Immunity
Volume 42, Issue 2, 17 February 2015, Pages 332-343
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Article
DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity

https://doi.org/10.1016/j.immuni.2015.01.012Get rights and content
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Highlights

  • The DNA repair kinase ATM restrains spontaneous type I IFNs in humans and mice

  • ATM defects prime the type I IFN system for robust anti-microbial host responses

  • DNA damage primes the type I IFN system for robust anti-microbial responses via STING

  • DNA accumulates in cytoplasm upon DNA damage, thereby activating the STING pathway

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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