| IED ID | IndEnz0002004057 |
| Enzyme Type ID | protease004057 |
| Protein Name |
Endoplasmic reticulum membrane sensor NFE2L1 Locus control region-factor 1 LCR-F1 Nuclear factor erythroid 2-related factor 1 NF-E2-related factor 1 NFE2-related factor 1 Nuclear factor, erythroid derived 2, like 1 Cleaved into: Transcription factor NRF1 |
| Gene Name | Nfe2l1 Nrf1 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MLSLKKYLTEGLLQFTILLSLIGVRVDVDTYLTSQLPPLREIILGPSSAYTQTQFHNLRNTLDGYGIHPKSIDLDNYFTARRLLSQVRALDRFQVPTTEVNAWLVHRDPEGSVSGSQPNSGLALESSSGLQDVTGPDNGVRESETEQGFGEDLEDLGAVAPPVSGDLTKEDIDLIDILWRQDIDLGAGREVFDYSHRQKEQDVDKELQDGREREDTWSGEGAEALARDLLVDGETGESFPAQFPADVSSIPEAVPSESESPALQNSLLSPLLTGTESPFDLEQQWQDLMSIMEMQAMEVNTSASEILYNAPPGDPLSTNYSLAPNTPINQNVSLHQASLGGCSQDFSLFSPEVESLPVASSSTLLPLVPSNSTSLNSTFGSTNLAGLFFPSQLNGTANDTSGPELPDPLGGLLDEAMLDEISLMDLAIEEGFNPVQASQLEEEFDSDSGLSLDSSHSPSSLSSSEGSSSSSSSSSSSSASSSASSSFSEEGAVGYSSDSETLDLEEAEGAVGYQPEYSKFCRMSYQDPSQLSCLPYLEHVGHNHTYNMAPSALDSADLPPPSTLKKGSKEKQADFLDKQMSRDEHRARAMKIPFTNDKIINLPVEEFNELLSKYQLSEAQLSLIRDIRRRGKNKMAAQNCRKRKLDTILNLERDVEDLQRDKARLLREKVEFLRSLRQMKQKVQSLYQEVFGRLRDEHGRPYSPSQYALQYAGDGSVLLIPRTMADQQARRQERKPKDRRK |
| Enzyme Length | 741 |
| Uniprot Accession Number | Q61985 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor (PubMed:20385086, PubMed:21536885, PubMed:23816881, PubMed:29149604). Constitutes a precursor of the transcription factor NRF1. Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition (PubMed:20385086, PubMed:21536885, PubMed:23816881, PubMed:29149604). In response to stress, it is released from the endoplasmic reticulum membrane following cleavage by the protease DDI2 and translocates into the nucleus to form the transcription factor NRF1 (PubMed:29149604). Acts as a key sensor of cholesterol excess: in excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal, such as CD36 (PubMed:29149604). Involved in proteasome homeostasis: in response to proteasome inhibition, it is released from the endoplasmic reticulum membrane, translocates to the nucleus and activates expression of genes encoding proteasome subunits (PubMed:20385086, PubMed:21536885, PubMed:23816881). {ECO:0000269|PubMed:20385086, ECO:0000269|PubMed:21536885, ECO:0000269|PubMed:23816881, ECO:0000269|PubMed:29149604}.; FUNCTION: [Transcription factor NRF1]: CNC-type bZIP family transcription factor that translocates to the nucleus and regulates expression of target genes in response to various stresses (PubMed:10601325, PubMed:11342101, PubMed:23144760, PubMed:16872277, PubMed:21911472, PubMed:23816881, PubMed:29149604). Heterodimerizes with small-Maf proteins (MAFF, MAFG or MAFK) and binds DNA motifs including the antioxidant response elements (AREs), which regulate expression of genes involved in oxidative stress response (PubMed:12808106, PubMed:15738389, PubMed:23144760, PubMed:16872277, PubMed:21911472, PubMed:23816881). Activates or represses expression of target genes, depending on the context (PubMed:12808106, PubMed:15738389, PubMed:23144760, PubMed:16872277, PubMed:21911472, PubMed:23816881). Plays a key role in cholesterol homeostasis by acting as a sensor of cholesterol excess: in low cholesterol conditions, translocates into the nucleus and represses expression of genes involved in defense against cholesterol excess, such as CD36 (PubMed:29149604). In excess cholesterol conditions, the endoplasmic reticulum membrane form of the protein directly binds cholesterol via its CRAC motif, preventing cleavage and release of the transcription factor NRF1, thereby allowing expression of genes promoting cholesterol removal (PubMed:29149604). Critical for redox balance in response to oxidative stress: acts by binding the AREs motifs on promoters and mediating activation of oxidative stress response genes, such as GCLC, GCLM, GSS, MT1 and MT2 (PubMed:10601325, PubMed:11342101, PubMed:12968018, PubMed:15738389, PubMed:18826952). Plays an essential role during fetal liver hematopoiesis: probably has a protective function against oxidative stress and is involved in lipid homeostasis in the liver (PubMed:9501099, PubMed:12808106, PubMed:15738389, PubMed:18826952, PubMed:22586274). Involved in proteasome homeostasis: in response to proteasome inhibition, mediates the 'bounce-back' of proteasome subunits by translocating into the nucleus and activating expression of genes encoding proteasome subunits (PubMed:20385086, PubMed:21536885, PubMed:23816881). Also involved in regulating glucose flux (PubMed:25041126). Together with CEBPB; represses expression of DSPP during odontoblast differentiation (By similarity). In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts (PubMed:17510056). {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:10601325, ECO:0000269|PubMed:11342101, ECO:0000269|PubMed:12808106, ECO:0000269|PubMed:12968018, ECO:0000269|PubMed:15738389, ECO:0000269|PubMed:16872277, ECO:0000269|PubMed:17510056, ECO:0000269|PubMed:18826952, ECO:0000269|PubMed:20385086, ECO:0000269|PubMed:21536885, ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:22586274, ECO:0000269|PubMed:23144760, ECO:0000269|PubMed:23816881, ECO:0000269|PubMed:25041126, ECO:0000269|PubMed:29149604, ECO:0000269|PubMed:9501099}.; FUNCTION: [Isoform 2]: Transcription factor that binds the antioxidant response elements (ARE) consensus sequence on promoters and activates their expression. {ECO:0000269|PubMed:23144760, ECO:0000269|PubMed:9580677}.; FUNCTION: [Isoform 3]: Transcription factor that binds the extended kappa 3 site of the TNF-alpha promoter after Fc gamma RIII stimulation and participates in the induction of this cytokine (PubMed:9580677). {ECO:0000269|PubMed:9580677}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (4); Chain (2); Compositional bias (3); Domain (1); Glycosylation (3); Modified residue (2); Motif (2); Mutagenesis (6); Region (9); Sequence conflict (2); Site (1); Transmembrane (1) |
| Keywords | Activator;Alternative promoter usage;Alternative splicing;Cholesterol metabolism;Cytoplasm;DNA-binding;Endoplasmic reticulum;Glycoprotein;Lipid metabolism;Lipid-binding;Membrane;Nucleus;Phosphoprotein;Reference proteome;Repressor;Signal-anchor;Steroid metabolism;Sterol metabolism;Transcription;Transcription regulation;Transmembrane;Transmembrane helix;Ubl conjugation |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic reticulum membrane {ECO:0000269|PubMed:16872277, ECO:0000269|PubMed:17705787, ECO:0000269|PubMed:18990090, ECO:0000269|PubMed:20629635, ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:29149604}; Single-pass type II membrane protein {ECO:0000250|UniProtKB:Q14494}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:16872277, ECO:0000269|PubMed:17705787, ECO:0000269|PubMed:18990090, ECO:0000269|PubMed:20629635, ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:29149604}; Single-pass type III membrane protein {ECO:0000250|UniProtKB:Q14494}. Note=In normal conditions, probably has a single-pass type II membrane protein topology, with the DNA-binding domain facing the endoplasmic reticulum lumen (By similarity). Following cellular stress, it is rapidly and efficiently retrotranslocated to the cytosolic side of the membrane, a process dependent on p97/VCP, to have a single-pass type III membrane protein topology with the major part of the protein facing the cytosol (By similarity). Retrotranslocated proteins are normally rapidly degraded by the proteasome and active species do not accumulate (By similarity). However, retrotranslocated protein NFE2L1 escapes degradation and is cleaved at Leu-104 by DDI2, releasing the protein from the endoplasmic reticulum membrane and forming the transcription factor NRF1 that translocates into the nucleus (By similarity). {ECO:0000250|UniProtKB:Q14494}.; SUBCELLULAR LOCATION: [Transcription factor NRF1]: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00978, ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:23144760, ECO:0000269|PubMed:29149604}. Note=Translocates into the nucleus following cleavage of Endoplasmic reticulum membrane sensor NFE2L1 by aspartyl protease DDI2. {ECO:0000305|PubMed:29149604}.; SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm {ECO:0000269|PubMed:23144760}. Nucleus {ECO:0000269|PubMed:23144760}. |
| Modified Residue | MOD_RES 497; /note=Phosphoserine; by CK2; /evidence=ECO:0000269|PubMed:23816881; MOD_RES 568; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q14494 |
| Post Translational Modification | PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Cleaved at Leu-104 by the aspartyl protease DDI2 following retrotranslocation, releasing the protein from the endoplasmic reticulum membrane and forming the transcription factor NRF1 that translocates into the nucleus. Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2. {ECO:0000250|UniProtKB:Q14494}.; PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: N-glycosylated in normal conditions, when it has a single-pass type II membrane protein topology, with the DNA-binding domain facing the endoplasmic reticulum lumen (PubMed:17705787, PubMed:18990090). Deglycosylated during retrotranslocation to the cytosolic side of the membrane, to have a single-pass type III membrane protein topology with the major part of the protein facing the cytosol (By similarity). {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:17705787, ECO:0000269|PubMed:18990090}.; PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Ubiquitinated by the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by the proteasome (PubMed:21953459, PubMed:21911472). Ubiquitinated during retrotranslocation to the cytosolic side of the membrane: ubiquitination does not lead to degradation and is required for processing by the aspartyl protease DDI2 and subsequent release from the endoplasmic reticulum membrane (By similarity). {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:21911472, ECO:0000269|PubMed:21953459}.; PTM: [Transcription factor NRF1]: Phosphorylation by CK2 at Ser-497 inhibits transcription factor activity, possibly by affecting DNA-binding activity (PubMed:9580677, PubMed:23816881). Phosphorylation at Ser-568 is required for interaction with CEBPB (By similarity). {ECO:0000250|UniProtKB:Q14494, ECO:0000269|PubMed:23816881, ECO:0000269|PubMed:9580677}.; PTM: [Transcription factor NRF1]: Ubiquitinated by the SCF(BTRC) complex in the nucleus, leading to its degradation by the proteasome. {ECO:0000269|PubMed:21911472}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10037736; 10615136; 11025215; 12466851; 12904583; 14517290; 14610273; 15308669; 15618518; 16141072; 16581765; 16687406; 17967808; 18799693; 19615412; 19887580; 20059953; 20300111; 20412781; 21267068; 21412055; 22971132; 22988430; 23702335; 23840004; 24448410; 24451648; 24462598; 24952961; 25043031; 25092871; 25290918; 25637874; 26222436; 26231763; 27060105; 27345029; 27920251; 28088524; 28549828; 29400713; 29421237; 29935181; 30135079; 30287392; 30559296; 31389006; 31709534; 31883458; 31931283; 32705174; 32973791; 32980394; 33376579; 34058615; 34489413; 7567998; 7726861; 8903741; 8932385; 9811942; |
| Motif | MOTIF 447..451; /note=Destruction motif; /evidence=ECO:0000269|PubMed:21911472; MOTIF 730..737; /note=Nuclear localization signal; /evidence=ECO:0000255 |
| Gene Encoded By | |
| Mass | 81,575 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |