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DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity

ABSTRACT: The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, anti-viral adaptive immunity, autoimmunity and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T cell activation in diseased lungs. Genetic depletion of the immunoproteasome as well as specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.

SUBMITTER: Dr. Xinyuan Wang

PROVIDER: S-SCDT-10_15252-EMBJ_2022110597 | biostudies-other |

REPOSITORIES: biostudies-other

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DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.

Project description:The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T-cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T-cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.

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The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer.

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Project description:Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a DNA sensor that elicits a robust type I interferon response by recognizing ubiquitous danger-associated molecules. The cGAS/stimulator of interferon genes (cGAS/STING) is activated by endogenous DNA, including DNA released from mitochondria and extranuclear chromatin, as well as exogenous DNA derived from pathogenic microorganisms. cGAS/STING is positioned as a key axis of autoimmunity, the inflammatory response, and cancer progression, suggesting that the cGAS/STING signaling pathway represents an efficient therapeutic target. Based on the accumulated evidence, we present insights into the prevention and treatment of cGAS/STING-related chronic immune and inflammatory diseases. This review presents the current state of clinical and nonclinical development of modulators targeting cGAS/STING, providing useful information on the design of therapeutic strategies.

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Project description:The role that human papillomavirus (HPV) oncogenes play in suppressing responses to immunotherapy in cancer deserves further investigation. In particular, the effects of HPV E5 remain poorly understood relative to E6 and E7. Here, we demonstrate that HPV E5 is a negative regulator of anti-viral interferon (IFN) response pathways, antigen processing, and antigen presentation. Using head and neck cancer as a model, we identify that E5 decreases expression and function of the immunoproteasome and that the immunoproteasome, but not the constitutive proteasome, is associated with improved overall survival in patients. Moreover, immunopeptidome analysis reveals that HPV E5 restricts the repertoire of antigens presented on the cell surface, likely contributing to immune escape. Mechanistically, we discover a direct interaction between E5 and stimulator of interferon genes (STING), which suppresses downstream IFN signaling. Taken together, these findings identify a powerful molecular mechanism by which HPV E5 limits immune detection and mediates resistance to immunotherapy.

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Project description:Microbial nucleic acids induce potent innate immune responses by stimulating the expression of type I interferons. Cyclic GMP-AMP synthase (cGAS) is a cytosolic dsDNA sensor mediating the innate immunity to microbial DNA. cGAS is activated by dsDNA and catalyze the synthesis of a cyclic dinucleotide cGAMP with 2',5' and 3',5'phosphodiester linkages. cGAMP binds to the adaptor STING located on the endoplasmic reticulum membrane and mediates the recruitment and activation of the protein kinase TBK1 and transcription factor IRF3. Phosphorylated IRF3 translocates to the nucleus and initiates the transcription of the IFN-β gene. The crystal structures of cGAS and its complex with dsDNA, STING and its complex with various cyclic dinucleotides have been determined recently. Here we summarize the results from these structural studies and provide an overview about the mechanism of cGAS activation by dsDNA, the catalytic mechanism of cGAS, and the structural basis of STING activation by cGAMP.

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p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

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Project description:The innate DNA sensing receptors are one family of pattern recognition receptors and play important roles in antiviral infections, especially DNA viral infections. Among the multiple DNA sensors, cGAS has been studied intensively and is most defined in mammals. However, DNA sensors in chickens have not been much studied, and the chicken cGAS is still not fully understood. In this study, we investigated the chicken cGAS-STING signal axis, revealed its synergistic activity, species-specificity, and the signal essential sites in cGAS. Importantly, both cGAS and STING exhibited antiviral effects against DNA viruses, retroviruses, and RNA viruses, suggesting the broad range antiviral functions and the critical roles in chicken innate immunity.

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