Control of innate immunity by the cGAS‐STING pathway

Within the cytoplasm of mammalian cells is a protein called cyclic GMP‐AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that should not exist in healthy cells – the existence of DNA in the cytosol. Upon DNA binding, cGAS synthesizes cyclic GMP‐AMP (cGAMP), a cyclic dinucleotide that activates the endoplasmic reticulum‐localized protein stimulator of interferon genes (STING). STING‐mediated signaling culminates in host defensive responses typified by inflammatory cytokine and interferon expression, and the induction of autophagy. Studies over the past several years have established a consensus in the field of the enzymatic activities of cGAS in vitro, as it relates to DNA‐induced production of cGAMP. However, much additional work is needed to understand the regulation of cGAS functions within cells, where multiple sources of DNA can create a problem of self and non‐self discrimination. In this review, we provide an overview of how the cGAS‐STING pathway mediates innate immune responses during infection and other cellular stresses. We then highlight recent progress in the understanding of the increasingly diverse ways in which this DNA‐sensing machinery is regulated inside cells, including how cGAS remains inactive to host‐derived DNA under conditions of homeostasis. The cGAS‐STING pathway plays a central role in health and disease. In this review, we describe the current understanding of the molecular mechanisms that control the activity of this pathway.