DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity

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.

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…cGAMP in turn binds to STING stimulating its transit from the endoplasmic-reticulum to perinuclear endosomes where it triggers IRF3 activation via TBK1. 30,31 Of note, STING-dependent Type-I-IFN production can also be activated by singlestranded DNA resulting from DNA damage or replication stress, 32 by mitochondrial DNA released following apoptotic mitochondrial outer membrane permeabilization 33 and possibly by retroelements not properly metabolized by the three prime repair exonuclease (TREX)1. 34 Two essential mediators of distinct DNA-activated innate responses seem to be the PYHIN proteins absent in melanoma (AIM)2 and IFN-g-inducible (IFI)16.…”

Mitotic progression following DNA damage enables pattern recognition within micronuclei

“…These findings firmly establish a significant relationship between the presence of micronuclei and inflammatory signaling. We cannot ascribe the inflammatory response solely to micronuclei as small DNA fragments in the cytoplasm could also contribute to cGAS-STING activation 10, 21 . However, our data show robust relocalization of cGAS to the micronucleus and activation of inflammatory responses within these micronucleated cells.…”

When our genome is targeted by pathogenic bacteria

“…In addition, cytoplasmic self-DNA release is detected in AT patients and ATM -/-mice, likely reflecting, at least in part, the spontaneous systemic inflammation present in AT patients [80].…”

“…Unrepaired DNA damage constitutively present in ATM -/-mice or induced DNA damage in ATM +/+ mice primes type 1 IFN responses, which, similar to Mre11 and DNA-PK, are mediated through the cytoplasmic DNA receptor STING [80]. In addition, cytoplasmic self-DNA release is detected in AT patients and ATM -/-mice, likely reflecting, at least in part, the spontaneous systemic inflammation present in AT patients [80].…”

“…DNA-PK binds cytoplasmic DNA, triggering the transcription of IFN, cytokine and chemokine genes through the STING pathway [79]. Concerning ATM, Härtlova and co-workers have established that ATM-/-mice or AT patients (patients owing a deficient ATM protein) show the spontaneous elevation of IFN levels, which primes cells for amplified antiviral and antibacterial responses [80]. Moreover, IL1β production is also evidenced upon L. monocytogenes infection in this ATM-deficient environment.…”