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

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.

Αnti-prion effects of anthocyanins

“…Indeed, previous studies in proteinopathies showed that Nrf2 activation inhibited the formation and/or reduced the number of existing aggregates of α-synuclein [ [97] , [98] , [99] , [100] ], amyloid beta [ [101] , [102] , [103] , [104] ] and tau [ [105] , [106] , [107] ], whereas Nrf2 deficiency promotes protein aggregation [ [108] , [109] , [110] ]. The Nrf2 transcription factor has long been identified as a modulator of autophagy [ [111] , [112] , [113] , [114] ], and is also associated with the Unfolded Protein Response (UPR) [ 100 , [115] , [116] , [117] , [118] , [119] , [120] ], which might explain its ability to reduce pathologic protein aggregation in several proteinopathies, including prion diseases [ 121 , 122 ]. Interestingly, activation of the UPR has been utilized as a potential treatment against CJD [ 123 ], whereas p62 mediated Nrf2 activation and subsequent upregulation of autophagy levels has been proposed as a therapeutic strategy for prion diseases [ 6 ].…”