Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 14, Pages 4451-4463Publisher
ELSEVIER
DOI: 10.1074/jbc.RA119.010734
Keywords
oxidative stress; senescence; DNA damage; autophagy; NF-kappaB (NF-KB); autolysosome; cGAS-STING pathway; cytosolic chromatin fragment (CCF); senescence-associated secretory phenotype (SASP)
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Funding
- National Natural Science Foundation of China [81771511]
- National Key R&D Program of China [2018YFC2000400]
- National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University [Z2018B04]
- Young Talent Found of the University Association for Science and technology in Shaanxi, China [20190308]
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Oxidative stress-induced DNA damage, the senescence-associated secretory phenotype (SASP), and impaired autophagy all are general features of senescent cells. However, the cross-talk among these events and processes is not fully understood. Here, using NIH3T3 cells exposed to hydrogen peroxide stress, we show that stress-induced DNA damage provokes the SASP largely via cytosolic chromatin fragment (CCF) formation, which activates a cascade comprising cGMP-AMP synthase (cGAS), stimulator of interferon genes protein (STING), NF-?B, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-?B signaling, promoting SASP and cellular senescence. We also present evidence that the persistent accumulation of CCFs in prematurely senescent cells is partially associated with a defect in DNA-degrading activity in autolysosomes and reduced abundance of activated DNase 2?. Intriguingly, we found that metformin- or rapamycin-induced activation of autophagy significantly lessened the size and levels of CCFs and repressed the activation of the cGAS-STING-NF-?B-SASP cascade and cellular senescence. These effects of autophagy activators indicated that autolysosomal function contributes to CCF clearance and SASP suppression, further supported by the fact that the lysosome inhibitor bafilomycin A1 blocked the role of autophagy-mediated CCF clearance and senescence repression.
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