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Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
11:44

Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo

Published on: September 18, 2014

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

Takeshi Kondo1, Junya Kobayashi, Tatsuya Saitoh

  • 1Laboratory of Host Defense, World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|February 8, 2013
PubMed

Insights

The meiotic recombination 11 homolog A (MRE11) protein acts as a cytosolic sensor for double-stranded DNA (dsDNA), initiating innate immune responses. The MRE11-RAD50 complex is crucial for dsDNA recognition and STING-dependent signaling.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • Intracellular double-stranded DNA (dsDNA) triggers innate immunity, but its primary recognition machinery remains unclear.
  • The DNA damage sensor meiotic recombination 11 homolog A (MRE11) is implicated in cellular responses.
  • Understanding dsDNA sensing is critical for innate immunity research.

Purpose of the Study:

  • To identify the primary sensor for cytosolic double-stranded DNA (dsDNA).
  • To elucidate the role of MRE11 in dsDNA-induced innate immune signaling.
  • To investigate the involvement of MRE11-associated proteins in dsDNA recognition.

Main Methods:

  • Utilized patient-derived cells with MRE11 mutations and MRE11 knockdown models.
  • Performed co-immunoprecipitation to assess MRE11-dsDNA interactions.
  • Analyzed the activation of STING (stimulator of IFN genes) and IRF3 (interferon regulatory factor 3) pathways.

Main Results:

  • Cells with MRE11 defects showed impaired dsDNA-induced type I interferon production.
  • MRE11 directly binds to dsDNA in the cytoplasm.
  • MRE11 is essential for STING and IRF3 activation, while RAD50 is required, but NBS1 is not.

Conclusions:

  • MRE11 functions as a cytosolic dsDNA sensor, initiating innate immune responses.
  • The MRE11-RAD50 complex plays a key role in dsDNA recognition and STING-mediated signaling.
  • This finding expands the known functions of MRE11 beyond DNA damage repair.

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