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.

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.

scholarly journals SOCS3 Drives Proteasomal Degradation of TBK1 and Negatively Regulates Antiviral Innate Immunity

2015 ◽  
Vol 35 (14) ◽  
pp. 2400-2413 ◽  
Author(s):  
Dong Liu ◽  
Chunjie Sheng ◽  
Shijuan Gao ◽  
Chen Yao ◽  
Jiandong Li ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Influenza A ◽  
Critical Role ◽  
Antiviral Agents ◽  
Ectopic Expression ◽  
Proteasomal Degradation ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Type I ◽  
Antiviral Innate Immunity

TANK-binding kinase 1 (TBK1)-mediated induction of type I interferon (IFN) plays a critical role in host antiviral responses and immune homeostasis. The negative regulation of TBK1 activity is largely unknown. We report that suppressor of cytokine signaling 3 (SOCS3) inhibits the IFN-β signaling pathway by promoting proteasomal degradation of TBK1. Overexpression and knockdown experiments indicated that SOCS3 is a negative regulator of IFN regulatory factor 3 (IRF3) phosphorylation and IFN-β transcription. Moreover, SOCS3 directly associates with TBK1, and they colocalize in the cytoplasm. SOCS3 catalyzes K48-linked polyubiquitination of TBK1 at Lys341 and Lys344 and promotes subsequent TBK1 degradation. On the contrary, SOCS3 knockdown markedly increases the abundance of TBK1. Interestingly, both the BOX domain of SOCS3 and Ser172 phosphorylation of TBK1 are indispensable for the processes of ubiquitination and degradation. Ectopic expression of SOCS3 significantly inhibits vesicular stomatitis virus (VSV) and influenza A virus strain A/WSN/33 (WSN)-induced IRF3 phosphorylation and facilitates the replication of WSN virus by detecting the transcription of its viral RNA (vRNA). Knockdown of SOCS3 represses WSN replication. Collectively, these results demonstrate that SOCS3 acts as a negative regulator of IFN-β signal by ubiquitinating and degrading TBK1, shed light on the understanding of antiviral innate immunity, and provide a potential target for developing antiviral agents.

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 E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peng Gao ◽  
Xianwei Ma ◽  
Ming Yuan ◽  
Yulan Yi ◽  
Guoke Liu ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Type I Interferon ◽  
Zinc Fingers ◽  
E3 Ligase ◽  
Type I ◽  
E3 Ligases ◽  
Protein Posttranslational Modifications ◽  
Antiviral Innate Immunity

AbstractUbiquitination is one of the most prevalent protein posttranslational modifications. Here, we show that E3 ligase Nedd4l positively regulates antiviral immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Deficiency of Nedd4l significantly impairs type I interferon and proinflammatory cytokine production induced by virus infection both in vitro and in vivo. Nedd4l deficiency inhibits virus-induced ubiquitination of TRAF3, the binding between TRAF3 and TBK1, and subsequent phosphorylation of TBK1 and IRF3. Nedd4l directly interacts with TRAF3 and catalyzes K29-linked ubiquitination of Cys56 and Cys124, two cysteines that constitute zinc fingers, resulting in enhanced association between TRAF3 and E3 ligases, cIAP1/2 and HECTD3, and also increased K48/K63-linked ubiquitination of TRAF3. Mutation of Cys56 and Cys124 diminishes Nedd4l-catalyzed K29-linked ubiquitination, but enhances association between TRAF3 and the E3 ligases, supporting Nedd4l promotes type I interferon production in response to virus by catalyzing ubiquitination of the cysteines in TRAF3.

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.

Chicken miR-126-5p Negatively Regulates Antiviral Innate Immunity By Targeting TRAF3

2021 ◽  
Author(s):  
Jie Wang ◽  
Yuqiang Cheng ◽  
Longlong Wang ◽  
Zhenyu Lin ◽  
Wenxian Zhu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cell Model ◽  
Rna Virus ◽  
Luciferase Reporter ◽  
Endogenous Expression ◽  
Immune Balance ◽  
Candidate Target ◽  
Candidate Target Gene ◽  
Antiviral Innate Immunity

Abstract Background Innate immunity plays an essential role in preventing the invasion of pathogenic microorganisms. However, innate immunity is a double-edged sword, whose excessively activated is detrimental to immune homeostasis and even leads to "cytokine storm" of the infected host. A series of negative regulatory mechanisms are developed by the host to balance the immune response. Here, we report a negative regulatory mechanism of chicken innate immunity mediated by miRNA. Results In this study we found that the miR-126-5p is markedly up-regulated in RNA virus infected chickens in GEO database. Then, the upregulation of the miR-126-5p by RNA virus was further verified via both cell model and in vivo test. Overexpression of miR-126-5p significantly inhibits the expression of interferon related genes and inflammatory cytokines evoked by RNA virus. The opposite result was achieved after knocking down miR-126-5p expression. Bioinformatics analysis indicated TRAF3 as the candidate target gene of miR-126-5p, and experimental evidence, such as the effects of miR-126-5p on the endogenous expression of TRAF3, and the effect of miR-126-5p on TRAF3 3'UTR drove luciferase reporter assay, were provided to further verify that miR-126-5p targets TRAF3. Furthermore, we demonstrated that miR-126-5p negatively regulates innate immunity by blocking the MAVS-TRAF3-TBK1 axis, with co-expression assay. Conclusion Our results suggest that miR-126-5p is involved in the negative regulation of the chicken innate immunity, which might contribute to maintaining immune balance.

scholarly journals Thioredoxin 2 Negatively Regulates Innate Immunity to RNA Viruses by Disrupting the Assembly of the Virus-Induced Signaling Adaptor Complex

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Dan Li ◽  
Wenping Yang ◽  
Yi Ru ◽  
Jingjing Ren ◽  
Xiangtao Liu ◽  
...  
Keyword(s):  
Complex Formation ◽  
Rna Viruses ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Host Proteins ◽  
Innate Antiviral Response ◽  
Thioredoxin 2

ABSTRACT The virus-induced signaling adaptor (VISA) complex plays a critical role in the innate immune response to RNA viruses. However, the mechanism of VISA complex formation remains unclear. Here, we demonstrate that thioredoxin 2 (TRX2) interacts with VISA at mitochondria both in vivo and in vitro. Knockdown and knockout of TRX2 enhanced the formation of the VISA-associated complex, as well as virus-triggered activation of interferon regulatory factor 3 (IRF3) and transcription of the interferon beta 1 (IFNB1) gene. TRX2 inhibits the formation of VISA aggregates by repressing reactive oxygen species (ROS) production, thereby disrupting the assembly of the VISA complex. Furthermore, our data suggest that the C93 residue of TRX2 is essential for inhibition of VISA aggregation, whereas the C283 residue of VISA is required for VISA aggregation. Collectively, these findings uncover a novel mechanism of TRX2 that negatively regulates VISA complex formation. IMPORTANCE The VISA-associated complex plays pivotal roles in inducing type I interferons (IFNs) and eliciting the innate antiviral response. Many host proteins are identified as VISA-associated-complex proteins, but how VISA complex formation is regulated by host proteins remains enigmatic. We identified the TRX2 protein as an important regulator of VISA complex formation. Knockout of TRX2 increases virus- or poly(I·C)-triggered induction of type I IFNs at the VISA level. Mechanistically, TRX2 inhibits the production of ROS at its C93 site, which impairs VISA aggregates at its C283 site, and subsequently impedes the assembly of the VISA complex. Our findings suggest that TRX2 plays an important role in the regulation of VISA complex assembly.

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