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Protein

Endoplasmic reticulum membrane sensor NFE2L1

Gene

NFE2L1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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:20932482, PubMed:24448410). Constitutes a precursor of the transcription factor NRF1 (By similarity). Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition (PubMed:20932482). 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 (By similarity). 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 (By similarity). 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:20932482).By similarity2 Publications
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:8932385, PubMed:9421508). 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:8932385, PubMed:9421508). Activates or represses expression of target genes, depending on the context (PubMed:8932385, PubMed:9421508). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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 (By similarity). 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:20932482). Also involved in regulating glucose flux (By similarity). Together with CEBPB; represses expression of DSPP during odontoblast differentiation (PubMed:15308669). In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts.By similarity4 Publications

Caution

Endoplasmic reticulum membrane sensor NFE2L1: According to a report, processing following retrotranslocation is dependent on the proteasome (PubMed:24998528). However, it was later shown that processing takes place in a proteasome-independent manner (PubMed:27676297, PubMed:27676298).3 Publications
Endoplasmic reticulum membrane sensor NFE2L1: its topology is subject to discussion. According to some groups, it has a single-pass type II membrane protein in normal conditions and is retrotranslocated into a single-pass type III membrane protein in response to stress (PubMed:24448410). According to other reports, it is integrated into the endoplasmic reticulum membrane via multiple membrane-spanning alpha-helices.By similarity1 Publication
Transcription factor NRF1: Was initially thought to activate erythroid-specific, globin gene expression (PubMed:8036168). Knockout experiments in mouse however demonstrated that it is not the case.By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

  • anatomical structure morphogenesis Source: ProtInc
  • cell redox homeostasis Source: UniProtKB
  • cellular response to cholesterol Source: UniProtKB
  • cellular response to oxidative stress Source: UniProtKB
  • cholesterol metabolic process Source: UniProtKB-KW
  • erythrocyte differentiation Source: Ensembl
  • heme biosynthetic process Source: ProtInc
  • inflammatory response Source: ProtInc
  • lipid homeostasis Source: UniProtKB
  • negative regulation of transcription by RNA polymerase II Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter in response to stress Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: GO_Central
  • positive regulation of transcription from RNA polymerase II promoter in response to stress Source: UniProtKB
  • regulation of cholesterol homeostasis Source: UniProtKB
  • regulation of odontoblast differentiation Source: UniProtKB
  • regulation of transcription by RNA polymerase II Source: GO_Central
  • transcription by RNA polymerase II Source: ProtInc

Keywordsi

Molecular functionActivator, DNA-binding, Repressor
Biological processCholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism, Transcription, Transcription regulation
LigandLipid-binding

Enzyme and pathway databases

SignaLinkiQ14494
SIGNORiQ14494

Names & Taxonomyi

Protein namesi
Recommended name:
Endoplasmic reticulum membrane sensor NFE2L1Curated
Alternative name(s):
Locus control region-factor 11 Publication
Short name:
LCR-F11 Publication
Nuclear factor erythroid 2-related factor 1
Short name:
NF-E2-related factor 12 Publications
Short name:
NFE2-related factor 12 Publications
Nuclear factor, erythroid derived 2, like 1
Protein NRF1, p120 form1 Publication
Transcription factor 111 Publication
Short name:
TCF-111 Publication
Cleaved into the following chain:
Alternative name(s):
Protein NRF1, p110 form1 Publication
Gene namesi
Name:NFE2L1
Synonyms:HBZ17, NRF12 Publications, TCF111 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

EuPathDBiHostDB:ENSG00000082641.15
HGNCiHGNC:7781 NFE2L1
MIMi163260 gene
neXtProtiNX_Q14494

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei7 – 24Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST18

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi101 – 106NAWLVH → AAAAAA in m1; impaired protein cleavage. 1 Publication6
Mutagenesisi101 – 103NAW → AAA in m2; impaired protein cleavage. 1 Publication3
Mutagenesisi103 – 104WL → AA in m5; impaired protein cleavage. 1 Publication2
Mutagenesisi103W → A in m3; impaired protein cleavage. 1 Publication1
Mutagenesisi104 – 106LVH → AAA in m6; Slightly impaired protein cleavage. 1 Publication3
Mutagenesisi104L → A in m4; Slightly impaired protein cleavage. 1 Publication1
Mutagenesisi599S → A: Impaired interaction with CEBPB. 1 Publication1

Organism-specific databases

DisGeNETi4779
OpenTargetsiENSG00000082641
PharmGKBiPA31587

Chemistry databases

DrugBankiDB04147 Lauryl Dimethylamine-N-Oxide

Polymorphism and mutation databases

BioMutaiNFE2L1
DMDMi3183180

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000764471 – 772Endoplasmic reticulum membrane sensor NFE2L1Add BLAST772
ChainiPRO_0000443103104 – 772Transcription factor NRF11 PublicationAdd BLAST669

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi348N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi360N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi412N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi423N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei528Phosphoserine; by CK2By similarity1
Modified residuei599Phosphoserine; by PKA1 Publication1

Post-translational modificationi

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 (PubMed:24448410, PubMed:27676297, PubMed:27676298, PubMed:27528193). Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2 (PubMed:27676298).4 Publications
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:20932482, PubMed:24998528, PubMed:24448410, PubMed:27528193). 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 (PubMed:20932482, PubMed:24998528, PubMed:24448410).4 Publications
Endoplasmic reticulum membrane sensor NFE2L1: Ubiquitinated by the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by the proteasome (PubMed:20932482). 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 (PubMed:24998528, PubMed:27676298).By similarity3 Publications
Transcription factor NRF1: Phosphorylation by CK2 at Ser-528 inhibits transcription factor activity, possibly by affecting DNA-binding activity (By similarity). Phosphorylation at Ser-599 is required for interaction with CEBPB (PubMed:15308669).By similarity1 Publication
Transcription factor NRF1: Ubiquitinated by the SCF(BTRC) complex in the nucleus, leading to its degradation by the proteasome.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei103 – 104Cleavage; by DDI21 Publication2

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ14494
PaxDbiQ14494
PeptideAtlasiQ14494
PRIDEiQ14494

PTM databases

iPTMnetiQ14494
PhosphoSitePlusiQ14494

Expressioni

Gene expression databases

BgeeiENSG00000082641
CleanExiHS_NFE2L1
HS_NRF1
ExpressionAtlasiQ14494 baseline and differential
GenevisibleiQ14494 HS

Organism-specific databases

HPAiHPA063384
HPA065424

Interactioni

Subunit structurei

Interacts with KEAP1 (PubMed:16687406). Endoplasmic reticulum membrane sensor NFE2L1: Interacts (via CPD region) with FBXW7; leading to its ubiquitination and degradation (By similarity). Endoplasmic reticulum membrane sensor NFE2L1: Interacts with SYVN1/HRD1; leading to its ubiquitination and degradation (By similarity). Endoplasmic reticulum membrane sensor NFE2L1: Interacts (when ubiquitinated) with DDI2; leading to its cleavage (By similarity). Transcription factor NRF1: Interacts (via the bZIP domain) with small MAF protein (MAFF, MAFG or MAFK); required for binding to antioxidant response elements (AREs) on DNA (PubMed:8932385, PubMed:9421508). Transcription factor NRF1: Interacts (via Destruction motif) with BTRC; leading to its ubiquitination and degradation (By similarity). Transcription factor NRF1: Interacts with CEBPB; the heterodimer represses expression of DSPP during odontoblast differentiation (PubMed:15308669).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • protein domain specific binding Source: Ensembl
  • protein heterodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi110851, 22 interactors
ELMiQ14494
IntActiQ14494, 21 interactors
STRINGi9606.ENSP00000354855

Structurei

3D structure databases

ProteinModelPortaliQ14494
SMRiQ14494
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini654 – 717bZIPPROSITE-ProRule annotationAdd BLAST64

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni191 – 199Cholesterol recognition/amino acid consensus (CRAC) regionBy similarity9
Regioni379 – 383CPDBy similarity5
Regioni656 – 675Basic motifPROSITE-ProRule annotationAdd BLAST20
Regioni682 – 696Leucine-zipperPROSITE-ProRule annotationAdd BLAST15

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi476 – 480Destruction motifBy similarity5

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi125 – 288Asp/Glu-rich (acidic)Add BLAST164
Compositional biasi496 – 517Poly-SerAdd BLAST22

Domaini

The cholesterol recognition/amino acid consensus (CRAC) region directly binds cholesterol, as well as campesterol and 27-hydroxycholesterol. Has much lower affinity for epicholesterol.By similarity

Sequence similaritiesi

Belongs to the bZIP family. CNC subfamily.Curated

Keywords - Domaini

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3863 Eukaryota
ENOG410ZGMS LUCA
GeneTreeiENSGT00910000144085
HOGENOMiHOG000234410
HOVERGENiHBG052609
InParanoidiQ14494
KOiK09040
OMAiHKHSGPS
OrthoDBiEOG091G02EB
PhylomeDBiQ14494
TreeFamiTF326681

Family and domain databases

InterProiView protein in InterPro
IPR004827 bZIP
IPR004826 bZIP_Maf
IPR029847 Nrf1_NFE2L1
IPR008917 TF_DNA-bd_sf
PANTHERiPTHR24411:SF31 PTHR24411:SF31, 1 hit
PfamiView protein in Pfam
PF03131 bZIP_Maf, 1 hit
SMARTiView protein in SMART
SM00338 BRLZ, 1 hit
SUPFAMiSSF47454 SSF47454, 1 hit
PROSITEiView protein in PROSITE
PS50217 BZIP, 1 hit
PS00036 BZIP_BASIC, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q14494-1) [UniParc]FASTAAdd to basket
Also known as: TCF111 Publication

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLSLKKYLTE GLLQFTILLS LIGVRVDVDT YLTSQLPPLR EIILGPSSAY
60 70 80 90 100
TQTQFHNLRN TLDGYGIHPK SIDLDNYFTA RRLLSQVRAL DRFQVPTTEV
110 120 130 140 150
NAWLVHRDPE GSVSGSQPNS GLALESSSGL QDVTGPDNGV RESETEQGFG
160 170 180 190 200
EDLEDLGAVA PPVSGDLTKE DIDLIDILWR QDIDLGAGRE VFDYSHRQKE
210 220 230 240 250
QDVEKELRDG GEQDTWAGEG AEALARNLLV DGETGESFPA QVPSGEDQTA
260 270 280 290 300
LSLEECLRLL EATCPFGENA EFPADISSIT EAVPSESEPP ALQNNLLSPL
310 320 330 340 350
LTGTESPFDL EQQWQDLMSI MEMQAMEVNT SASEILYSAP PGDPLSTNYS
360 370 380 390 400
LAPNTPINQN VSLHQASLGG CSQDFLLFSP EVESLPVASS STLLPLAPSN
410 420 430 440 450
STSLNSTFGS TNLTGLFFPP QLNGTANDTA GPELPDPLGG LLDEAMLDEI
460 470 480 490 500
SLMDLAIEEG FNPVQASQLE EEFDSDSGLS LDSSHSPSSL SSSEGSSSSS
510 520 530 540 550
SSSSSSSSSA SSSASSSFSE EGAVGYSSDS ETLDLEEAEG AVGYQPEYSK
560 570 580 590 600
FCRMSYQDPA QLSCLPYLEH VGHNHTYNMA PSALDSADLP PPSALKKGSK
610 620 630 640 650
EKQADFLDKQ MSRDEHRARA MKIPFTNDKI INLPVEEFNE LLSKYQLSEA
660 670 680 690 700
QLSLIRDIRR RGKNKMAAQN CRKRKLDTIL NLERDVEDLQ RDKARLLREK
710 720 730 740 750
VEFLRSLRQM KQKVQSLYQE VFGRLRDENG RPYSPSQYAL QYAGDGSVLL
760 770
IPRTMADQQA RRQERKPKDR RK
Length:772
Mass (Da):84,704
Last modified:November 1, 1996 - v1
Checksum:iC868807C6046BEF5
GO
Isoform 2 (identifier: Q14494-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     242-271: Missing.

Show »
Length:742
Mass (Da):81,499
Checksum:iB99AAEF1C5F598E6
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04844063D → H. Corresponds to variant dbSNP:rs2229367Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_000579242 – 271Missing in isoform 2. 2 PublicationsAdd BLAST30

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L24123 mRNA No translation available.
X77366 mRNA Translation: CAA54555.1
CH471109 Genomic DNA Translation: EAW94762.1
CH471109 Genomic DNA Translation: EAW94763.1
CH471109 Genomic DNA Translation: EAW94764.1
CH471109 Genomic DNA Translation: EAW94765.1
CH471109 Genomic DNA Translation: EAW94766.1
CH471109 Genomic DNA Translation: EAW94767.1
BC010623 mRNA Translation: AAH10623.1
U08853 mRNA Translation: AAA20466.1
CCDSiCCDS11524.1 [Q14494-1]
CCDS82150.1 [Q14494-2]
PIRiA49672
A55004
RefSeqiNP_001317191.1, NM_001330262.1 [Q14494-2]
NP_003195.1, NM_003204.2 [Q14494-1]
XP_005257467.1, XM_005257410.3 [Q14494-1]
XP_005257469.1, XM_005257412.3 [Q14494-2]
UniGeneiHs.514284

Genome annotation databases

EnsembliENST00000357480; ENSP00000350072; ENSG00000082641 [Q14494-2]
ENST00000362042; ENSP00000354855; ENSG00000082641 [Q14494-1]
ENST00000585291; ENSP00000461960; ENSG00000082641 [Q14494-2]
GeneIDi4779
KEGGihsa:4779
UCSCiuc002imz.5 human [Q14494-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNF2L1_HUMAN
AccessioniPrimary (citable) accession number: Q14494
Secondary accession number(s): D3DTU3
, D3DTU5, Q12877, Q96FN6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: April 25, 2018
This is version 173 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
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Main funding by: National Institutes of Health