1. Academic Validation
  2. Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence

Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress-induced senescence

  • J Biol Chem. 2020 Apr 3;295(14):4451-4463. doi: 10.1074/jbc.RA119.010734.
Xiaojuan Han 1 2 Honghan Chen 1 Hui Gong 1 Xiaoqiang Tang 3 Ning Huang 1 Weitong Xu 1 Haoran Tai 1 4 Gongchang Zhang 1 Tingting Zhao 1 Chuhui Gong 1 Shuang Wang 1 Yu Yang 1 Hengyi Xiao 5
Affiliations

Affiliations

  • 1 Laboratory for Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 1 Keyuan 4 Road, Gaopeng Avenue, Chengdu 610041, China.
  • 2 Shaanxi Key Laboratory of Brain Disorders and Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710049, China.
  • 3 Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
  • 4 Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, Chengdu Medical College, Chengdu 610031, China.
  • 5 Laboratory for Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 1 Keyuan 4 Road, Gaopeng Avenue, Chengdu 610041, China hengyix@scu.edu.cn.
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.

Keywords

DNA damage; NF-kappaB (NF-KB); autolysosome; autophagy; cGAS-STING pathway; cytosolic chromatin fragment (CCF); oxidative stress; senescence; senescence-associated secretory phenotype (SASP).

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