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      Study on the regulation of the type 1 interferon signaling mediated by viral nucleic acids

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      https://www.riss.kr/link?id=T14508369

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      다국어 초록 (Multilingual Abstract)

      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 microtubuleassociated
      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.
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      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 (IRF...

      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 microtubuleassociated
      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.

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      목차 (Table of Contents)

      • INTRODUCTION 1
      • 1. Type I IFN signaling 1
      • 2. Butyrophilin (BTN) family 5
      • 3. Microtubule associated proteins and motor proteins 9
      • RESULTS 10
      • INTRODUCTION 1
      • 1. Type I IFN signaling 1
      • 2. Butyrophilin (BTN) family 5
      • 3. Microtubule associated proteins and motor proteins 9
      • RESULTS 10
      • 1. Identification and characterization of BTN3A1 as a novel regulator of type I IFN responses 10
      • 2. BTN3A1 regulates the phosphorylation of IRF3 30
      • 3. BTN3A1 directs the interaction of TBK1 with IRF3 56
      • 4. Microtubule-dependent transport of BTN3A1 to the perinuclear region 72
      • 5. MAP4 is essential for type I IFN signaling by controlling the trafficking of BTN3A1 82
      • 6. BTN3A1 interacts with dynein for trafficking to the perinuclear region 102
      • DISCUSSION 108
      • EXPERIMENTAL PROCEDURES 111
      • REFERENCES 119
      • ABSTRACT IN KOREAN 125
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