scholarly journals MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1–IRF3 signaling axis

2016 ◽  
Vol 113 (50) ◽  
pp. 14390-14395 ◽  
Author(s):  
Minji Seo ◽  
Seong-Ok Lee ◽  
Ji-Hoon Kim ◽  
Yujin Hong ◽  
Seongchan Kim ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Upstream Regulator ◽  
Spatiotemporal Regulation ◽  
Signaling Axis ◽  
Dependent Transport ◽  
Irf3 Activation

The innate immune system detects viral nucleic acids and induces type I interferon (IFN) responses. The RNA- and DNA-sensing pathways converge on the protein kinase TANK-binding kinase 1 (TBK1) and the transcription factor IFN-regulatory factor 3 (IRF3). Activation of the IFN signaling pathway is known to trigger the redistribution of key signaling molecules to punctate perinuclear structures, but the mediators of this spatiotemporal regulation have yet to be defined. Here we identify butyrophilin 3A1 (BTN3A1) as a positive regulator of nucleic acid-mediated type I IFN signaling. Depletion of BTN3A1 inhibits the cytoplasmic nucleic acid- or virus-triggered activation of IFN-β production. In the resting state, BTN3A1 is constitutively associated with TBK1. Stimulation with nucleic acids induces the redistribution of the BTN3A1–TBK1 complex to the perinuclear region, where BTN3A1 mediates the interaction between TBK1 and IRF3, leading to the phosphorylation of IRF3. Furthermore, we show that microtubule-associated protein 4 (MAP4) controls the dynein-dependent transport of BTN3A1 in response to nucleic acid stimulation, thereby identifying MAP4 as an upstream regulator of BTN3A1. Thus, the depletion of either MAP4 or BTN3A1 impairs cytosolic DNA- or RNA-mediated type I IFN responses. Our findings demonstrate a critical role for MAP4 and BTN3A1 in the spatiotemporal regulation of TBK1, a central player in the intracellular nucleic acid-sensing pathways involved in antiviral signaling.

scholarly journals Cyclin-dependent kinase activity is required for type I interferon production

2018 ◽  
Vol 115 (13) ◽  
pp. E2950-E2959 ◽  
Author(s):  
Oya Cingöz ◽  
Stephen P. Goff
Keyword(s):  
Nucleic Acid ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Mrna Induction ◽  
Type I Ifns ◽  
Cellular Mrnas ◽  
Infection Inhibition ◽  
Culture Supernatants ◽  
Translational Block

Recognition of nucleic acids results in the production of type I IFNs, which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes. In a search for modulators of this pathway, we discovered an unexpected requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and IFN-stimulated gene expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-β mRNA induction, nor for the response to exogenous IFN-α/β, but are critical for IFN-β release into culture supernatants, suggesting a posttranscriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN-β, in which IFN-β mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-β.

scholarly journals Cyclin-Dependent Kinase Activity is Required for Type I Interferon Production

2017 ◽  
Author(s):  
Oya Cingöz ◽  
Stephen P. Goff
Keyword(s):  
Nucleic Acid ◽  
Critical Role ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Mrna Induction ◽  
Cellular Mrnas ◽  
Infection Inhibition ◽  
Culture Supernatants ◽  
Translational Block

AbstractRecognition of nucleic acids results in the production of type I interferons (IFN), which activate the JAK/STAT pathway and promote the expression of IFN-stimulated genes (ISG). In a search for modulators of this pathway, we discovered a previously unknown requirement for cyclin-dependent kinases (CDK) in the production of type I IFN following nucleic acid sensing and virus infection. Inhibition of CDK activity or knockdown of CDK levels leads to a striking block in STAT activation and ISG expression. CDKs are not required for the initial nucleic acid sensing leading to IFN-β mRNA induction, nor for the response to exogenous IFN-α/β, but are critical for IFN-β release into culture supernatants, suggesting a post-transcriptional role for CDKs in type I IFN production. In the absence of CDK activity, we demonstrate a translational block specific for IFN-β, in which IFN-β mRNA is removed from the actively translating polysomes, while the distribution of other cellular mRNAs or global translation rates are unaffected. Our findings reveal a critical role for CDKs in the translation of IFN-β.

scholarly journals Control of Herpes Simplex Virus Replication Is Mediated through an Interferon Regulatory Factor 3-Dependent Pathway

2009 ◽  
Vol 83 (23) ◽  
pp. 12399-12406 ◽  
Author(s):  
Vineet D. Menachery ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
Early Recognition ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The type I interferon (IFN) cascade is critical in controlling viral replication and pathogenesis. Recognition pathways triggered by viral infection rapidly induce the type I IFN cascade, often in an IFN regulatory factor 3 (IRF-3)-dependent fashion. This dependence predicts that loss of IRF-3 would render early recognition pathways inoperative and thereby impact virus replication, but this has not been observed previously with herpes simplex virus type 1 (HSV-1) in vitro. In this study, HSV-1-infected IRF-3−/− bone marrow-derived dendritic cells (BMDCs) and macrophages supported increased HSV replication compared to control cells. In addition, IRF-3-deficient BMDCs exhibited delayed type I IFN synthesis compared to control cells. However, while IFN pretreatment of IRF-3−/− BMDCs resulted in reduced virus titers, a far greater reduction was seen after IFN treatment of wild-type cells. This suggests that even in the presence of exogenously supplied IFN, IRF-3−/− BMDCs are inherently defective in the control of HSV-1 replication. Together, these results demonstrate a critical role for IRF-3-mediated pathways in controlling HSV-1 replication in cells of the murine immune system.

Role of the chaperone protein 14-3-3ε in the regulation of influenza A virus-activated beta interferon

2021 ◽  
Author(s):  
Ee-Hong Tam ◽  
Yen-Chin Liu ◽  
Chian-Huey Woung ◽  
Helene Minyi Liu ◽  
Guan-Hong Wu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Ns1 Protein ◽  
Chaperone Protein ◽  
Influenza A Virus Infection

The NS1 protein of the influenza A virus plays a critical role in regulating several biological processes in cells, including the type I interferon (IFN) response. We previously profiled the cellular factors that interact with the NS1 protein of influenza A virus and found that the NS1 protein interacts with proteins involved in RNA splicing/processing, cell cycle regulation, and protein targeting processes, including 14-3-3ε. Since 14-3-3ε plays an important role in RIG-I translocation to MAVS to activate type I IFN expression, the interaction of the NS1 and 14-3-3ε proteins may prevent the RIG-I-mediated IFN response. In this study, we confirmed that the 14-3-3ε protein interacts with the N-terminal domain of the NS1 protein and that the NS1 protein inhibits RIG-I-mediated IFN-β promoter activation in 14-3-3ε-overexpressing cells. In addition, our results showed that knocking down 14-3-3ε can reduce IFN-β expression elicited by influenza A virus and enhance viral replication. Furthermore, we found that threonine in the 49 th amino acid position of the NS1 protein plays a role in the interaction with 14-3-3ε. Influenza A virus expressing C-terminus-truncated NS1 with T49A mutation dramatically increases IFN-β mRNA in infected cells and causes slower replication than that of virus without the T-to-A mutation. Collectively, this study demonstrates that 14-3-3ε is involved in influenza A virus-initiated IFN-β expression and that the interaction of the NS1 protein and 14-3-3ε may be one of the mechanisms for inhibiting type I IFN activation during influenza A virus infection. IMPORTANCE Influenza A virus is an important human pathogen causing severe respiratory disease. The virus has evolved several strategies to dysregulate the innate immune response and facilitate its replication. We demonstrate that the NS1 protein of influenza A virus interacts with the cellular chaperone protein 14-3-3ε, which plays a critical role in RIG-I translocation that induces type I IFN expression, and that NS1 protein prevents RIG-I translocation to mitochondrial membrane. The interaction site for 14-3-3ε is the RNA-binding domain (RBD) of the NS1 protein. Therefore, this research elucidates a novel mechanism by which the NS1 RBD mediates IFN-β suppression to facilitate influenza A viral replication. Additionally, the findings reveal the antiviral role of 14-3-3ε during influenza A virus infection.

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

scholarly journals Cutting Edge: Critical Role of IκB Kinase α in TLR7/9-Induced Type I IFN Production by Conventional Dendritic Cells

2010 ◽  
Vol 184 (7) ◽  
pp. 3341-3345 ◽  
Author(s):  
Katsuaki Hoshino ◽  
Izumi Sasaki ◽  
Takahiro Sugiyama ◽  
Takahiro Yano ◽  
Chihiro Yamazaki ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Cutting Edge ◽  
Type I ◽  
Type I Ifn ◽  
Iκb Kinase

scholarly journals A Critical Role for Type I IFN in Arthritis Development followingBorrelia burgdorferiInfection of Mice

2008 ◽  
Vol 181 (12) ◽  
pp. 8492-8503 ◽  
Author(s):  
Jennifer C. Miller ◽  
Ying Ma ◽  
Jiantao Bian ◽  
Kathleen C. F. Sheehan ◽  
James F. Zachary ◽  
...  
Keyword(s):  
Critical Role ◽  
Type I ◽  
Type I Ifn

scholarly journals STAT1 maintains naïve CD8 + T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis

2021 ◽  
Vol 7 (36) ◽  
Author(s):  
Yoon-Chul Kye ◽  
Gil-Woo Lee ◽  
Sung-Woo Lee ◽  
Young-Jun Ju ◽  
Hee-Ok Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Mtorc1 Signaling ◽  
Cell Quiescence ◽  
Signaling Axis

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.

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