Abstract
Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.
Highlights
Type I interferons (IFNs) can be secreted by a wide range of immune and non-immune cells in response to various biological stimuli [danger associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs)] that activate nuclear, cytosolic, or membrane-anchored nucleic acid sensors [1, 2]
CGAS-mediated detection of vaccinia virus (VACV) leads to the production of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) that could be efficiently transferred to bystander cells, triggering the activation of a STING-dependent antiviral immunity in non-infected cells [65]
In addition to its role in anti-pathogenic surveillance and response, accumulating evidence suggests a key role for cGAS in immune activation in cancer cells
Summary
Type I interferons (IFNs) can be secreted by a wide range of immune and non-immune cells in response to various biological stimuli [danger associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs)] that activate nuclear, cytosolic, or membrane-anchored nucleic acid sensors [1, 2]. Despite an important evolutionary conservation of the cGAS-STING functions in innate immunity, recent data have highlighted certain species specificities, which must be considered when using biomedical models for the identification of biomarkers or therapeutic screening for human health [8, 39, 40].
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