title: DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking.
abstract: Double-stranded DNA (dsDNA) derived from pathogen- or host-damaged cells triggers innate immune responses when exposed to cytoplasm. However, the machinery underlying the primary recognition of intracellular dsDNA is obscure. Here we show that the DNA damage sensor, meiotic recombination 11 homolog A (MRE11), serves as a cytosolic sensor for dsDNA. Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia-like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production. MRE11 physically interacted with dsDNA in the cytoplasm and was required for activation of stimulator of IFN genes (STING) and IRF3. RAD50, a binding protein to MRE11, was also required for dsDNA responses, whereas NBS1, another binding protein to MRE11, was dispensable. Collectively, our results suggest that the MRE11-RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage responses.
authors: Laboratory of Host Defense, World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors: Takeshi
authors: T
authors: Kondo
authors: Junya
authors: J
authors: Kobayashi
authors: Tatsuya
authors: T
authors: Saitoh
authors: Kenta
authors: K
authors: Maruyama
authors: Ken J
authors: KJ
authors: Ishii
authors: Glen N
authors: GN
authors: Barber
authors: Kenshi
authors: K
authors: Komatsu
authors: Shizuo
authors: S
authors: Akira
authors: Taro
authors: T
authors: Kawai
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000096:biosynthesis*; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000099197:STING Protein
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D000076228:MRE11 Homologue Protein; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C512689:Mre11a protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C576325:Atm protein, mouse
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