UniProt functional annotation for Q9Z2X8



	UniProt functional annotation for Q9Z2X8

UniProt code: Q9Z2X8.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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:9887101, PubMed:12682069, PubMed:15282312, PubMed:15367669, PubMed:15581590). 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:9887101, PubMed:12193649, PubMed:14764894). 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:20421418, PubMed:20173742, 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}.

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:20421418, PubMed:20173742, 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}.

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}.

Subunit: Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1 (PubMed:15282312, PubMed:16790436, PubMed:27697860). Interacts with NFE2L2/NRF2; the interaction is direct (PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:16581765, PubMed:27697860, PubMed:16507366). Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (By similarity). Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (PubMed:20495340, PubMed:20421418, PubMed:20173742, PubMed:24011591). Interacts with NFE2L1 (By similarity). Interacts with BPTF and PTMA (By similarity). Interacts with MAP1LC3B (By similarity). Interacts indirectly with ENC1 (By similarity). Interacts with SESN1 and SESN2 (By similarity). Interacts with HSP90AA1 and HSP90AB1 (By similarity). {ECO:0000250|UniProtKB:Q14145, ECO:0000269|PubMed:15282312, ECO:0000269|PubMed:15367669, ECO:0000269|PubMed:15581590, ECO:0000269|PubMed:16507366, ECO:0000269|PubMed:16581765, ECO:0000269|PubMed:16790436, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20495340, ECO:0000269|PubMed:24011591, ECO:0000269|PubMed:27697860}.

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:20495340, PubMed:20421418, PubMed:20173742). {ECO:0000269|PubMed:17903176, ECO:0000269|PubMed:20173742, ECO:0000269|PubMed:20421418, ECO:0000269|PubMed:20495340}.

Domain: The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5. {ECO:0000250|UniProtKB:Q14145}.

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. {ECO:0000269|PubMed:12193649, ECO:0000269|PubMed:14764894, ECO:0000269|PubMed:20498371, ECO:0000269|PubMed:22014577, ECO:0000269|PubMed:26527616}.

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. {ECO:0000250|UniProtKB:Q14145}.

Disruption phenotype: Early postnatal lethality caused by abnormal cornification (PubMed:14517554). Mice survive until weaning and probably die from malnutrition resulting from hyperkeratosis in the esophagus and forestomach that cause gastric obstruction (PubMed:14517554). Defects are caused by constitutive activation Nfe2l2/Nrf2, leading to constitutive expression of phase 2 detoxifying enzymes (PubMed:14517554). Mice lacking both Nfe2l2/Nrf2 and Keap1 reverse the hyperkeratosis phenotype and are healthy and viable in normal conditions (PubMed:14517554). {ECO:0000269|PubMed:14517554}.

Similarity: Belongs to the KEAP1 family. {ECO:0000305}.

Sequence caution: Sequence=BAC97871.1; Type=Erroneous initiation; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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:9887101, PubMed:12682069, PubMed:15282312, PubMed:15367669, PubMed:15581590). 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:9887101, PubMed:12193649, PubMed:14764894). 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:20421418, PubMed:20173742, 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}.


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:20421418, PubMed:20173742, 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}.
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}.
Subunit:		Component of the BCR(KEAP1) E3 ubiquitin ligase complex, at least composed of 2 molecules of CUL3, 2 molecules of KEAP1, and RBX1 (PubMed:15282312, PubMed:16790436, PubMed:27697860). Interacts with NFE2L2/NRF2; the interaction is direct (PubMed:15282312, PubMed:15367669, PubMed:15581590, PubMed:16790436, PubMed:16581765, PubMed:27697860, PubMed:16507366). Forms a ternary complex with NFE2L2/NRF2 and PGAM5 (By similarity). Interacts with (phosphorylated) SQSTM1/p62; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering it in inclusion bodies, promoting its degradation (PubMed:20495340, PubMed:20421418, PubMed:20173742, PubMed:24011591). Interacts with NFE2L1 (By similarity). Interacts with BPTF and PTMA (By similarity). Interacts with MAP1LC3B (By similarity). Interacts indirectly with ENC1 (By similarity). Interacts with SESN1 and SESN2 (By similarity). Interacts with HSP90AA1 and HSP90AB1 (By similarity). {ECO:0000250\|UniProtKB:Q14145, ECO:0000269\|PubMed:15282312, ECO:0000269\|PubMed:15367669, ECO:0000269\|PubMed:15581590, ECO:0000269\|PubMed:16507366, ECO:0000269\|PubMed:16581765, ECO:0000269\|PubMed:16790436, ECO:0000269\|PubMed:20173742, ECO:0000269\|PubMed:20421418, ECO:0000269\|PubMed:20495340, ECO:0000269\|PubMed:24011591, ECO:0000269\|PubMed:27697860}.
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:20495340, PubMed:20421418, PubMed:20173742). {ECO:0000269\|PubMed:17903176, ECO:0000269\|PubMed:20173742, ECO:0000269\|PubMed:20421418, ECO:0000269\|PubMed:20495340}.
Domain:		The Kelch repeats mediate interaction with NFE2L2/NRF2, BPTF and PGAM5. {ECO:0000250\|UniProtKB:Q14145}.
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. {ECO:0000269\|PubMed:12193649, ECO:0000269\|PubMed:14764894, ECO:0000269\|PubMed:20498371, ECO:0000269\|PubMed:22014577, ECO:0000269\|PubMed:26527616}.
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. {ECO:0000250\|UniProtKB:Q14145}.
Disruption phenotype:		Early postnatal lethality caused by abnormal cornification (PubMed:14517554). Mice survive until weaning and probably die from malnutrition resulting from hyperkeratosis in the esophagus and forestomach that cause gastric obstruction (PubMed:14517554). Defects are caused by constitutive activation Nfe2l2/Nrf2, leading to constitutive expression of phase 2 detoxifying enzymes (PubMed:14517554). Mice lacking both Nfe2l2/Nrf2 and Keap1 reverse the hyperkeratosis phenotype and are healthy and viable in normal conditions (PubMed:14517554). {ECO:0000269\|PubMed:14517554}.
Similarity:		Belongs to the KEAP1 family. {ECO:0000305}.
Sequence caution:		Sequence=BAC97871.1; Type=Erroneous initiation; Evidence={ECO:0000305};