Cytosolic DNA sensors (CDSs) are molecules that detect double-stranded (ds) DNA in the cytosol and activate signaling pathways that initiate antimicrobial responses, including type I IFN production and autophagy. DNA may be released into the cytosol from intracellular microbes. Furthermore, host DNA damage due to various factors, such as radiation, toxins, or mutations, may lead to the delivery of that DNA into the cytosol in micronuclei whose nuclear envelopes degrade, exposing the DNA to cytosolic CDSs. Damaged or released mitochondrial DNA may also be transiently located in the cytosol of cells but is usually rapidly degraded by endonucleases. The ability of the innate immune system to distinguish and react to microbial or damaged self DNA and not normal self DNA is partly related to the location of most of the DNA sensors in the cytosol, where DNA should not normally be.
The STING (stimulator of IFN genes) pathway is an important mechanism of DNA-induced activation of type I IFN responses (Fig. 1). In this pathway, cytosolic dsDNA activates the enzyme cGAS (cyclic guanosine monophosphate–adenosine monophosphate [GMP-AMP] synthase), which generates a signaling molecule called cGAMP (cyclic GMP-AMP). STING is an endoplasmic reticulum–localized transmembrane adaptor protein whose cytosolic tail binds to cGAMP with high affinity, inducing a conformational change that leads to its translocation from the endoplasmic reticulum to the Golgi apparatus. After localization to the Golgi, STING acts as an adaptor protein that promotes the activation TBK1, which phosphorylates and activates the IRF3 and IRF7 transcription factors, and also phosphorylates IKK, which leads to NF-κB activation. The IRFs and NF-κB translocate to the nucleus and induce type I IFN gene expression. STING also responds to other cytosolic DNA sensors besides cGAS, including DAI (DNA-dependent activator of IFN-regulatory factors) and IFI16 (interferon inducible protein 16). In addition to inducing IFN production, STING stimulates autophagy, a mechanism by which cells degrade their own organelles, such as mitochondria, by sequestering them within membrane-bound vesicles and fusing the vesicles with lysosomes. In innate immunity, autophagy is a mechanism for delivering cytosolic microbes to the lysosome, where they are killed by proteolytic enzymes. In adaptive immunity, autophagy is one of several mechanisms for generating microbial peptides in lysosomes of antigen-presenting cells for presentation to T cells.
Fig1. The stimulator of interferon (IFN) genes (STING) cytosolic DNA sensing pathway. Cytoplasmic microbial DNA and self DNA that accumulates in the cytosol activate the enzyme cyclic guanosine mono phosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS), which catalyzes the synthesis of cyclic GMP-AMP (cGAMP) from adenosine triphosphate (ATP) and guanosine triphosphate (GTP). cGAMP binds to STING in the endoplasmic reticulum (ER) membrane, causing STING to translocate to the Golgi (not shown), and then STING recruits and activates the kinase TANK-binding kinase 1 (TBK1), which phosphorylates interferon regulatory factor 3 (IRF3) and IRF7. Phospo-IRF3 and -7 move to the nucleus, where they induce type I IFN gene expression. Self DNA in the cytosol may be produced as a result of genomic or mitochondrial dam age. The bacterial second messenger molecules cyclic di-GMP (c-di-GMP) and cyclic di-AMP (c-di-AMP) are directly sensed by STING. NF-κB, Nuclear factor kappa B.
Gain-of-function mutations in the gene that encodes STING result in systemic inflammatory disease with manifestations in skin and lung, driven by excess type I IFN production. This disorder is one example of a group of diseases characterized by excess type I IFN production, called interferonopathies. These disorders include some in which there are gain-of-function mutations of innate nucleic acid sensors, some in which there are loss-of-function mutations of the regulators of these pathways, and others caused by genetic defects that result in increased amounts of nucleic acids in cells (e.g., mutations affecting endonucleases). Interferonopathies are a subset of autoinflammatory syndromes (see Table 1).
Table1. Selected Monogenic Autoinflammatory Syndromes
Some cytosolic DNA sensors may work through STING independent pathways. Two examples of such pathways are the following.
• RNA polymerase 3 binds and transcribes AT-rich microbial dsDNA into an RNA-containing-triphosphate moiety, which then activates the RIG-I pathway leading to type I IFN expression, as described later.
• AIM2 (absent in melanoma-2) is another cytosolic sensor that binds cytosolic dsDNA and forms an inflammasome, which proteolytically generates the biologically active inflammatory cytokine IL-1β, as described earlier.
