KEAP1
entrez
9817
canonical
uniprot
Q14145
canonical
ensembl
ENSG00000079999
resolver
ensp
ENSP00000171111
resolver
ensp
ENSP00000377245
resolver
ensp
ENSP00000580223
resolver
ensp
ENSP00000580225
resolver
ensp
ENSP00000580226
resolver
ensp
ENSP00000623746
resolver
enst
ENST00000171111
resolver
enst
ENST00000393623
resolver
enst
ENST00000910164
resolver
enst
ENST00000910166
resolver
enst
ENST00000910167
resolver
enst
ENST00000953687
resolver
genesymbol
KEAP1
resolver
genesymbol_syn
INRF2
resolver
genesymbol_syn
KIAA0132
resolver
genesymbol_syn
KLHL19
resolver
hgnc
HGNC:23177
resolver
uniprot
B3KPD5
resolver
uniprot
Q6LEP0
resolver
uniprot
Q8WTX1
resolver
uniprot
Q9BPY9
resolver
uniprot_entry
KEAP1_HUMAN
resolver
uniprot_sec
B3KPD5
resolver
uniprot_sec
Q6LEP0
resolver
uniprot_sec
Q8WTX1
resolver
uniprot_sec
Q9BPY9
resolver
activity_regulation
ACTIVITY REGULATION: Ubiquitin ligase activity of the BCR(KEAP1) complex is inhibited by oxidative stress and electrophile metabolites such as sulforaphane (PubMed:15983046, PubMed:17046835, PubMed:29590092, PubMed:30323285). Electrophile metabolites react with reactive cysteine residues in KEAP1 and trigger non-enzymatic covalent modifications of these cysteine residues, leading to inactivate the ubiquitin ligase activity of the BCR(KEAP1) complex (PubMed:17127771, PubMed:18251510, PubMed:19489739, PubMed:29590092, PubMed:30323285). Selective autophagy also inactivates the BCR(KEAP1) complex via interaction between KEAP1 and SQSTM1/p62, which sequesters the complex in inclusion bodies and promotes its degradation (PubMed:20452972, PubMed:20495340). {ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:17127771, ECO:0000269|PubMed:18251510, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:20495340, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:30323285}.
uniprot
proteins
amino_acid_sequence
MQPDPRPSGAGACCRFLPLQSQCPEGAGDAVMYASTECKAEVTPSQHGNRTFSYTLEDHTKQAFGIMNELRLSQQLCDVTLQVKYQDAPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISMGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCVELHQRAREYIYMHFGEVAKQEEFFNLSHCQLVTLISRDDLNVRCESEVFHACINWVKYDCEQRRFYVQALLRAVRCHSLTPNFLQMQLQKCEILQSDSRCKDYLVKIFEELTLHKPTQVMPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSDGTWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCAPMSVPRNRIGVGVIDGHIYAVGGSHGCIHHNSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITAMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMKHRRSALGITVHQGRIYVLGGYDGHTFLDSVECYDPDTDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC
uniprot
proteins
function
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). {ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:15572695, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:16006525, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:17127771, ECO:0000269|PubMed:18251510, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:20452972, ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:37339955}.
uniprot
proteins
mass_dalton
69666
uniprot
proteins
mutagenesis
MUTAGEN 15; /note="R->A: Reduced formation of a high-molecular mass KEAP1 molecule when methylglyoxal accumulates."; /evidence="ECO:0000269|PubMed:30323285"; MUTAGEN 123..127; /note="VSIEG->ASAEA: Abolished interaction with NFE2L2/NRF2; when associated with 161-A-A-162."; /evidence="ECO:0000269|PubMed:15601839"; MUTAGEN 125..127; /note="IEG->AAA: Increases ubiquitination and proteolytic degradation."; /evidence="ECO:0000269|PubMed:15572695"; MUTAGEN 135; /note="R->A: Reduced formation of a high-molecular mass KEAP1 molecule when methylglyoxal accumulates."; /evidence="ECO:0000269|PubMed:30323285"; MUTAGEN 151; /note="C->S,N,D,L: Substitution with a small side chain that prevents covalent modification by an electrophile; promotes constitutive ubiquitination of NFE2L2/NRF2 and subsequent repression of phase 2 detoxifying enzymes. Resistance of ubiquitination of PGAM5 to inhibition by oxidative stress and sulforaphane. Impaired interaction with CUL3. Reduced formation of a high-molecular mass KEAP1 molecule when methylglyoxal accumulates."; /evidence="ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:18251510, ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:30323285"; MUTAGEN 151; /note="C->W,Y: Substitution with a bulky side chain that mimicks covalent modification by an electrophile; prevents ubiquitination and degradation of NFE2L2/NRF2, leading to constitutive activation of NFE2L2/NRF2 and subsequent expression of phase 2 detoxifying enzymes."; /evidence="ECO:0000269|PubMed:19489739, ECO:0000269|PubMed:24896564"; MUTAGEN 161..162; /note="MY->AA: Abolished interaction with NFE2L2/NRF2; when associated with 123-A--A-127."; /evidence="ECO:0000269|PubMed:15601839"; MUTAGEN 162..164; /note="YQI->AAA: Increases ubiquitination and proteolytic degradation."; /evidence="ECO:0000269|PubMed:15572695"; MUTAGEN 273; /note="C->S: Abolishes repression of NFE2L2/NRF2-dependent gene expression. Slows down degradation of NFE2L2/NRF2."; /evidence="ECO:0000269|PubMed:14585973"; MUTAGEN 288; /note="C->S: Abolishes repression of NFE2L2/NRF2-dependent gene expression. Slows down degradation of NFE2L2/NRF2."; /evidence="ECO:0000269|PubMed:14585973"; MUTAGEN 308; /note="L->A: Loss of export from nucleus; when associated with A-310."; /evidence="ECO:0000269|PubMed:15657435"; MUTAGEN 310; /note="L->A: Loss of export from nucleus; when associated with A-308."; /evidence="ECO:0000269|PubMed:15657435"; MUTAGEN 334; /note="Y->A: Loss of interaction with NFE2L2/NRF2. Strongly reduces repression of NFE2L2/NRF2-dependent gene expression. Loss of interaction with PGAM5."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:17046835"; MUTAGEN 380; /note="R->A: Loss of interaction with NFE2L2/NRF2. Abolishes repression of NFE2L2/NRF2-dependent gene expression. Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:20452972"; MUTAGEN 382; /note="N->A: Loss of interaction with NFE2L2/NRF2. Strongly reduces repression of NFE2L2/NRF2-dependent gene expression. Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:20452972"; MUTAGEN 415; /note="R->A: Loss of interaction with NFE2L2/NRF2. Abolishes repression of NFE2L2/NRF2-dependent gene expression. Loss of interaction with PGAM5. Does not affect interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:20452972"; MUTAGEN 436; /note="H->A: Loss of interaction with NFE2L2/NRF2. Abolishes repression of NFE2L2/NRF2-dependent gene expression. Does not affect interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:20452972"; MUTAGEN 478; /note="F->A: Abolishes repression of NFE2L2/NRF2-dependent gene expression."; /evidence="ECO:0000269|PubMed:16888629"; MUTAGEN 483; /note="R->A: Loss of interaction with NFE2L2/NRF2. Abolishes repression of NFE2L2/NRF2-dependent gene expression. Loss of interaction with PGAM5. Does not affect interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:20452972"; MUTAGEN 525; /note="Y->A: Loss of interaction with NFE2L2/NRF2. Strongly reduces repression of NFE2L2/NRF2-dependent gene expression. Abolishes interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:20452972"; MUTAGEN 572; /note="Y->A: Loss of interaction with NFE2L2/NRF2. Strongly reduces repression of NFE2L2/NRF2-dependent gene expression. Loss of interaction with PGAM5. Abolishes interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:16888629, ECO:0000269|PubMed:17046835, ECO:0000269|PubMed:20452972"; MUTAGEN 615; /note="K->R: Decreases binding to PGCKA1. Increases protein half-life."; /evidence="ECO:0000269|PubMed:36882524
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:15572695, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15983046}.
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000250|UniProtKB:Q9Z2X8, ECO:0000269|PubMed:17127771, ECO:0000269|PubMed:18251510, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:30323285}.; PTM: Degraded via a proteasomal-independent process during selective autophagy: interaction with phosphorylated SQSTM1/p62 sequesters KEAP1 in inclusion bodies, leading to its degradation. {ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:20452972}.; PTM: 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). Ubiquitinated by TRIM25; leading to degradation upon ER stress (PubMed:31953436, PubMed:36882524). {ECO:0000269|PubMed:15572695, ECO:0000269|PubMed:15983046, ECO:0000269|PubMed:31953436, ECO:0000269|PubMed:36882524, ECO:0000269|PubMed:37339955}.
uniprot
proteins
protein_family
KEAP1 family
uniprot
proteins
pubmed
14585973
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15057824
uniprot
proteins
pubmed
15379550
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15572695
uniprot
proteins
pubmed
15583386
uniprot
proteins
pubmed
15601839
uniprot
proteins
pubmed
15657435
uniprot
proteins
pubmed
15983046
uniprot
proteins
pubmed
16006525
uniprot
proteins
pubmed
16204884
uniprot
proteins
pubmed
16507366
uniprot
proteins
pubmed
16687406
uniprot
proteins
pubmed
16888629
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17020408
uniprot
proteins
pubmed
17046835
uniprot
proteins
pubmed
17127771
uniprot
proteins
pubmed
18251510
uniprot
proteins
pubmed
18387606
uniprot
proteins
pubmed
19424503
uniprot
proteins
pubmed
19489739
uniprot
proteins
pubmed
20452972
uniprot
proteins
pubmed
20495340
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
23274085
uniprot
proteins
pubmed
24089205
uniprot
proteins
pubmed
24630991
uniprot
proteins
pubmed
24896564
uniprot
proteins
pubmed
26517842
uniprot
proteins
pubmed
28380357
uniprot
proteins
pubmed
28842501
uniprot
proteins
pubmed
29590092
uniprot
proteins
pubmed
30323285
uniprot
proteins
pubmed
31953436
uniprot
proteins
pubmed
36882524
uniprot
proteins
pubmed
37339955
uniprot
proteins
pubmed
8590280
uniprot
proteins
sequence_length
624
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14585973, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:15657435, ECO:0000269|PubMed:19424503}. Nucleus {ECO:0000269|PubMed:15657435}. Note=Mainly cytoplasmic (PubMed:15601839). In response to selective autophagy, relocalizes to inclusion bodies following interaction with SQSTM1/p62 (PubMed:20452972). {ECO:0000269|PubMed:15601839, ECO:0000269|PubMed:20452972}.
uniprot
proteins