ArticleMolecular and cellular biology2018
p62-Dependent Phase Separation of Patient-Derived KEAP1 Mutations and NRF2.
Article in Molecular and cellular biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 67 citations in OpenAlex.
- Keap1-Inhibitory Peptides fromMolecules (Basel, Switzerland) · 2026Article
- Article
- The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.Toxicological research · 2026Review
- NRF2-Targeted Therapy in Cardiovascular Disease Transitions from Systemic Activation to Precision Redox Medicine.Antioxidants (Basel, Switzerland) · 2026Review
- NRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting.Oncogene · 2025Review
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- KEAP1 retention in phase-separated p62 bodies drives liver damage under autophagy-deficient conditions.EMBO reports · 2025Article
- Antioxidant Activity In Vitro and Protective Effects Against Lipopolysaccharide-Induced Oxidative Stress and Inflammation in RAW264.7 Cells ofFoods (Basel, Switzerland) · 2025Article
- KEAP1-NRF2 Interaction in Cancer: Competitive Interactors and Their Role in Carcinogenesis.Cancers · 2025Review
- Utilizing liquid-liquid biopolymer regulators to predict the prognosis and drug sensitivity of hepatocellular carcinoma.Biology direct · 2025Article
- Phase separation is regulated by post-translational modifications and participates in the developments of human diseases.Heliyon · 2024Review
- Machine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions.Nature communications · 2024Article
- Physiology and pharmacological targeting of phase separation.Journal of biomedical science · 2024Review
- [Research Progress in the Role of Liquid-Liquid Phase Separation in Human Cancer].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Review
- Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.Journal of hematology & oncology · 2023Review
- Proximity proteomic analysis of the NRF family reveals the Parkinson's disease protein ZNF746/PARIS as a co-complexed repressor of NRF2.Science signaling · 2023Article
- Sequence variations of phase-separating proteins and resources for studying biomolecular condensates.Acta biochimica et biophysica Sinica · 2023Review
- Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family.Life (Basel, Switzerland) · 2023Article
- STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Antioxidant mechanisms of mesenchymal stem cells and their therapeutic potential in vitiligo.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Cancer-derived loss-of-function mutations in the KEAP1 tumor suppressor gene stabilize the NRF2 transcription factor, resulting in a prosurvival gene expression program that alters cellular metabolism and neutralizes oxidative stress. In a recent genotype-phenotype study, we classified 40% of KEAP1 mutations as ANCHOR mutants. By immunoprecipitation, these mutants bind more NRF2 than wild-type KEAP1 and ubiquitylate NRF2, but they are incapable of promoting NRF2 degradation. BioID-based protein interaction studies confirmed increased abundance of NRF2 within the KEAP1 ANCHOR mutant complexes, with no other statistically significant changes to the complexes. Discrete molecular dynamic simulation modeling and limited proteolysis suggest that the ANCHOR mutations stabilize residues in KEAP1 that contact NRF2. The modeling supports an intramolecular salt bridge between the R470C ANCHOR mutation and E493; mutation of the E493 residue confirmed the model, resulting in the ANCHOR phenotype. In live cells, the KEAP1 R320Q and R470C ANCHOR mutants colocalize with NRF2, p62/SQSTM1, and polyubiquitin in structured spherical droplets that rapidly fuse and dissolve. Transmission electron microscopy coupled with confocal fluorescent imaging revealed membraneless phase-separated biomolecular condensates. We present a model wherein ANCHOR mutations form p62-dependent biomolecular condensates that may represent a transitional state between impaired proteasomal degradation and autophagy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.