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Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.

  • Glück S Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
  • Guey B Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
  • Gulen MF Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
  • Wolter K Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.
  • Kang TW Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.
  • Schmacke NA Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
  • Bridgeman A Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • Rehwinkel J Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • Zender L Department of Internal Medicine VIII, University Hospital Tübingen, 72076 Tübingen, Germany.
  • Ablasser A Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
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  • 2017-08-01
Published in:
  • Nature cell biology. - 2017
Animals
Cell Proliferation
Cells, Cultured
Cellular Senescence
Chromatin
Cytosol
Enzyme Activation
Female
Genotype
Immunity, Innate
Male
Membrane Proteins
Mice, Inbred C57BL
Mice, Knockout
Nucleotidyltransferases
Oxidative Stress
Paracrine Communication
Phenotype
RNA Interference
Signal Transduction
Time Factors
Transfection
English Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/226062
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