title: STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway.
abstract: Cytosolic double-stranded DNA (dsDNA) stimulates the production of type I interferon (IFN) through the endoplasmic reticulum (ER)-resident adaptor protein STING (stimulator of IFN genes), which activates the transcription factor interferon regulatory factor 3 (IRF3); however, how STING activates IRF3 is unclear. Here, we showed that STING stimulates phosphorylation of IRF3 by the kinase TBK1 (TANK-binding kinase 1) in an in vitro reconstitution system. With this system, we identified a carboxyl-terminal region of STING that was both necessary and sufficient to activate TBK1 and stimulate the phosphorylation of IRF3. We also found that STING interacted with both TBK1 and IRF3 and that mutations in STING that selectively disrupted its binding to IRF3 abrogated phosphorylation of IRF3 without impairing the activation of TBK1. These results suggest that STING functions as a scaffold protein to specify and promote the phosphorylation of IRF3 by TBK1. This scaffolding function of STING (and possibly of other adaptor proteins) may explain why IRF3 is activated in only a subset of signaling pathways that activate TBK1.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000099197:STING Protein
chemical_list: D004247:DNA; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human