Keap1
entrez
50868
canonical
uniprot
Q9Z2X8
canonical
ensembl
ENSMUSG00000003308
resolver
ensp
ENSMUSP00000062467
resolver
ensp
ENSMUSP00000131029
resolver
ensp
ENSMUSP00000141807
resolver
ensp
ENSMUSP00000141840
resolver
enst
ENSMUST00000049567
resolver
enst
ENSMUST00000164812
resolver
enst
ENSMUST00000193982
resolver
enst
ENSMUST00000194542
resolver
genesymbol
Keap1
resolver
genesymbol_syn
Inrf2
resolver
genesymbol_syn
Kiaa0132
resolver
uniprot
Q3U243
resolver
uniprot
Q3U8N7
resolver
uniprot
Q547S3
resolver
uniprot
Q6ZQI6
resolver
uniprot
Q8BQY3
resolver
uniprot_entry
KEAP1_MOUSE
resolver
uniprot_sec
Q3U243
resolver
uniprot_sec
Q3U8N7
resolver
uniprot_sec
Q547S3
resolver
uniprot_sec
Q6ZQI6
resolver
uniprot_sec
Q8BQY3
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:12193649, PubMed:14764894, PubMed:22014577). 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:20498371, PubMed:22014577). 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:20173742, PubMed:20421418, PubMed:24011591). {ECO:0000269|PubMed:12193649, ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20498371, ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:24011591}.
uniprot
proteins
amino_acid_sequence
MQPEPKLSGAPRSSQFLPLWSKCPEGAGDAVMYASTECKAEVTPSQDGNRTFSYTLEDHTKQAFGVMNELRLSQQLCDVTLQVKYEDIPAAQFMAHKVVLASSSPVFKAMFTNGLREQGMEVVSIEGIHPKVMERLIEFAYTASISVGEKCVLHVMNGAVMYQIDSVVRACSDFLVQQLDPSNAIGIANFAEQIGCTELHQRAREYIYMHFGEVAKQEEFFNLSHCQLATLISRDDLNVRCESEVFHACIDWVKYDCPQRRFYVQALLRAVRCHALTPRFLQTQLQKCEILQADARCKDYLVQIFQELTLHKPTQAVPCRAPKVGRLIYTAGGYFRQSLSYLEAYNPSNGSWLRLADLQVPRSGLAGCVVGGLLYAVGGRNNSPDGNTDSSALDCYNPMTNQWSPCASMSVPRNRIGVGVIDGHIYAVGGSHGCIHHSSVERYEPERDEWHLVAPMLTRRIGVGVAVLNRLLYAVGGFDGTNRLNSAECYYPERNEWRMITPMNTIRSGAGVCVLHNCIYAAGGYDGQDQLNSVERYDVETETWTFVAPMRHHRSALGITVHQGKIYVLGGYDGHTFLDSVECYDPDSDTWSEVTRMTSGRSGVGVAVTMEPCRKQIDQQNCTC
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:12682069, PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:9887101). 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:12193649, PubMed:14764894, PubMed:9887101). 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:12193649, PubMed:20498371, PubMed:22014577, 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:20173742, PubMed:20421418, PubMed:24011591). 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 (By similarity). {ECO:0000250|UniProtKB:Q14145, ECO:0000269|PubMed:12193649, ECO:0000269|PubMed:12682069, ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20498371, ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:24011591, ECO:0000269|PubMed:28380357, ECO:0000269|PubMed:29590092, ECO:0000269|PubMed:9887101}.
uniprot
proteins
mass_dalton
69553
uniprot
proteins
mutagenesis
MUTAGEN 71; /note="R->G: Abolished ability to ubiquitinate NFE2L2/NRF2 without affecting homodimerization."; /evidence="ECO:0000269|PubMed:16790436"; MUTAGEN 151; /note="C->S: 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. Knockin mice are healthy and viable in normal conditions but do not activate NFE2L2/NRF2 in response to oxidative stress."; /evidence="ECO:0000269|PubMed:18268004, ECO:0000269|PubMed:20956331"; MUTAGEN 273; /note="C->A: Abolishes repression of NFE2L2/NRF2-dependent gene expression. Knockin mice die approximately three weeks after birth because of impaired ability of the BCR(KEAP1) complex to ubiquitinate NFE2L2/NRF2; when associated with A-288."; /evidence="ECO:0000269|PubMed:14764894"; MUTAGEN 273; /note="C->W,M: Retains ability to degrade NFE2L2/NRF2; when associated with E-288."; /evidence="ECO:0000269|PubMed:26527616"; MUTAGEN 288; /note="C->A: Abolishes repression of NFE2L2/NRF2-dependent gene expression. Slows down degradation of NFE2L2/NRF2. Knockin mice die approximately three weeks after birth because of impaired ability of the BCR(KEAP1) complex to ubiquitinate NFE2L2/NRF2; when associated with A-273."; /evidence="ECO:0000269|PubMed:14764894"; MUTAGEN 288; /note="C->E,N,R: Retains ability to degrade NFE2L2/NRF2; when associated with W-273. Abolishes ability to be activated by 15-deoxy-delta(12,14)-prostaglandin J2."; /evidence="ECO:0000269|PubMed:26527616"; MUTAGEN 334; /note="Y->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 363; /note="S->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 380; /note="R->A: Impaired interaction with SQSTM1/p62. Abolished interaction with SQSTM1/p62; when associated with A-415 and A-483."; /evidence="ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418"; MUTAGEN 380; /note="R->M: Impaired interaction with NFE2L2/NRF2."; /evidence="ECO:0000269|PubMed:16790436"; MUTAGEN 382; /note="N->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 415; /note="R->A: Impaired interaction with SQSTM1/p62. Abolished interaction with SQSTM1/p62; when associated with A-380 and A-483."; /evidence="ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418"; MUTAGEN 415; /note="R->M: Impaired interaction with NFE2L2/NRF2."; /evidence="ECO:0000269|PubMed:16790436"; MUTAGEN 483; /note="R->A: Does not affect interaction with SQSTM1/p62. Abolished interaction with SQSTM1/p62; when associated with A-380 and A-415."; /evidence="ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418"; MUTAGEN 483; /note="R->M: Impaired interaction with NFE2L2/NRF2."; /evidence="ECO:0000269|PubMed:16790436"; MUTAGEN 508; /note="S->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 530; /note="Q->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 555; /note="S->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 599..601; /note="SGR->AAA: Decreases repression of NFE2L2/NRF2-dependent gene expression."; /evidence="ECO:0000269|PubMed:16507366"; MUTAGEN 602..604; /note="SGV->AAA: Abolishes repression of NFE2L2/NRF2-dependent gene expression."; /evidence="ECO:0000269|PubMed:16507366"; MUTAGEN 602; /note="S->A: Impaired interaction with SQSTM1/p62."; /evidence="ECO:0000269|PubMed:20173742"; MUTAGEN 605..608; /note="GVAV->AAAA: Decreases repression of NFE2L2/NRF2-dependent gene expression."; /evidence="ECO:0000269|PubMed:16507366
uniprot
proteins
pathway_participation
PATHWAY: Protein modification; protein ubiquitination. {ECO:0000269|PubMed:12682069, ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:9887101}.
uniprot
proteins
post_translational_modification
PTM: Non-enzymatic covalent modifications of reactive cysteines by electrophile metabolites inactivate the BCR(KEAP1) complex (PubMed:12193649, PubMed:20498371, PubMed:22014577). 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 (PubMed:22014577). Nitric oxide-dependent 8-Nitro-cGMP formation promotes cysteine guanylation (S-cGMP-cysteine), leading to NFE2L2/NRF2 nuclear accumulation and activation (PubMed:17906641, PubMed:20498371). 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 (By similarity). {ECO:0000250|UniProtKB:Q14145, ECO:0000269|PubMed:12193649, ECO:0000269|PubMed:17906641, ECO:0000269|PubMed:20498371, ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:29590092}.; 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:22872865, ECO:0000269|PubMed:24011591}.; PTM: Auto-ubiquitinated by the BCR(KEAP1) complex. Quinone-induced oxidative stress, but not sulforaphane, increases its ubiquitination. 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. Deubiquitinated by USP25; leading to stabilization. Ubiquitinated by TRIM25; leading to degradation upon ER stress (By similarity). {ECO:0000250|UniProtKB:Q14145}.
uniprot
proteins
protein_family
KEAP1 family
uniprot
proteins
pubmed
12193649
uniprot
proteins
pubmed
12682069
uniprot
proteins
pubmed
14517554
uniprot
proteins
pubmed
14621295
uniprot
proteins
pubmed
14764894
uniprot
proteins
pubmed
15282312
uniprot
proteins
pubmed
15367669
uniprot
proteins
pubmed
15379550
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15581590
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16507366
uniprot
proteins
pubmed
16581765
uniprot
proteins
pubmed
16790436
uniprot
proteins
pubmed
17903176
uniprot
proteins
pubmed
17906641
uniprot
proteins
pubmed
18268004
uniprot
proteins
pubmed
20173742
uniprot
proteins
pubmed
20421418
uniprot
proteins
pubmed
20495340
uniprot
proteins
pubmed
20498371
uniprot
proteins
pubmed
20956331
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
22014577
uniprot
proteins
pubmed
22872865
uniprot
proteins
pubmed
24011591
uniprot
proteins
pubmed
26527616
uniprot
proteins
pubmed
27697860
uniprot
proteins
pubmed
28380357
uniprot
proteins
pubmed
28842501
uniprot
proteins
pubmed
29590092
uniprot
proteins
pubmed
9887101
uniprot
proteins
sequence_length
624
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15379550, ECO:0000269|PubMed:17903176, ECO:0000269|PubMed:27697860}. Nucleus {ECO:0000269|PubMed:15379550}. Note=Mainly cytoplasmic (PubMed:17903176). In response to selective autophagy, relocalizes to inclusion bodies following interaction with SQSTM1/p62 (PubMed:20173742, PubMed:20421418, PubMed:20495340). {ECO:0000269|PubMed:17903176, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20495340}.
uniprot
proteins