KEAP1
GeneName
KEAP1
Summary
KEAP1, also known as Kelch like ECH associated protein 1 or Keap-1, is a 70kDa protein that functions primarily as a regulator of the transcription factor NRF2, playing a critical role in the cellular response to oxidative stress. It is predominantly expressed in the cytoplasm and is involved in various cellular processes, including the regulation of autophagy and protein ubiquitination. KEAP1 is part of the Cul3-RING ubiquitin ligase complex and interacts with multiple cellular components such as actin filaments and the endoplasmic reticulum. By facilitating the degradation of NRF2 under normal conditions, KEAP1 helps maintain cellular homeostasis and protects cells from oxidative damage.
Importance
KEAP1 is relevant to: - Cancer research due to its role in the regulation of oxidative stress and its impact on tumourigenesis - Neurodegenerative diseases, as it influences cellular responses to oxidative stress, which is implicated in conditions like Alzheimer’s - Inflammatory responses, given its involvement in the regulation of interleukin-4 responses - Developmental biology, due to its role in embryonic development and differentiation processes
Top Products
For researchers investigating KEAP1, we highly recommend the well-cited polyclonal antibody, Anti-Keap1 antibody (ab139729). This antibody has garnered 61 citations, reflecting its reliability and trust within the scientific community. It is particularly effective for Western blotting (WB) and immunocytochemistry (ICC), making it a versatile choice for various experimental needs. Its proven performance in these applications ensures that you can confidently explore the role of KEAP1 in your research.
Abcam Product Citation Summary
The data indicates that KEAP1 is being studied in various contexts, particularly in relation to ferroptosis and the Nrf2 signalling pathway. The use of different species, including rats and humans, highlights the relevance of KEAP1 in both basic and translational research, particularly in understanding oxidative stress and neuroprotection.
Abcam Product Citation Table
Domain
KEAP1 contains reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules, which react with sulfhydryl groups and modify the cysteine sensors, leading to impair ability of the BCR(KEAP1) complex to ubiquitinate target proteins.
The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5.
Function
Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that regulates the response to oxidative stress by targeting NFE2L2/NRF2 for ubiquitination (PubMed:14585973, PubMed:15379550, PubMed:15572695, PubMed:15601839, PubMed:15983046, PubMed:37339955). KEAP1 acts as a key sensor of oxidative and electrophilic stress: in normal conditions, the BCR(KEAP1) complex mediates ubiquitination and degradation of NFE2L2/NRF2, a transcription factor regulating expression of many cytoprotective genes (PubMed:15601839, PubMed:16006525). In response to oxidative stress, different electrophile metabolites trigger non-enzymatic covalent modifications of highly reactive cysteine residues in KEAP1, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes (PubMed:16006525, PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092). In response to selective autophagy, KEAP1 is sequestered in inclusion bodies following its interaction with SQSTM1/p62, leading to inactivation of the BCR(KEAP1) complex and activation of NFE2L2/NRF2 (PubMed:20452972). The BCR(KEAP1) complex also mediates ubiquitination of SQSTM1/p62, increasing SQSTM1/p62 sequestering activity and degradation (PubMed:28380357). The BCR(KEAP1) complex also targets BPTF and PGAM5 for ubiquitination and degradation by the proteasome (PubMed:15379550, PubMed:17046835).
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
Non-enzymatic covalent modifications of reactive cysteines by electrophile metabolites inactivate the BCR(KEAP1) complex (PubMed:17127771, PubMed:18251510, PubMed:29590092, PubMed:30323285). Accumulation of fumarate promotes the formation of cysteine S-succination (S-(2-succinyl)cysteine), leading to inactivate the BCR(KEAP1) complex and promote NFE2L2/NRF2 nuclear accumulation and activation (By similarity). Nitric oxide-dependent 8-Nitro-cGMP formation promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear accumulation and activation (By similarity). Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates cysteines, activating NFE2L2/NRF2 (PubMed:29590092). Methylglyoxal, a reactive metabolite that accumulates when the glycolytic enzyme PGK1 is inhibited, promotes formation of a methylimidazole cross-link between proximal Cys-151 and Arg-135 on another KEAP1 molecule, resulting in an inactive dimer that inactivates the BCR(KEAP1) complex (PubMed:30323285).
Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation.
Auto-ubiquitinated by the BCR(KEAP1) complex (PubMed:15572695, PubMed:15983046). Quinone-induced oxidative stress, but not sulforaphane, increases its ubiquitination (PubMed:15572695, PubMed:15983046). Ubiquitination and subsequent degradation is most pronounced following prolonged exposure of cells to oxidative stress, particularly in glutathione-deficient cells that are highly susceptible to oxidative stress (PubMed:15572695, PubMed:15983046). Deubiquitinated by USP25; leading to stabilization (PubMed:37339955).
Sequence Similarities
Belongs to the KEAP1 family.
Tissue Specificity
Broadly expressed, with highest levels in skeletal muscle.
Cellular localization
- Cytoplasm
- Nucleus
- Mainly cytoplasmic (PubMed:15601839). In response to selective autophagy, relocalizes to inclusion bodies following interaction with SQSTM1/p62 (PubMed:20452972).
Alternative names
INRF2, KIAA0132, KLHL19, KEAP1, Kelch-like ECH-associated protein 1, Cytosolic inhibitor of Nrf2, Kelch-like protein 19, INrf2