期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：14390-14395
DOI：10.1073/pnas.1615287113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceType I IFN signaling is the most important innate immune response induced by viral infection. However, it is not completely known how the components of type I IFN signaling are spatiotemporally coordinated to elicit effective immune responses upon stimulation. We identified microtubule-associated protein 4 (MAP4) and butyrophilin 3A1 (BTN3A1) as novel regulators of the type I IFN signaling pathway triggered by cytosolic nucleic acids. In response to nucleic acid stimulation, BTN3A1-mediated transport of TANK-binding kinase 1 (TBK1) along microtubules facilitated the localization of TBK1 to IFN-regulatory factor 3 (IRF3) on punctate perinuclear structures, promoting IRF3 phosphorylation and IFN-{beta} secretion. BTN3A1 activity was controlled by an upstream regulator, MAP4. Our findings could be translated into a novel therapeutic approach to a broad spectrum of nucleic acid-mediated inflammatory and viral diseases. 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-{beta} 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.
关键词：BTN3A1 ; type I IFN signaling ; TBK1–IRF3 axis ; MAP4 ; dynein
