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 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 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 Neutrophils infected with highly virulent influenza H3N2 virus exhibit augmented early cell death and rapid induction of type I interferon signaling pathways

Genomics ◽  
2013 ◽  
Vol 101 (2) ◽  
pp. 101-112 ◽  
Author(s):  
Fransiskus X. Ivan ◽  
K.S. Tan ◽  
M.C. Phoon ◽  
Bevin P. Engelward ◽  
Roy E. Welsch ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathways ◽  
Type I Interferon ◽  
H3n2 Virus ◽  
Type I ◽  
Interferon Signaling ◽  
Rapid Induction ◽  
Influenza H3n2 ◽  
Highly Virulent

scholarly journals Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10

2006 ◽  
Vol 179 (1-2) ◽  
pp. 46-52 ◽  
Author(s):  
Todd Wuest ◽  
Bobbie Ann Austin ◽  
Satoshi Uematsu ◽  
Manoj Thapa ◽  
Shizuo Akira ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Signaling ◽  
Hsv 1

scholarly journals Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice

2020 ◽  
Author(s):  
Alexandra I. Wells ◽  
Kalena A. Grimes ◽  
Kenneth Kim ◽  
Emilie Branche ◽  
Christopher J. Bakkenist ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Neurological Complications ◽  
Host Factors ◽  
Type I ◽  
Interferon Signaling ◽  
Systemic Immune Response ◽  
Severe Hepatitis ◽  
Host Determinants ◽  
Type I Ifns

AbstractNeonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR−/−, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR−/− mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR−/− mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease.

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 A New In Vivo Model to Study Protective Immunity to Zika Virus Infection in Mice With Intact Type I Interferon Signaling

2018 ◽  
Vol 9 ◽  
Author(s):  
Loulieta Nazerai ◽  
Amalie Skak Schøller ◽  
Peter Overbeck Sharma Rasmussen ◽  
Søren Buus ◽  
Anette Stryhn ◽  
...  
Keyword(s):  
Virus Infection ◽  
Zika Virus ◽  
Protective Immunity ◽  
Type I Interferon ◽  
In Vivo Model ◽  
Type I ◽  
Interferon Signaling ◽  
Zika Virus Infection

scholarly journals Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice

2021 ◽  
Vol 17 (1) ◽  
pp. e1009252
Author(s):  
Alexandra I. Wells ◽  
Kalena A. Grimes ◽  
Kenneth Kim ◽  
Emilie Branche ◽  
Christopher J. Bakkenist ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Neurological Complications ◽  
Host Factors ◽  
Type I ◽  
Interferon Signaling ◽  
Systemic Immune Response ◽  
Severe Hepatitis ◽  
Host Determinants ◽  
Type I Ifns

Neonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR-/-, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR-/- mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR-/- mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease in humans.

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