2. Academic Validation
  3. Reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

Reciprocal regulation of NRF2 by autophagy and ubiquitin-proteasome modulates vascular endothelial injury induced by copper oxide nanoparticles

  • J Nanobiotechnology. 2022 Jun 11;20(1):270. doi: 10.1186/s12951-022-01486-7.
Na Li  # 1,  Hang Du  # 2,  Lejiao Mao 1 3,  Ge Xu 1,  Mengling Zhang 4,  Yinzhen Fan 1,  Xiaomei Dong 1,  Lijun Zheng 1,  Bin Wang 1,  Xia Qin 5,  Xuejun Jiang 6,  Chengzhi Chen 7 3,  Zhen Zou 8 9,  Jun Zhang 10 11
Affiliations

Affiliations

  • 1 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 2 Chongqing Prevention and Treatment Center for Occupational Diseases, Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, Chongqing, 400060, People's Republic of China.
  • 3 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 4 College of Pharmacy, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 5 Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 6 Center of Experimental Teaching for Public Health, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, 400016, People's Republic of China.
  • 7 Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, 400016, Chongqing, People's Republic of China.
  • 8 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zouzhen@cqmu.edu.cn.
  • 9 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zouzhen@cqmu.edu.cn.
  • 10 Molecular Biology Laboratory of Respiratory Disease, Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zhangjun@cqmu.edu.cn.
  • 11 Research Center for Environment and Human Health, School of Public Health, Chongqing Medical University, Chongqing, 400016, People's Republic of China. zhangjun@cqmu.edu.cn.
  • # Contributed equally.
PMID: 35690781 DOI: 10.1186/s12951-022-01486-7
Abstract

NRF2 is the key antioxidant molecule to maintain redox homeostasis, however the intrinsic mechanisms of NRF2 activation in the context of nanoparticles (NPs) exposure remain unclear. In this study, we revealed that copper oxide NPs (CuONPs) exposure activated NRF2 pathway in vascular endothelial cells. NRF2 knockout remarkably aggravated oxidative stress, which were remarkably mitigated by ROS scavenger. We also demonstrated that KEAP1 (the negative regulator of NRF2) was not primarily involved in NRF2 activation in that KEAP1 knockdown did not significantly affect CuONPs-induced NRF2 activation. Notably, we demonstrated that Autophagy promoted NRF2 activation as evidenced by that ATG5 knockout or Autophagy inhibitors significantly blocked NRF2 pathway. Mechanically, CuONPs disturbed ubiquitin-proteasome pathway and consequently inhibited the proteasome-dependent degradation of NRF2. However, Autophagy deficiency reciprocally promoted Proteasome activity, leading to the acceleration of degradation of NRF2 via ubiquitin-proteasome pathway. In addition, the notion that the reciprocal regulation of NRF2 by Autophagy and ubiquitin-proteasome was further proven in a CuONPs pulmonary exposure mice model. Together, this study uncovers a novel regulatory mechanism of NRF2 activation by protein degradation machineries in response to CuONPs exposure, which opens a novel intriguing scenario to uncover therapeutic strategies against NPs-induced vascular injury and disease.

Keywords

Autophagy; CuONPs; NRF2; Ubiquitin–proteasome system; Vascular injury.

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