NF2L1_PONAB
ID NF2L1_PONAB Reviewed; 772 AA.
AC Q5RA25;
DT 01-JUL-2008, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 25-MAY-2022, entry version 92.
DE RecName: Full=Endoplasmic reticulum membrane sensor NFE2L1 {ECO:0000305};
DE AltName: Full=Nuclear factor erythroid 2-related factor 1 {ECO:0000250|UniProtKB:Q14494};
DE Short=NF-E2-related factor 1 {ECO:0000250|UniProtKB:Q14494};
DE Short=NFE2-related factor 1 {ECO:0000250|UniProtKB:Q14494};
DE AltName: Full=Nuclear factor, erythroid derived 2, like 1 {ECO:0000250|UniProtKB:Q14494};
DE Contains:
DE RecName: Full=Transcription factor NRF1 {ECO:0000250|UniProtKB:Q14494};
GN Name=NFE2L1 {ECO:0000250|UniProtKB:Q14494};
GN Synonyms=NRF1 {ECO:0000250|UniProtKB:Q14494};
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: [Endoplasmic reticulum membrane sensor NFE2L1]: Endoplasmic
CC reticulum membrane sensor that translocates into the nucleus in
CC response to various stresses to act as a transcription factor (By
CC similarity). Constitutes a precursor of the transcription factor NRF1
CC (By similarity). Able to detect various cellular stresses, such as
CC cholesterol excess, oxidative stress or proteasome inhibition (By
CC similarity). In response to stress, it is released from the endoplasmic
CC reticulum membrane following cleavage by the protease DDI2 and
CC translocates into the nucleus to form the transcription factor NRF1 (By
CC similarity). Acts as a key sensor of cholesterol excess: in excess
CC cholesterol conditions, the endoplasmic reticulum membrane form of the
CC protein directly binds cholesterol via its CRAC motif, preventing
CC cleavage and release of the transcription factor NRF1, thereby allowing
CC expression of genes promoting cholesterol removal, such as CD36 (By
CC similarity). Involved in proteasome homeostasis: in response to
CC proteasome inhibition, it is released from the endoplasmic reticulum
CC membrane, translocates to the nucleus and activates expression of genes
CC encoding proteasome subunits (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000250|UniProtKB:Q61985}.
CC -!- FUNCTION: [Transcription factor NRF1]: CNC-type bZIP family
CC transcription factor that translocates to the nucleus and regulates
CC expression of target genes in response to various stresses.
CC Heterodimerizes with small-Maf proteins (MAFF, MAFG or MAFK) and binds
CC DNA motifs including the antioxidant response elements (AREs), which
CC regulate expression of genes involved in oxidative stress response.
CC Activates or represses expression of target genes, depending on the
CC context (By similarity). Plays a key role in cholesterol homeostasis by
CC acting as a sensor of cholesterol excess: in low cholesterol
CC conditions, translocates into the nucleus and represses expression of
CC genes involved in defense against cholesterol excess, such as CD36 (By
CC similarity). In excess cholesterol conditions, the endoplasmic
CC reticulum membrane form of the protein directly binds cholesterol via
CC its CRAC motif, preventing cleavage and release of the transcription
CC factor NRF1, thereby allowing expression of genes promoting cholesterol
CC removal (By similarity). Critical for redox balance in response to
CC oxidative stress: acts by binding the AREs motifs on promoters and
CC mediating activation of oxidative stress response genes, such as GCLC,
CC GCLM, GSS, MT1 and MT2 (By similarity). Plays an essential role during
CC fetal liver hematopoiesis: probably has a protective function against
CC oxidative stress and is involved in lipid homeostasis in the liver (By
CC similarity). Involved in proteasome homeostasis: in response to
CC proteasome inhibition, mediates the 'bounce-back' of proteasome
CC subunits by translocating into the nucleus and activating expression of
CC genes encoding proteasome subunits (By similarity). Also involved in
CC regulating glucose flux (By similarity). Together with CEBPB; represses
CC expression of DSPP during odontoblast differentiation. In response to
CC ascorbic acid induction, activates expression of SP7/Osterix in
CC osteoblasts (By similarity). {ECO:0000250|UniProtKB:Q14494,
CC ECO:0000250|UniProtKB:Q61985}.
CC -!- SUBUNIT: Interacts with KEAP1. {ECO:0000250|UniProtKB:Q14494}.
CC -!- SUBUNIT: [Endoplasmic reticulum membrane sensor NFE2L1]: Interacts (via
CC CPD region) with FBXW7; leading to its ubiquitination and degradation.
CC Interacts with SYVN1/HRD1; leading to its ubiquitination and
CC degradation. Interacts (when ubiquitinated) with DDI2; leading to its
CC cleavage. {ECO:0000250|UniProtKB:Q14494, ECO:0000250|UniProtKB:Q61985}.
CC -!- SUBUNIT: [Transcription factor NRF1]: Interacts (via the bZIP domain)
CC with small MAF protein (MAFF, MAFG or MAFK); required for binding to
CC antioxidant response elements (AREs) on DNA. Interacts (via Destruction
CC motif) with BTRC; leading to its ubiquitination and degradation.
CC Interacts with CEBPB; the heterodimer represses expression of DSPP
CC during odontoblast differentiation. Interacts with MOTS-c, a peptide
CC produced by the mitochondrially encoded 12S rRNA MT-RNR1.
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000250|UniProtKB:Q61985}.
CC -!- SUBCELLULAR LOCATION: [Endoplasmic reticulum membrane sensor NFE2L1]:
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q14494}; Single-
CC pass type II membrane protein {ECO:0000250|UniProtKB:Q14494}.
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q14494}; Single-
CC pass type III membrane protein {ECO:0000250|UniProtKB:Q14494}. Note=In
CC normal conditions, probably has a single-pass type II membrane protein
CC topology, with the DNA-binding domain facing the endoplasmic reticulum
CC lumen. Following cellular stress, it is rapidly and efficiently
CC retrotranslocated to the cytosolic side of the membrane, a process
CC dependent on p97/VCP, to have a single-pass type III membrane protein
CC topology with the major part of the protein facing the cytosol.
CC Retrotranslocated proteins are normally rapidly degraded by the
CC proteasome and active species do not accumulate. However,
CC retrotranslocated protein NFE2L1 escapes degradation and is cleaved at
CC Leu-104 by DDI2, releasing the protein from the endoplasmic reticulum
CC membrane and forming the transcription factor NRF1 that translocates
CC into the nucleus. {ECO:0000250|UniProtKB:Q14494}.
CC -!- SUBCELLULAR LOCATION: [Transcription factor NRF1]: Nucleus
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000255|PROSITE-ProRule:PRU00978}.
CC Note=Translocates into the nucleus following cleavage of Endoplasmic
CC reticulum membrane sensor NFE2L1 by aspartyl protease DDI2.
CC {ECO:0000250|UniProtKB:Q14494}.
CC -!- DOMAIN: The cholesterol recognition/amino acid consensus (CRAC) region
CC directly binds cholesterol, as well as campesterol and 27-
CC hydroxycholesterol. Has much lower affinity for epicholesterol.
CC {ECO:0000250|UniProtKB:Q61985}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Cleaved at Leu-104
CC by the aspartyl protease DDI2 following retrotranslocation, releasing
CC the protein from the endoplasmic reticulum membrane and forming the
CC transcription factor NRF1 that translocates into the nucleus.
CC Ubiquitination is prerequisite for cleavage by aspartyl protease DDI2.
CC {ECO:0000250|UniProtKB:Q14494}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: N-glycosylated in
CC normal conditions, when it has a single-pass type II membrane protein
CC topology, with the DNA-binding domain facing the endoplasmic reticulum
CC lumen (By similarity). Deglycosylated during retrotranslocation to the
CC cytosolic side of the membrane, to have a single-pass type III membrane
CC protein topology with the major part of the protein facing the cytosol
CC (By similarity). {ECO:0000250|UniProtKB:Q14494,
CC ECO:0000250|UniProtKB:Q61985}.
CC -!- PTM: [Endoplasmic reticulum membrane sensor NFE2L1]: Ubiquitinated by
CC the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by
CC the proteasome (By similarity). Ubiquitinated during retrotranslocation
CC to the cytosolic side of the membrane: ubiquitination does not lead to
CC degradation and is required for processing by the aspartyl protease
CC DDI2 and subsequent release from the endoplasmic reticulum membrane (By
CC similarity). {ECO:0000250|UniProtKB:Q14494,
CC ECO:0000250|UniProtKB:Q61985}.
CC -!- PTM: [Transcription factor NRF1]: Phosphorylation by CK2 at Ser-528
CC inhibits transcription factor activity, possibly by affecting DNA-
CC binding activity (By similarity). Phosphorylation at Ser-599 is
CC required for interaction with CEBPB (By similarity).
CC {ECO:0000250|UniProtKB:Q14494, ECO:0000250|UniProtKB:Q61985}.
CC -!- PTM: [Transcription factor NRF1]: Ubiquitinated by the SCF(BTRC)
CC complex in the nucleus, leading to its degradation by the proteasome.
CC {ECO:0000250|UniProtKB:Q61985}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
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DR EMBL; CR859198; CAH91385.1; -; mRNA.
DR RefSeq; NP_001125819.1; NM_001132347.1.
DR AlphaFoldDB; Q5RA25; -.
DR SMR; Q5RA25; -.
DR STRING; 9601.ENSPPYP00000009969; -.
DR GeneID; 100172747; -.
DR KEGG; pon:100172747; -.
DR CTD; 4779; -.
DR eggNOG; KOG3863; Eukaryota.
DR InParanoid; Q5RA25; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0015485; F:cholesterol binding; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IEA:InterPro.
DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; ISS:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0045454; P:cell redox homeostasis; ISS:UniProtKB.
DR GO; GO:0071397; P:cellular response to cholesterol; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0055088; P:lipid homeostasis; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0097201; P:negative regulation of transcription from RNA polymerase II promoter in response to stress; ISS:UniProtKB.
DR GO; GO:0036003; P:positive regulation of transcription from RNA polymerase II promoter in response to stress; ISS:UniProtKB.
DR GO; GO:1901329; P:regulation of odontoblast differentiation; ISS:UniProtKB.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR029847; NFE2L1.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR PANTHER; PTHR24411:SF31; PTHR24411:SF31; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; SSF47454; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 2: Evidence at transcript level;
KW Activator; Cholesterol metabolism; DNA-binding; Endoplasmic reticulum;
KW Glycoprotein; Lipid metabolism; Lipid-binding; Membrane; Nucleus;
KW Phosphoprotein; Reference proteome; Repressor; Signal-anchor;
KW Steroid metabolism; Sterol metabolism; Transcription;
KW Transcription regulation; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..772
FT /note="Endoplasmic reticulum membrane sensor NFE2L1"
FT /id="PRO_0000341947"
FT CHAIN 104..772
FT /note="Transcription factor NRF1"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT /id="PRO_0000443105"
FT TRANSMEM 7..24
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT DOMAIN 654..717
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 108..148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 191..199
FT /note="Cholesterol recognition/amino acid consensus (CRAC)
FT region"
FT /evidence="ECO:0000250|UniProtKB:Q61985"
FT REGION 379..383
FT /note="CPD"
FT /evidence="ECO:0000250|UniProtKB:Q61985"
FT REGION 470..532
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 656..675
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 682..696
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 753..772
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 476..480
FT /note="Destruction motif"
FT /evidence="ECO:0000250|UniProtKB:Q61985"
FT MOTIF 761..768
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 112..141
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 470..526
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 103..104
FT /note="Cleavage; by DDI2"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT MOD_RES 528
FT /note="Phosphoserine; by CK2"
FT /evidence="ECO:0000250|UniProtKB:Q61985"
FT MOD_RES 599
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:Q14494"
FT CARBOHYD 348
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 412
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 423
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 772 AA; 84643 MW; 51410A3C84882863 CRC64;
MLSLKKYLTE GLLQFTILLS LIGVRVDVDT YLTSQLPPLR EIILGPSSAY TQTQFHNLRN
TLDGYGIHPK SIDLDNYFTA RRLLSQVRAL DRFQVPTTEV NAWLVHRDPE GSVSGSQPNS
GLALESSSGL QDVTGPDNGV RESETEQGFG EDLEDLGAVA PPVSGDLTKE DIDLIDILWR
QDIDLGAGRE VFDYSHRQKE QDVEKELRDG GEQDTWAGEG AEALARNLLV DGETGESFPA
QVPSGEDQTA LSLEECLRLL EATCPFGENA EFPADISSIT EAVPSESEPP ALQNNLLSPL
LAGTESPFDL EQQWQDLMSI MEMQAMEVNT SASEILYSAP PGDPLSTNYS LAPNTPINQN
VSPHQASLGG CSQDFLLFSP EVESLPVASS STLLPLAPSN STSLNSTFGS TNLTGLFFPP
QLNGTANDTA GPELPDPLGG LLDEAMLDEI SLMDLAIEEG FNPVQASQLE EEFDSDSGLS
LDSSHSPSSL SSSEGSSSSS SSSSSSSSSA SSSASSSFSE EGAVGYSSDS ETLDLEEAEG
AVGYQPEYSK FCRMSYQDPA QLSCLPYLEH VGHNHTYNMA PSALDSADLP PPSALKKGSK
EKLADFLDKQ MSRDEHRARA MKIPFTNDKI INLPVEEFNE LLSKYQLSEA QLSLIRDIRR
RGKNKMAAQN CRKRKLDTIL NLERDVEDLQ RDKARLLREK VEFLRSLRQM KQKVQSLYQE
VFGRLRDENG RPYSPSQYAL QYAGDGSVLL IPRTMADQQA RRQERKPKDR RK
