Innate immune recognition of DNA: A recent history

Abstract

Innate immune DNA sensing underpins many physiological and pathological responses to DNA, including anti-viral immunity to DNA viruses. Although it has been appreciated for many years that cytosolic DNA can evoke a type I interferon response, it is only within the past decade that the cellular mechanisms responsible for such a response have been defined. Here we review the discoveries that led to an appreciation of the existence of cytosolic DNA sensor proteins, and discuss two key such sensors, cGAS and IFI16, in detail. DNA sensors operate via STING, a protein shown to have a central role in controlling altered gene induction in response to DNA in vivo, and as such to be central to a rapidly expanding list of both protective and harmful responses to DNA. We also discuss recent insights into how and when DNA stimulates innate immunity, and highlight current outstanding questions in the DNA sensing field.

Keywords: DNA sensing; Gene induction; Herpes viruses; Innate immunity; Pattern recognition receptors.

Figure 1. Timeline for discovery of putative cytosolic DNA sensors and associated signaling molecules

The chronology of the identification of intracellular DNA sensors is shown. DNA sensors are in red, key signaling proteins in green, and the RNA sensors Rig-I and MDA5 shown for comparison (orange). As detailed in the text, certain DNA sensors (boxed in grey here) have been confirmed to have a role in DNA- and/or DNA-virus dependent cytokine and IFN-I production in vivo, by using knockout mice.

Figure 2. Cytosolic DNA sensors and their signaling pathways

Upon recognition of dsDNA in the cytosol or nucleus, DNA sensors signal via adaptor proteins to altered gene induction via transcription factors (IRFs and NF-κB), and to pro-IL-1β processing, via Caspase 1. DNA sensors described in the main text are shown in red.