Trends in Immunology
Volume 38, Issue 3, March 2017, Pages 194-205
Journal home page for Trends in Immunology

Review
Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways

https://doi.org/10.1016/j.it.2016.12.004Get rights and content

Trends

cGAS–STING and RIG-I–MAVS pathways are critical cytosolic PRRs that recognize and respond to DNA and RNA, respectively, from invading microbial pathogens.

Although activated by distinct nucleic acids, cGAS–STING and RIG-I–MAVS signaling are functionally interconnected; STING and MAVS physically interact, and coordinate their expression levels through positive feedback mechanisms.

Natural and synthetic RIG-I and STING agonists are being explored as antiviral or anticancer agents, given their broad spectrum efficacy in in vitro and in vivo models of infection. These agonists can trigger cell death in malignant cells, recruit immune cells into the tumor microenvironment, and represent promising tools in cancer immunotherapies.

In some types of cancer, STING may facilitate tumor development by promoting chronic inflammation, and by promoting immunosuppression rather than cytotoxicity.

Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected. This review highlights the importance of the crosstalk between retinoic acid inducible gene-I (RIG-I)–mitochondrial antiviral-signaling protein (MAVS) RNA sensing and the cyclic GMP–AMP synthase (cGAS)– stimulator of interferon genes (STING) DNA sensing pathways in potentiating efficient antiviral responses. The potential of cGAS–STING manipulation as a component of cancer immunotherapy is also reviewed.

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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