cyclic-guanosine-monophosphate-adenosine-monophosphate and Autoimmune-Diseases

Innate immunity is regulated by a broad set of evolutionary conserved receptors to finely probe the local environment and maintain host integrity. Besides pathogen recognition through conserved motifs, several of these receptors also sense aberrant or misplaced self-molecules as a sign of perturbed homeostasis. Among them, self-nucleic acid sensing by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway alerts on the presence of both exogenous and endogenous DNA in the cytoplasm. We review recent literature demonstrating that self-nucleic acid detection through the STING pathway is central to numerous processes, from cell physiology to sterile injury, auto-immunity and cancer. We address the role of STING in autoimmune diseases linked to dysfunctional DNAse or related to mutations in DNA sensing pathways. We expose the role of the cGAS/STING pathway in inflammatory diseases, neurodegenerative conditions and cancer. Connections between STING in various cell processes including autophagy and cell death are developed. Finally, we review proposed mechanisms to explain the sources of cytoplasmic DNA.

Topics: Adenosine Triphosphate; Adult; Autoimmune Diseases; Autophagy; Cytokines; Cytoplasm; DNA; Guanosine Triphosphate; Humans; Immunity, Innate; Infant; Inflammation; Interferon Type I; Membrane Proteins; Mitochondria; Neoplasms; Neurodegenerative Diseases; NF-kappa B; Nucleotides, Cyclic; Nucleotidyltransferases; Signal Transduction

Stimulator of interferon genes (STING) is an adaptor protein that induces the secretion of type I interferons and proinflammatory cytokines and is triggered by cytosolic DNA of pathogen and host origins. Given that STING is a mediator in the immune system, pharmacological modulation of STING has shown viable therapeutic effects for pathogen infection, cancer, and inflammatory diseases. In the past decade, the substantial development in this field has encouraged the discovery of STING modulators. Here, we will summarize the current understanding of STING structure, survey the status quo of STING modulators, compare established bioassay methods, review the chemical structures and bioactivities of agonists and inhibitors, and propose suggestions and insights for the future exploitation of STING modulators.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Autoimmune Diseases; Binding Sites; Chemistry, Pharmaceutical; Drug Delivery Systems; Humans; Membrane Proteins; Neoplasms; Protein Structure, Secondary; Signal Transduction

Various intracellular pattern recognition receptors (PRRs) recognize cytosolic pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Cyclic GMP-AMP synthase (cGAS), a cytosolic PRR, recognizes cytosolic nucleic acids including dsDNAs. The recognition of dsDNA by cGAS generates cyclic GMP-AMP (GAMP). The cGAMP is then recognized by STING generating type 1 IFNs and NF-κB-mediated generation of pro-inflammatory cytokines and molecules. Thus, cGAS-STING signaling mediated recognition of cytosolic dsDNA causing the induction of type 1 IFNs plays a crucial role in innate immunity against cytosolic pathogens, PAMPs, and DAMPs. The overactivation of this system may lead to the development of autoinflammation and autoimmune diseases. The article opens with the introduction of different PRRs involved in the intracellular recognition of dsDNA and gives a brief introduction of cGAS-STING signaling. The second section briefly describes cGAS as intracellular PRR required to recognize intracellular nucleic acids (dsDNA and CDNs) and the formation of cGAMP. The cGAMP acts as a second messenger to activate STING- and TANK-binding kinase 1-mediated generation of type 1 IFNs and the activation of NF-κB. The third section of the article describes the role of cGAS-STING signaling in the induction of autoinflammation and various autoimmune diseases. The subsequent fourth section describes both chemical compounds developed and the endogenous negative regulators of cGAS-STING signaling required for its regulation. Therapeutic targeting of cGAS-STING signaling could offer new ways to treat inflammatory and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; DNA; Exodeoxyribonucleases; Extracellular Traps; Humans; Inflammation; Interferon Type I; Membrane Proteins; Nucleotides, Cyclic; Nucleotidyltransferases; Phosphoproteins; Signal Transduction

The innate immune system deploys a variety of sensors to detect signs of infection. Nucleic acids represent a major class of pathogen signatures that can trigger robust immune responses. The presence of DNA in the cytoplasm of mammalian cells is a danger signal that activates innate immune responses; however, how cytosolic DNA triggers these responses remained unclear until recently. In this review, we focus on the mechanism of DNA sensing by the newly discovered cGAS-cGAMP-STING pathway and highlight recent progress in dissecting the in vivo functions of this pathway in immune defense as well as autoimmunity.

Topics: Autoimmune Diseases; Cytosol; DNA; Humans; Immunity, Innate; Membrane Proteins; Models, Immunological; Models, Molecular; Nucleotides, Cyclic; Nucleotidyltransferases; Signal Transduction

Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.

Topics: Autoimmune Diseases; Cells, Cultured; Crystallography, X-Ray; DNA; Drug Discovery; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Immunity, Innate; Interferons; Macrophages; Models, Molecular; Nucleotides, Cyclic; Nucleotidyltransferases; Primary Cell Culture; Recombinant Proteins