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Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence

Nature cell biology, 2017-09, Vol.19 (9), p.1061-1070 [Peer Reviewed Journal]

COPYRIGHT 2017 Nature Publishing Group ;Copyright Nature Publishing Group Sep 2017 ;ISSN: 1465-7392 ;EISSN: 1476-4679 ;DOI: 10.1038/ncb3586 ;PMID: 28759028

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Title:
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Author: Glück, Selene ; Guey, Baptiste ; Gulen, Muhammet Fatih ; Wolter, Katharina ; Kang, Tae-Won ; Schmacke, Niklas Arndt ; Bridgeman, Anne ; Rehwinkel, Jan ; Zender, Lars ; Ablasser, Andrea
Subjects: Activation ; AMP ; Animals ; Biological response modifiers ; Cell cycle ; Cell Proliferation ; Cells, Cultured ; Cellular Senescence - radiation effects ; Chromatin ; Chromatin - enzymology ; Chromatin - immunology ; Chromatin - radiation effects ; Cyclic GMP ; Cyclic guanylic acid ; Cytosol - enzymology ; Cytosol - immunology ; Cytosol - radiation effects ; Deoxyribonucleic acid ; DNA ; Enzyme Activation ; Female ; Fragments ; Genes ; Genotype ; Immunity, Innate - radiation effects ; Inflammation ; Interferon ; Irradiation ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - immunology ; Nucleotidyltransferases - metabolism ; Oxidative Stress ; Paracrine Communication ; Paracrine signalling ; Phenotype ; Radiation ; RNA Interference ; Senescence ; Signal Transduction ; Time Factors ; Transfection
Is Part Of: Nature cell biology, 2017-09, Vol.19 (9), p.1061-1070
Description: 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.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 1465-7392
EISSN: 1476-4679
DOI: 10.1038/ncb3586
PMID: 28759028
Source: MEDLINE
ProQuest Central

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Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence

COPYRIGHT 2017 Nature Publishing Group ;Copyright Nature Publishing Group Sep 2017 ;ISSN: 1465-7392 ;EISSN: 1476-4679 ;DOI: 10.1038/ncb3586 ;PMID: 28759028

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