Cytoplasmic chromatin triggers inflammation in senescence and cancer

• Published in: Nature (London) 2017-10, Vol.550 (7676), p.402-406
• Main Authors: Dou, Zhixun, Ghosh, Kanad, Vizioli, Maria Grazia, Zhu, Jiajun, Sen, Payel, Wangensteen, Kirk J., Simithy, Johayra, Lan, Yemin, Lin, Yanping, Zhou, Zhuo, Capell, Brian C., Xu, Caiyue, Xu, Mingang, Kieckhaefer, Julia E., Jiang, Tianying, Shoshkes-Carmel, Michal, Tanim, K. M. Ahasan Al, Barber, Glen N., Seykora, John T., Millar, Sarah E., Kaestner, Klaus H., Garcia, Benjamin A., Adams, Peter D., Berger, Shelley L.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/51; 13/89; 14; 14/19; 59; 59/5; 631/67; 631/80/509; Aging (Biology); AMP; Animals; Cancer; Cell Line, Tumor; Cellular Senescence - genetics; Chromatin; Chromatin - immunology; Chromatin - metabolism; Cyclic GMP; Cytokines - immunology; Cytokines - metabolism; Cytoplasm; Cytoplasm - genetics; Cytoplasm - immunology; Deoxyribonucleic acid; DNA; DNA damage; Female; Fragments; Gene expression; Genotype & phenotype; Health aspects; Humanities and Social Sciences; Humans; Immunity; Immunity, Innate; Infections; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Innate immunity; Interferon; Ionizing radiation; Kinases; letter; Liver - metabolism; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Nuclei; Nuclei (cytology); Nucleotidyltransferases - metabolism; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - immunology; Phosphorylation; Physiological aspects; Radiation; Radiation, Ionizing; Rodents; Science; Senescence
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24050

Cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. Tumours feel the sting from chromatin It has been observed that cells undergoing senescence—meaning that they can no longer divide and grow—contain cytoplasmic chromatin fragments. Shelley Berger and colleagues now show that these fragments are sensed by the cGAS–STING pathway, which senses foreign DNA during infection with pathogens. Activation of this pathway leads to an inflammatory phenotype and, in mice, allows the immune system to restrain tumour growth. These findings hint at the possibility that other endogenous sources of DNA may also elicit an inflammatory phenotype and influence various biological processes. Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing 1 , 2 , 3 . However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence 4 , 5 , a form of terminal cell-cycle arrest associated with pro-inflammatory responses 6 . The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING (cyclic GMP–AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin–cGAS–STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.