1. Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress–induced senescence
- Author
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Shuang Wang, Hengyi Xiao, Honghan Chen, Tingting Zhao, Gongchang Zhang, Ning Huang, Chuhui Gong, Xiaoqiang Tang, Yu Yang, Haoran Tai, Xiaojuan Han, Weitong Xu, and Hui Gong
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,0301 basic medicine ,Senescence ,DNA damage ,Autolysosome ,medicine.disease_cause ,Biochemistry ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Lysosome ,Autophagy ,medicine ,Animals ,RNA, Small Interfering ,Cyclic GMP ,Molecular Biology ,Cellular Senescence ,Endodeoxyribonucleases ,030102 biochemistry & molecular biology ,Interleukin-6 ,fungi ,NF-kappa B ,Membrane Proteins ,Bafilomycin ,Hydrogen Peroxide ,Cell Biology ,Nucleotidyltransferases ,Chromatin ,Cell biology ,Oxidative Stress ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,NIH 3T3 Cells ,RNA Interference ,Lysosomes ,Oxidative stress ,DNA Damage ,Signal Transduction - Abstract
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-κB, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-κB 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 2α. 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-κB-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.
- Published
- 2020