Trends in Immunology
ReviewCrosstalk between Cytoplasmic RIG-I and STING Sensing Pathways
Section snippets
Innate Sensing of Pathogens
Scattered throughout the body and particularly concentrated in mucous membranes and skin, the cells of the innate immune system provide a first line of defense against the potential pathogens. Granulocytes, macrophages, dendritic and natural killer cells recognize microbes using a small set of evolutionarily ancient, germline-encoded sensors called pattern recognition receptors (PRRs). These receptors identify conserved structures, such as cell wall components, that are usually unique to
RIG-I-Mediated Sensing of Cytosolic RNA
RIG-I-like receptors (RLRs) are responsible for the detection of single-stranded (ss) and double-stranded (ds) RNA generated in the course of a virus infection [6]. This receptor family contains three members: RIG-I, melanoma differentiation associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). All RLRs are characterized by a central DEAD box helicase/ATPase domain and a C-terminal regulatory domain (CTD), essential for RNA binding and for the autorepression of RLR
Cytoplasmic Nucleic Acids Lead to Generation of Additional Ligands for RIG-I–MAVS and cGAS–STING
While the RNA and DNA pathways rely on different receptors and adaptors, it is clear that they at least partially overlap, as highlighted by the fact that the IFN response to poly(dA:dT) was reduced by >99% in STING−/−, MAVS−/− macrophages and DCs, but not in phagocytes deficient in STING alone [40]. A molecular mechanism linking DNA sensing with the RIG-I pathway was first identified by Chiu et al., who demonstrated that cytosolic DNA could be used as a template for RNA polymerase (pol)
Implications of STING and RIG-I Agonists in Cancer Therapy
In addition to its essential function in the detection of invading microbe genomes, STING also has an equally important function as a sensor of self DNA, released from the nucleus into the cytoplasm after DNA damage; a scenario characteristic of autoimmune diseases. In fact, the cGAS–STING pathway contributes to the high levels of circulating cytokines found in inflammation-related disorders [64]. Furthermore, numerous studies have highlighted the importance of STING in antitumor immunity. DNA
Concluding Remarks
Innate cytosolic sensing of foreign nucleic acids represents an important trigger of innate immune responses in several pathological conditions, ranging from microbial and viral infections to inflammatory diseases and cancer. The pathways that converge to MAVS and STING-dependent signaling are involved in RNA and DNA sensing, respectively, but there is also a high degree of interconnection between those two pathways. These interactions rely on the conversion of nucleic acid ligands by the host
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