Immune sensing of DNA

Abstract

Although it has been appreciated for some years that cytosolic DNA is immune stimulatory, it is only in the past five years that the molecular basis of DNA sensing by the innate immune system has begun to be revealed. In particular it has been described how DNA induces type I interferon, central in antiviral responses and a mediator of autoimmunity. To date more than ten cytosolic receptors of DNA have been proposed, but STING is a key adaptor protein for most DNA-sensing pathways, and we are now beginning to understand the signaling mechanisms for STING. In this review we describe the recent progress in understanding signaling mechanisms activated by DNA and the relevance of DNA sensing to pathogen responses and autoimmunity. We highlight new insights gained into how and why the immune system responds to both pathogen and self DNA and define important questions that now need to be addressed in the field of innate immune activation by DNA.

Figure 1. Cellular functions stimulated by DNA

Intracellular DNA is recognized by DNA sensors leading to activation of multiple pathways. The best characterized DNA-stimulated pathway is the one leading to activation of IRFs and induction of IFNs. Other well-characterized pathways activated by DNA recognition are the inflammatory NF-κB and inflammasome pathways, which stimulate expression of inflammatory genes and cleavage of pro-IL-1β and IL-18, respectively. Intracellular DNA also stimulates autophagy and different types of cell death.

Figure 2. Immunostimulatory DNA and host sensors

DNA from microbes or the host has the potential to activate innate immune responses if delivered to the cytoplasm, and in some instances also the nucleus. DNA can end up in the cytoplasm through a variety of different pathways, and several different proteins have been proposed to function as PRR for DNA. The main DNA activated signaling pathways proceed through MyD88 for TLR9, DHX9 or DHX36, through ASC-caspase1 for AIM2, and via STING-TBK1-IRF3 for most other cytosolic IFN-inducing sensors.

Figure 3. Models for STING activation

(A) STING resides in the ER either as a monomer or more likely as a dimer (shown) in an autoinhibited state and is ‘activated’ by intracellular DNA, CDNs, and membrane perturbation. This leads to formation of an active STING dimer and mobilization to perinuclear vesicular structures where the C-terminal domain of STING serves as a platform for TBK1-mediated phosphorylation of IRF3. (B) Based on the current literature several models for STING ‘activation’ are possible. 1, DNA is sensed by a DNA sensor which initiates downstream signaling involving production of a second messenger (cGAMP) which binds to STING causing a conformational change essential for STING to recruit TBK1. 2, cGAS is the initial sensor of DNA and is activated by DNA binding to produce cGAMP, hence triggering STING activation as in (1). 3, DNA sensors directly interact with STING upon DNA binding and thereby stimulate the conformational change required for STING to recruit TBK1. 4, STING ‘activation’ involves other mechanisms such as redox-regulated covalent linkage of the monomers (Jin et al., 2011). 5, STING binds DNA directly and stimulates downstream signaling.