DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type i interferon by regulating STING trafficking

Takeshi Kondo, Junya Kobayashi, Tatsuya Saitoh, Kenta Maruyama, Ken J. Ishii, Glen N Barber, Kenshi Komatsu, Shizuo Akira, Taro Kawai

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Double-stranded DNA (dsDNA) derived from pathogen-or hostdamaged cells triggers innate immune responses when exposed to cytoplasm. However, the machinery underlying the primary recognition of intracellular dsDNA is obscure. Here we showthat 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 inwhichMre11was knockeddown, 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 theMRE11-RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage responses.

Original languageEnglish
Pages (from-to)2969-2974
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
StatePublished - Feb 19 2013

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Interferons
Genetic Recombination
DNA
Genes
Carrier Proteins
Cytoplasm
Innate Immunity
Mutation

Keywords

  • Innate immunity
  • Pattern recognition receptor
  • Signal transduction

ASJC Scopus subject areas

  • General

Cite this

DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type i interferon by regulating STING trafficking. / Kondo, Takeshi; Kobayashi, Junya; Saitoh, Tatsuya; Maruyama, Kenta; Ishii, Ken J.; Barber, Glen N; Komatsu, Kenshi; Akira, Shizuo; Kawai, Taro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 8, 19.02.2013, p. 2969-2974.

Research output: Contribution to journalArticle

Kondo, Takeshi ; Kobayashi, Junya ; Saitoh, Tatsuya ; Maruyama, Kenta ; Ishii, Ken J. ; Barber, Glen N ; Komatsu, Kenshi ; Akira, Shizuo ; Kawai, Taro. / DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type i interferon by regulating STING trafficking. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 8. pp. 2969-2974.
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