RESUMO
Self-DNA is present in the cytosol of many cancer cells and can promote effective immune rejection of tumor cells, but the mechanisms leading to the presence of cytosolic DNA are unknown. Here, we report that the cleavage of genomic DNA by DNA structure-specific endonuclease MUS81 and PARP-dependent DNA repair pathways leads to the accumulation of cytosolic DNA in prostate cancer cells. The number of nuclear MUS81 foci and the amount of cytosolic dsDNA increased in tandem from hyperplasia to clinical stage II prostate cancers and decreased at stage III. Cytosolic DNA generated by MUS81 stimulated DNA sensor STING-dependent type I interferon (IFN) expression and promoted phagocytic and T cell responses, resulting in type I and II IFN-mediated rejection of prostate tumor cells via mechanisms that partly depended on macrophages. Our results demonstrate that the tumor suppressor MUS81 alerts the immune system to the presence of transformed host cells.
Assuntos
Autoantígenos/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA/metabolismo , Endonucleases/metabolismo , Neoplasias da Próstata/imunologia , Linfócitos T/imunologia , Animais , Autoantígenos/imunologia , Linhagem Celular Tumoral , DNA/imunologia , Humanos , Interferon Tipo I/metabolismo , Ativação Linfocitária , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estadiamento de Neoplasias , Neoplasias Experimentais , Fagocitose , Neoplasias da Próstata/patologiaRESUMO
The presence of damaged and microbial DNA can pose a threat to the survival of organisms. Cells express various sensors that recognize specific aspects of such potentially dangerous DNA. Recognition of damaged or microbial DNA by sensors induces cellular processes that are important for DNA repair and inflammation. Here, we review recent evidence that the cellular response to DNA damage and microbial DNA are tightly intertwined. We also discuss insights into the parameters that enable DNA sensors to distinguish damaged and microbial DNA from DNA present in healthy cells.
Assuntos
Bactérias/imunologia , Reparo do DNA/imunologia , DNA Bacteriano/imunologia , Animais , Bactérias/genética , Reparo do DNA/genética , DNA Bacteriano/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologiaRESUMO
Apoptosis is a controlled means of eliminating damaged cells without causing an inflammatory response or tissue damage. The mechanisms that contribute to the suppression of an inflammatory response upon apoptosis of cells are poorly understood. Here, we report that apoptotic cells release the interleukin-1 receptor antagonist (IL1RA). The release of IL1RA depended on the DNA damage response, caspase 9, and caspase 3.De novotranslation, classical secretion pathways, or N-glycosylation was not required for the release of IL1RA. The amounts of IL1RA released by apoptotic cells impaired IL1-induced expression of IL6 In summary, we demonstrate that the release of IL1RA in response to genotoxic stress contributes to the immunosuppressive effects of apoptotic cells.