Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence

By S. Glück, B. Guey, M. F. Gulen, K. Wolter, T. Kang, Niklas A. Schmacke, A. Bridgeman, J. Rehwinkel, Lars Zender, A. Ablasser. Nature Cell Biology, 2017

1,037 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/b42ec1a61c900d39cf3930205ad831973635c376

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Zhijian J. Chen
2. Jesús Gil
3. M. Demaria

In Immunology

1. Tuo Li
2. Zhijian J. Chen
3. A. Ablasser
4. Jesús Gil
5. M. Demaria
6. Shizuo Akira
7. N. Perkins
8. G. Barber

Citations in the corpus

• Senescence and aging: Causes, consequences, and therapeutic avenues (2018, neutral): “Recently, sensing of cytoplasmic chromatin by the cGAS/STI NG pathway has been suggested as a trigger for SASP induction (Dou et al., 2017; Glück et al., 2017).”
• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “cGAS is a DNA sensor that, through the adaptor protein STING, triggers cellular senescence and the transcription of genes that control the SASPs (104, 139, 353).”
• Senescence and the SASP: many therapeutic avenues (2020, background): “Genetic interference with the cGAS-STING pathway results in SASP inhibition and reduces tissue inflammation in vivo (Dou et al. 2017; Glück et al. 2017).”
• The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “Recent research has provided strong evidence that cGAS also has an essential role in promoting cellular senescence (Dou et al., 2017; Glück et al., 2017; Yang et al., 2017).”
• The senescence-associated secretory phenotype and its physiological and pathological implications (2024, neutral): “…studies in humans demonstrated that five SASP factors (GDF15, receptor for advanced glycation end-products (RAGE), VEGFA, PARC (also known as CCL18) and MMP2) are strongly associated with mortality 213 and that the plasma level of a panel of SASP factors is predictive of COVID-19 severity 214 .”
• cGAS in action: Expanding roles in immunity and inflammation (2019, background): “After periods of progressive stress, senescent cells remodel their nuclear envelope, and this is accompanied with the repetitive release of cytosolic chromatin fragments, which present potent triggers of inflammation via cGAS (47, 48, 68).”