1. Academic Validation
  2. SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway

SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway

  • Cell Death Dis. 2023 Jun 14;14(6):361. doi: 10.1038/s41419-023-05873-2.
Lei Dong # 1 Mengchuan Xu # 1 Yang Li 1 Wanting Xu 1 Chengwei Wu 1 Hanfei Zheng 1 Zhenyu Xiao 1 Guochen Sun 2 Lei Ding 3 Xiaobo Li 4 Wenming Li 4 Liying Zhou 4 Qin Xia 5
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
  • 2 Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, China.
  • 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Anesthesiology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 4 BeiJing Tide Pharmaceutical Co. LTD, BeiJing, 102600, China.
  • 5 Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing, 100081, China. qin.xia@bit.edu.cn.
  • # Contributed equally.
Abstract

Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring Keap1-Nrf2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell Apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires Keap1-Nrf2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.

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