In the cytoplasm,
DNA is sensed as a universal danger signal by the innate immune system.
Cyclic GMP-AMP synthase (cGAS) is a cytosolic
DNA sensor/
enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-
nucleotide second messenger that binds and activates the Stimulator of
Interferon Genes (
STING), resulting in recruitment of Tank Binding
Kinase 1 (TBK1), activation of the
transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including
type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS-STING-IRF3 response is triggered by direct recognition of the
DNA genomes of bacteria and viruses, but also during
RNA virus infection, neoplastic transformation,
tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory
DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived
DNA substrates, including endogenous retroviral elements,
mitochondrial DNA (
mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.