Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

Khan, Kashif Aziz; Dô, Florence; Marineau, Alexandre; Doyon, Priscilla; Clément, Jean‐François; Woodgett, James R.; Doble, Bradley W.; Servant, Marc J.

doi:10.1128/mcb.00344-15

Cited by 27 publications

(26 citation statements)

References 86 publications

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“…Since the transcriptional factor IRF3 is a pivotal molecule to facilitate the induction of IFN-β in RLR pathway [19]. Consistently, over-expression of ZWINT markedly increases the abundance of Sendai virus-triggered IRF3 dimerization ( Figure 2E).…”

Section: Zwint Not Only Enhances Sendai Virus-induced But Also Enhancsupporting

confidence: 57%

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

Li¹,

Xu²,

He³

et al. 2018

biomedicalresearch

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TANK-BindingKinase 1 (TBK1) is a serine/threonine kinase ubiquitously expressed in many tissues and plays an important role in the RLR antiviral signaling pathway. Upon viral infection, various virus components, including viral DNA, RNA are sensed by different pattern recognition receptors (PRRs). Among these PRRs, TLR3, RIG-I/MDA5, and cGAS recruit different adaptors including TRIF, VISA/ MAVS, and MITA/STING to activate TBK1. Activated TBK1 then promote the phosphorylation and homodimerization of IFN-regulatory factors 3 and 7 (IRF3/7), in turn promoting type-I Interferon (IFN-I) production. In this study, we reported that ZW10 Interacting Kinetochore Protein (ZWINT) positively regulates RLR antiviral signaling by targeting RIG-I/VISA/TBK1. Ectopic expression of ZWINT potentiated Sendai virus-induced, as well as TBK1-or VISA/MAVS-mediated IFN-β promoter activation by enhancing dimerization of IRF3. In contrast, knocking down of ZWINT expression with siRNA resulted in reduced IFN-β promoter activation and IRF3 dimerization induced by Sendai virus, indicating that ZWINT positively regulates TBK1-mediated RLR antiviral signaling.

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Section: Zwint Not Only Enhances Sendai Virus-induced But Also Enhancsupporting

confidence: 57%

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

Li¹,

Xu²,

He³

et al. 2018

biomedicalresearch

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“…GSK3B has been shown before to be an important player in IAV entry (53). Recently, it was shown that GSK3B activation is needed for the expression of IRF3-regulated IFN-stimulated genes (54). The KEA analysis results included substrates of several members of the MAPK family (p38␣, JNK2, ERK1, JNK1, ERK2, MAPKAPK5, MAPK10, MAPK11, and MAPK13) as highly enriched after infection.…”

Section: Phosphoproteomic Analysis Of Influenza Infectionmentioning

confidence: 99%

Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages

Söderholm

Kainov

Öhman

et al. 2016

Molecular & Cellular Proteomics

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Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase- signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin-dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections.

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“…In support of this, we showed that the deletion of the phosphodegron motif of β-catenin decreases the DNA binding activity of IRF3 and the antiviral innate immune response following SeV and VSV infections. The phosphorylation of glycogen synthase at Ser641 following SeV infection and the increase in the phosphotransferase activity of GSK-3 observed through immunocomplex in vitro kinase assays have been additional observations demonstrating an increase in the catalytic activity of GSK-3 towards its substrates [74]. Interestingly, in addition to SeV and VSV, the activation of GSK-3 has previously been reported during infection with coxsackievirus, an RNA virus [103], as well as in response to the HIV-1 Tat protein [104].…”

Section: Cytosolic Rna Sensorsmentioning

confidence: 88%

“…Due to the paucity of these studies, the working models have sometimes been in contradiction. However, pictures are emerging where (1) GSK-3 operates at the level of β-catenin [74] and/or TBK1 [75,76]; and (2) β-catenin acts via the classical holocomplex formed by IRF3 and CBP/p300 [74,[77][78][79][80][81] or TCF [82] to regulate the production of type I IFNs (Figure 3). receptor-associated factors (TRAFs) to polymerized MAVS results in the activation of the constitutively expressed protein kinase TANK-binding kinase 1 (TBK1) and its inducible homologue IKKi (or IKKε).…”

Section: Cytosolic Rna Sensorsmentioning

confidence: 99%

“…Nevertheless, the GSK-3-modified version of β-catenin would be required for an optimal antiviral immune response. In fact, upon SeV infection, we recently documented the presence of the "inactive" GSK-3 phosphorylated form of β-catenin within the IFIT1 promoter in association with the IRF3 holocomplex in primary, immortalized, and transformed cell lines [74], arguing that the phosphotransferase activity of GSK-3 is required for an optimal type I IFN antiviral response. In support of this, we showed that the deletion of the phosphodegron motif of β-catenin decreases the DNA binding activity of IRF3 and the antiviral innate immune response following SeV and VSV infections.…”

Section: Cytosolic Rna Sensorsmentioning

confidence: 99%

See 1 more Smart Citation

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

Marineau

Khan

Servant

2020

Cells

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The rapid activation of the type I interferon (IFN) antiviral innate immune response relies on ubiquitously expressed RNA and DNA sensors. Once engaged, these nucleotide-sensing receptors use distinct signaling modules for the rapid and robust activation of mitogen-activated protein kinases (MAPKs), the IκB kinase (IKK) complex, and the IKK-related kinases IKKε and TANK-binding kinase 1 (TBK1), leading to the subsequent activation of the activator protein 1 (AP1), nuclear factor-kappa B (NF-κB), and IFN regulatory factor 3 (IRF3) transcription factors, respectively. They, in turn, induce immunomodulatory genes, allowing for a rapid antiviral cellular response. Unlike the MAPKs, the IKK complex and the IKK-related kinases, ubiquitously expressed glycogen synthase kinase 3 (GSK-3) α and β isoforms are active in unstimulated resting cells and are involved in the constitutive turnover of β-catenin, a transcriptional coactivator involved in cell proliferation, differentiation, and lineage commitment. Interestingly, studies have demonstrated the regulatory roles of both GSK-3 and β-catenin in type I IFN antiviral innate immune response, particularly affecting the activation of IRF3. In this review, we summarize current knowledge on the mechanisms by which GSK-3 and β-catenin control the antiviral innate immune response to RNA and DNA virus infections.

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Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

Cited by 27 publications

References 86 publications

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

ZWINT positively regulates TBK1-mediated RLR antiviral signaling

Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages

Roles of GSK-3 and β-Catenin in Antiviral Innate Immune Sensing of Nucleic Acids

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