Research summary
The Keap1-Nrf2 system is dissected as the principal antioxidant-response regulator. Keap1 was identified as a Drosophila-Kelch-like cytoplasmic protein that binds the conserved N-terminal Neh2 domain of Nrf2 to suppress its transactivation, with electrophilic agents antagonizing repression and licensing nuclear translocation to drive antioxidant-response-element-mediated phase II gene induction [1]. Keap1 was then shown to function as an adaptor for a Cul3-based E3 ubiquitin ligase that ubiquitinates Nrf2 (half-life <20 min) through both its BTB and intervening-region domains, establishing the ubiquitin-proteasome basis of cytoplasmic Nrf2 turnover [3]. Native gels of purified murine Keap1 complexed with the Neh2 domain demonstrated that inducer concentrations correlate with sulfhydryl group reactivity, providing direct evidence that Keap1 cysteine thiols act as sensors regulating phase II induction [4]. A 2018 Physiological Reviews synthesis frames Keap1 as a thiol-rich redox sensor and Nrf2 as a derepression-activated cytoprotective transcription factor, organizing two decades of mechanism and disease relevance [5]. The system's therapeutic potential in kidney disease is reviewed in the context of oxidative stress as a driver of CKD progression [2]. Nrf2-mediated anti-inflammatory action was shown to operate independently of its DNA-binding motif and of ROS levels: ChIP-seq and ChIP-qPCR demonstrated that Nrf2 binds near proinflammatory cytokine loci including Il6 and Il1b in macrophages and blocks RNA Pol II recruitment to suppress LPS-induced transcription [6]. The corpus defines Keap1-Nrf2 as a redox-cysteine sensor-effector and as a tractable therapeutic node.
Recent publications
- Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domainDOI
- Targeting the KEAP1-NRF2 System to Prevent Kidney Disease ProgressionDOI
- The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1DOI
- A cross-population atlas of genetic associations for 220 human phenotypesDOI
- Oxidative Stress Sensor Keap1 Functions as an Adaptor for Cul3-Based E3 Ligase To Regulate Proteasomal Degradation of Nrf2DOI
- Homeostatic Levels of p62 Control Cytoplasmic Inclusion Body Formation in Autophagy-Deficient MiceDOI
- Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidantsDOI
- The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox HomeostasisDOI
- Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcriptionDOI
- Nrf2鈥揔eap1 defines a physiologically important stress response mechanismDOI
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External profiles
- ORCID: https://orcid.org/0000-0002-9073-9436
- OpenAlex: openalex.org
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