Title: Cytoplasmic chromatin triggers inflammation in senescence and cancer.
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
Published In Nature, (2017 10 19)
Abstract: Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. 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.
PubMed ID:
28976970
MeSH Terms: Animals; Cell Line, Tumor; Cellular Senescence/genetics*; Chromatin/immunology; Chromatin/metabolism*; Cytokines/immunology; Cytokines/metabolism; Cytoplasm/genetics*; Cytoplasm/immunology; Female; Humans; Immunity, Innate*; Inflammation/genetics*; Inflammation/immunology; Inflammation/pathology*; Liver/metabolism; Male; Membrane Proteins/deficiency; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Neoplasms/genetics*; Neoplasms/immunology*; Neoplasms/pathology; Nucleotidyltransferases/metabolism; Oncogene Protein p21(ras)/genetics; Oncogene Protein p21(ras)/immunology; Radiation, Ionizing