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cGAS sensing of DNA: A comprehensive look The immune system uses the cGAS-STING (cyclic GMP-AMP synthase–stimulator of interferon genes) signaling pathway to detect the presence of intracellular DNA. This is beneficial because cytosolic DNA is often a sign of host damage or invasion by pathogens. However, inappropriate responses to self-DNA must be suppressed to prevent detrimental effects on the host. Ablasser and Chen review the latest advances uncovering how cGAS and STING control inflammatory responses and are themselves regulated. Special attention is paid to the role of cGAS in sterile inflammatory conditions as well as to the therapeutic potential of modulating this pathway. Science, this issue p. eaat8657 BACKGROUND The life of any organism depends on the ability of cells to accurately recognize and eliminate harmful microbes. To detect the immense repertoire of pathogenic entities, the mammalian innate immune system has evolved distinct sensing strategies, including a central one based on the recognition of DNA—the basic building block of “life” itself. Integral to this process is the intracellular enzyme cGAS, which upon binding to double-stranded DNA (dsDNA), initiates a tightly regulated signaling cascade involving the adapter STING to trigger a variety of inflammatory effector responses. Although this process was originally discovered as a crucial component of innate immune defense against pathogens, recent work has elucidated a role for cytosolic DNA recognition pathways beyond the “classical” realm of innate immunity. The realization of an important involvement of cGAS and STING in various biological contexts has broadened its implications for human health and disease—much more than initially anticipated. ADVANCES Early structural and functional studies on cyclic guanosine monophosphate–adenosine monophosphate (GMP–AMP) synthase (cGAS) have established its capability to interact with dsDNA in a sequence-independent manner. Although this indiscriminate sensing strategy ensures the detection of almost all pathogenic entities, it also enables immune responses to be elicited upon encountering self-DNA. Mechanistically, self-DNA–sensing phenomena can be provoked by diverse alterations of both the extracellular and intracellular milieu, such as perturbations of DNA compartmentalization or disturbances in endogenous DNA metabolism. Initial studies on the relevance of cGAS-dependent recognition of self-DNA have largely focused on bona fide immunological consequences, such as inherited autoimmune and autoinflammatory disorders. Indeed, mutations in genes affecting intracellular DNA turnover can cause rare monogenic autoinflammatory syndromes in which the aberrant stimulation of innate DNA sensing is unequivocally central in driving associated pathologies. In addition to these rather traditional immunological disease entities, the aberrant activation of innate DNA sensing has recently emerged as an underlying cause for a number of distinct biological phenomena. Studies have documented the benefits of innate self-DNA sensing through cGAS by facilitating the recognition of cellular damage and indirectly, the presence of pathogens. Likewise, cGAS and STING have proven to be a central element in both iatrogenic and naturally occurring antitumor immunity and in promoting cellular senescence. However, the inflammatory consequences of the cGAS-STING pathway can also become maladaptive through the potentiation of tissue destruction or through the initiation of more subtle forms of chronic inflammatory diseases. OUTLOOK The broad biological roles of intracellular DNA sensing create new opportunities for the exploration and therapeutic manipulation for the prevention and treatment of multiple human diseases. Initial successes with therapies targeting the immunostimulatory effects of the cGAS-STING pathway suggest a major clinical impact in areas of cancer immunotherapy and vaccine development. Furthermore, pharmacological interventions aimed at antagonizing cGAS or STING functions hold similar promise, not only in the context of classical autoinflammatory conditions, but also in the treatment of more complex diseases. We are optimistic that an improved understanding of the molecular basis of innate DNA sensing and signaling via cGAS and STING will aid the design of new therapeutic strategies to manipulate its outcomes in a safe and specific manner. At the same time, we envision that this evolutionarily conserved DNA-sensing system may participate in diverse biological processes that are just beginning to be explored. Infectious and noninfectious functions of cGAS. cGAS is a universal sensor of dsDNA. A well-established function of cGAS in infections is the recognition of foreign DNA linked to the orchestration of host defense programs. Through sensing of self-DNA, cGAS also participates in various noninfectious contexts, including antitumor immunity, cellular senescence, and inflammatory diseases. DNA is highly immunogenic. It represents a key pathogen-associated molecular pattern (PAMP) during infection. Host DNA can, however, also act as a danger-associated molecular pattern (DAMP) and elicit strong inflammatory responses. The cGAS-STING pathway has emerged as a major pathway that detects intracellular DNA. Here, we highlight recent advances on how cGAS and STING mediate inflammatory responses and how these are regulated, allowing cells to readily respond to infections and noxious agents while avoiding the inappropriate sensing of self-DNA. A particular focus is placed on the role of cGAS in the context of sterile inflammatory conditions. Manipulating cGAS or STING may open the door for new therapeutic strategies for the treatment of acute and chronic inflammation relevant to many human diseases.