SynopsisĮfficient activation of anti-microbial activity upon exposure to pathogens, while avoiding improper immune activation under homeostatic conditions, is one of the main functions of the innate immune system. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length-dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. This is observed over a wide length-span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Using low DNA concentrations, we show that dsDNA induces IFN in a length-dependent manner. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities.
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