ArticleMolecular and cellular biology2017
p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex.
Article in Molecular and cellular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 109 citations in OpenAlex.
- Article
- Proteomic Analysis Reveals That P97 Inhibitors Induce Ferroptosis in Gastric Cancer AGS Cells.Pharmaceuticals (Basel, Switzerland) · 2026Article
- The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP.bioRxiv : the preprint server for biology · 2026Article
- Driver or passenger? A new assessment of genes in the schizophrenia-associated 3q29 deletion locus for contribution to neurodevelopmental disorders.Journal of neurodevelopmental disorders · 2026Review
- Nutritional Strategies and Aging: Current Evidence and Future Directions.Molecules (Basel, Switzerland) · 2026Review
- In Vivo and In Vitro Antioxidant Effects ofAntioxidants (Basel, Switzerland) · 2025Article
- UBXN7 facilitates SARS-CoV-2 replication via inhibiting the K48-linked ubiquitination of viral N protein.PLoS pathogens · 2025Article
- Deregulated Nrf2-Keap1-BACH1 axis in autism spectrum disorder.Redox biology · 2025Article
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- Multi-proteomic profiling of the varicella-zoster virus-host interface reveals host susceptibilities to severe infection.Nature microbiology · 2025Article
- Thirty years of NRF2: advances and therapeutic challenges.Nature reviews. Drug discovery · 2025Review
- Targeting epigenetic and post-translational modifications of NRF2: key regulatory factors in disease treatment.Cell death discovery · 2025Review
- USP37 as a novel regulator of NRF2 protein stability and chemoresistance in HCC.Discover oncology · 2025Article
- Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass.Frontiers in endocrinology · 2025Review
- Macranthoside B Suppresses the Growth of Adenocarcinoma of Esophagogastric Junction by Regulating Iron Homeostasis and Ferroptosis through NRF2 Inhibition.Current cancer drug targets · 2025Article
- The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis.Cell death & disease · 2024Article
- NRF2 in age-related musculoskeletal diseases: Role and treatment prospects.Genes & diseases · 2024Review
- Promising tools into oxidative stress: A review of non-rodent model organisms.Redox biology · 2024Review
- Research into overcoming drug resistance in lung cancer treatment using CRISPR-Cas9 technology: a narrative review.Translational lung cancer research · 2024Review
- Nrf2-mediated ferroptosis of spermatogenic cells involved in male reproductive toxicity induced by polystyrene nanoplastics in mice.Journal of Zhejiang University. Science. B · 2024Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX-containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.
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