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DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Feb 19; Vol. 110 (8), pp. 2969-74. Date of Electronic Publication: 2013 Feb 06. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins metabolism
Cells, Cultured
DNA Repair Enzymes genetics
DNA-Binding Proteins genetics
MRE11 Homologue Protein
Mice
Mutation
Phosphorylation
Protein Serine-Threonine Kinases metabolism
Protein Transport
Tumor Suppressor Proteins metabolism
Cytosol metabolism
DNA metabolism
DNA Damage
DNA Repair Enzymes metabolism
DNA-Binding Proteins metabolism
Interferon Type I biosynthesis
Membrane Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23388631
- Full Text :
- https://doi.org/10.1073/pnas.1222694110