Regulation and inhibition of the DNA sensor cGAS

Cell-autonomous sensing of nucleic acids is essential for host defence against invading pathogens by inducing antiviral and inflammatory cytokines. cGAS has emerged in recent years as a non-redundant DNA sensor important for detection of many viruses and bacteria. Upon binding to DNA, cGAS synthesises the cyclic dinucleotide 2'3'-cGAMP that binds to the adaptor protein STING and thereby triggers IRF3- and NFκB-dependent transcription. In addition to infection, the pathophysiology of an ever-increasing number of sterile inflammatory conditions in humans involves the recognition of DNA through cGAS. Consequently, the cGAS/STING signalling axis has emerged as an attractive target for pharmacological modulation. However, the development of cGAS and STING inhibitors has just begun and a need for specific and effective compounds persists. In this review, we focus on cGAS and explore how its activation by immunostimulatory DNA is regulated by cellular mechanisms, viral immune modulators and small molecules. We further use our knowledge of cGAS modulation by cells and viruses to conceptualise potential new ways of pharmacological cGAS targeting.