  
Antiviral Innate Immunity ◽  
Retroviral Infections ◽  
Avian Leukosis Virus Subgroup ◽  
Chicken Embryo Fibroblasts

Abstract Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections dating back many millions of years, and their derived transcripts with viral signatures are important sources of long noncoding RNAs (lncRNAs). We have previously shown that the chicken ERV-derived lncRNA lnc-ALVE1-AS1 exerts antiviral innate immunity in chicken embryo fibroblasts. However, it is not clear whether this endogenous retroviral RNA has a similar function in immune cells. Here, we found that lnc-ALVE1-AS1 was persistently inhibited in chicken macrophages after avian leukosis virus subgroup J (ALV-J) infection. Furthermore, overexpression of lnc-ALVE1-AS1 significantly inhibited the proliferation of exogenous ALV-J, whereas knockdown of lnc-ALVE1-AS1 promoted the proliferation of ALV-J in chicken macrophages. This phenomenon is attributed to the induction of antiviral innate immunity by lnc-ALVE1-AS1 in macrophages, whereas knockdown of lnc-ALVE1-AS1 had the opposite effect. Mechanistically, lnc-ALVE1-AS1 can be sensed by the cytosolic pattern recognition receptor TLR3 and trigger the type I interferons response. The present study provides novel insights into the antiviral defense of ERV-derived lncRNAs in macrophages and offers new strategies for future antiviral solutions.

scholarly journals The methyltransferase NSD3 promotes antiviral innate immunity via direct lysine methylation of IRF3

2017 ◽  
Vol 214 (12) ◽  
pp. 3597-3610 ◽  
Author(s):  
Chunmei Wang ◽  
Qinlan Wang ◽  
Xiaoqing Xu ◽  
Bin Xie ◽  
Yong Zhao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Critical Role ◽  
Mass Spectrometry Analysis ◽  
Type I ◽  
Lysine Methylation ◽  
Set Domain ◽  
Transcription Activity ◽  
Domain 3 ◽  
Antiviral Innate Immunity

Lysine methylation is an important posttranslational modification, implicated in various biological pathological conditions. The transcription factor interferon regulatory factor 3 (IRF3) is essential for antiviral innate immunity, yet the mechanism for methylation control of IRF3 activation remains unclear. In this paper, we discovered monomethylation of IRF3 at K366 is critical for IRF3 transcription activity in antiviral innate immunity. By mass spectrometry analysis of IRF3-associated proteins, we identified nuclear receptor–binding SET domain 3 (NSD3) as the lysine methyltransferase that directly binds to the IRF3 C-terminal region through its PWWP1 domain and methylates IRF3 at K366 via its SET domain. Deficiency of NSD3 impairs the antiviral innate immune response in vivo. Mechanistically, NSD3 enhances the transcription activity of IRF3 dependent on K366 monomethylation, which maintains IRF3 phosphorylation by promoting IRF3 dissociation of protein phosphatase PP1cc and consequently promotes type I interferon production. Our study reveals a critical role of NSD3-mediated IRF3 methylation in enhancing antiviral innate immunity.

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