title: MAP4-regulated dynein-dependent trafficking of BTN3A1 controls the TBK1-IRF3 signaling axis.
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 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.
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.|School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Seo
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.|School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Seong-Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.|School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.|Department of Chemistry, Seoul National University, Seoul 08826, Korea.
authors.forename: Seongchan
authors.initials: S
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Yeumin
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea.|Department of Chemistry, Seoul National University, Seoul 08826, Korea.
authors.forename: Dal-Hee
authors.initials: DH
authors.lastname: Min
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.affiliation: Department of Microbiology, Inha University College of Medicine, Incheon 22212, Korea.
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.affiliation: Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea; ksahn@snu.ac.kr.|School of Biological Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Kwangseog
authors.initials: K
authors.lastname: Ahn
mesh_terms: D021581:Active Transport, Cell Nucleus; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000071797:Butyrophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004279:DNA, Viral / Q000276:immunology; D004398:Dyneins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000276:immunology; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D004279:DNA, Viral; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; C000601103:MAP4 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D012367:RNA, Viral; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D004398:Dyneins
keywords: BTN3A1; MAP4; TBK1–IRF3 axis; dynein; type I IFN signaling