How Does cGAS Avoid Sensing Self-DNA under Normal Physiological Conditions?

cGAS is a cytosolic DNA sensor that activates innate immune responses by producing the second messenger 2′3′-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, meaning it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, cellular DNA is sequestered in the nucleus by a nuclear envelope and in mitochondria by a mitochondrial membrane. When self-DNA leaks into the cytosol during cellular stress or mitosis, the cGAS can be exposed to self-DNA and activated. Recently, many studies have investigated how cGAS keeps inactive and avoids being aberrantly activated by self-DNA. Thus, this narrative review aims to summarize the mechanisms by which cGAS avoids sensing self-DNA under normal physiological conditions.