Cytoplasmic chromatin triggers inflammation in senescence and cancer

Nature. 2017 Oct 19;550(7676):402-406. doi: 10.1038/nature24050. Epub 2017 Oct 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Chromatin
  • Cytokines
  • MPYS protein, mouse
  • Membrane Proteins
  • Nucleotidyltransferases
  • cGAS protein, mouse
  • Oncogene Protein p21(ras)