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

A Härtlova, SF Erttmann, FAM Raffi, AM Schmalz… - Immunity, 2015 - cell.com
A Härtlova, SF Erttmann, FAM Raffi, AM Schmalz, U Resch, S Anugula, S Lienenklaus…
Immunity, 2015cell.com
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 …
Summary
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.
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