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Immunity. 2015 Feb 17;42(2):332-343. doi: 10.1016/j.immuni.2015.01.012.

DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.

Author information

1
Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden.
2
Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
3
Sahlgrenska Cancer Center, University of Gothenburg, 41390 Gothenburg, Sweden.
4
Department of Paediatrics, Hospital of Halland, 30185 Halmstad, Sweden.
5
Laboratory for Molecular Infection Medicine Sweden, Umeå University, 90 187 Umeå, Sweden; Department of Molecular Biology, Umeå University, 90 187 Umeå, Sweden; Umeå Centre for Microbial Research, Umeå University, 90 187 Umeå, Sweden. Electronic address: nelson.gekara@mims.umu.se.

Abstract

Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

PMID:
25692705
DOI:
10.1016/j.immuni.2015.01.012
[Indexed for MEDLINE]
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