ID NF2L2_BOVIN Reviewed; 607 AA.
AC Q5NUA6; Q3T0S8;
DT 01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2007, sequence version 2.
DT 24-JAN-2024, entry version 112.
DE RecName: Full=Nuclear factor erythroid 2-related factor 2 {ECO:0000303|Ref.1};
DE Short=NF-E2-related factor 2 {ECO:0000303|Ref.1};
DE Short=NFE2-related factor 2 {ECO:0000303|Ref.1};
DE AltName: Full=Nuclear factor, erythroid derived 2, like 2 {ECO:0000250|UniProtKB:Q16236};
GN Name=NFE2L2 {ECO:0000250|UniProtKB:Q16236};
GN Synonyms=NRF2 {ECO:0000250|UniProtKB:Q16236};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Artery;
RA Hara S., Nishimoto M., Kunimoto M.;
RT "Characterization of bovine endothelial NF-E2-related factor-2.";
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-522.
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Transcription factor that plays a key role in the response to
CC oxidative stress: binds to antioxidant response (ARE) elements present
CC in the promoter region of many cytoprotective genes, such as phase 2
CC detoxifying enzymes, and promotes their expression, thereby
CC neutralizing reactive electrophiles. In normal conditions,
CC ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex.
CC In response to oxidative stress, electrophile metabolites inhibit
CC activity of the BCR(KEAP1) complex, promoting nuclear accumulation of
CC NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and
CC binding to ARE elements of cytoprotective target genes. The NFE2L2/NRF2
CC pathway is also activated in response to selective autophagy: autophagy
CC promotes interaction between KEAP1 and SQSTM1/p62 and subsequent
CC inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear
CC accumulation and expression of cytoprotective genes (By similarity).
CC May also be involved in the transcriptional activation of genes of the
CC beta-globin cluster by mediating enhancer activity of hypersensitive
CC site 2 of the beta-globin locus control region (By similarity). Plays
CC also an important role in the regulation of the innate immune response.
CC It is a critical regulator of the innate immune response and survival
CC during sepsis by maintaining redox homeostasis and restraint of the
CC dysregulation of pro-inflammatory signaling pathways like MyD88-
CC dependent and -independent and TNF-alpha signaling. Suppresses
CC macrophage inflammatory response by blocking pro-inflammatory cytokine
CC transcription and the induction of IL6. Binds to the proximity of pro-
CC inflammatory genes in macrophages and inhibits RNA Pol II recruitment.
CC The inhibition is independent of the Nrf2-binding motif and reactive
CC oxygen species level (By similarity). Represses antiviral cytosolic DNA
CC sensing by suppressing the expression of the adapter protein STING1 and
CC decreasing responsiveness to STING1 agonists while increasing
CC susceptibility to infection with DNA viruses (By similarity).
CC {ECO:0000250|UniProtKB:Q16236, ECO:0000250|UniProtKB:Q60795}.
CC -!- SUBUNIT: Heterodimer; heterodimerizes with small Maf proteins.
CC Interacts (via the bZIP domain) with MAFG and MAFK; required for
CC binding to antioxidant response elements (AREs) on DNA. Interacts with
CC KEAP1; the interaction is direct and promotes ubiquitination by the
CC BCR(KEAP1) E3 ubiquitin ligase complex (By similarity). Forms a ternary
CC complex with PGAM5 and KEAP1. Interacts with EEF1D at heat shock
CC promoter elements (HSE) (By similarity). Interacts via its leucine-
CC zipper domain with the coiled-coil domain of PMF1 (By similarity).
CC Interacts with CHD6; involved in activation of the transcription (By
CC similarity). Interacts with ESRRB; represses NFE2L2 transcriptional
CC activity (By similarity). Interacts with MOTS-c, a peptide produced by
CC the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in
CC the nucleus following metabolic stress (By similarity).
CC {ECO:0000250|UniProtKB:O54968, ECO:0000250|UniProtKB:Q16236,
CC ECO:0000250|UniProtKB:Q60795}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q60795}. Nucleus {ECO:0000250|UniProtKB:Q60795,
CC ECO:0000255|PROSITE-ProRule:PRU00978}. Note=Cytosolic under unstressed
CC conditions: ubiquitinated and degraded by the BCR(KEAP1) E3 ubiquitin
CC ligase complex. Translocates into the nucleus upon induction by
CC electrophilic agents that inactivate the BCR(KEAP1) E3 ubiquitin ligase
CC complex. {ECO:0000250|UniProtKB:Q60795}.
CC -!- DOMAIN: The ETGE motif, and to a lower extent the DLG motif, mediate
CC interaction with KEAP1. {ECO:0000250|UniProtKB:Q60795}.
CC -!- PTM: Ubiquitinated in the cytoplasm by the BCR(KEAP1) E3 ubiquitin
CC ligase complex leading to its degradation. In response to oxidative
CC stress, electrophile metabolites, such as sulforaphane, modify KEAP1,
CC leading to inhibit activity of the BCR(KEAP1) complex, promoting
CC NFE2L2/NRF2 nuclear accumulation and activity. In response to
CC autophagy, the BCR(KEAP1) complex is inactivated.
CC {ECO:0000250|UniProtKB:Q60795}.
CC -!- PTM: Phosphorylation of Ser-40 by PKC in response to oxidative stress
CC dissociates NFE2L2 from its cytoplasmic inhibitor KEAP1, promoting its
CC translocation into the nucleus. {ECO:0000250|UniProtKB:O54968}.
CC -!- PTM: Acetylation at Lys-598 and Lys-601 increases nuclear localization
CC whereas deacetylation by SIRT1 enhances cytoplasmic presence.
CC {ECO:0000250|UniProtKB:Q16236}.
CC -!- PTM: Glycation impairs transcription factor activity by preventing
CC heterodimerization with small Maf proteins. Deglycation by FN3K
CC restores activity. {ECO:0000250|UniProtKB:Q16236}.
CC -!- SIMILARITY: Belongs to the bZIP family. CNC subfamily. {ECO:0000305}.
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DR EMBL; AB162435; BAD81030.1; -; mRNA.
DR EMBL; BC102275; AAI02276.1; ALT_TERM; mRNA.
DR AlphaFoldDB; Q5NUA6; -.
DR SMR; Q5NUA6; -.
DR STRING; 9913.ENSBTAP00000059632; -.
DR GlyCosmos; Q5NUA6; 6 sites, No reported glycans.
DR PaxDb; 9913-ENSBTAP00000025637; -.
DR eggNOG; KOG3863; Eukaryota.
DR InParanoid; Q5NUA6; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; ISS:UniProtKB.
DR GO; GO:0045454; P:cell redox homeostasis; ISS:UniProtKB.
DR GO; GO:0071498; P:cellular response to fluid shear stress; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0010499; P:proteasomal ubiquitin-independent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0045088; P:regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR CDD; cd14720; bZIP_NFE2-like; 1.
DR Gene3D; 1.10.880.10; Transcription factor, Skn-1-like, DNA-binding domain; 1.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR004826; bZIP_Maf.
DR InterPro; IPR046347; bZIP_sf.
DR InterPro; IPR047167; NFE2-like.
DR InterPro; IPR008917; TF_DNA-bd_sf.
DR PANTHER; PTHR24411; NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR; 1.
DR PANTHER; PTHR24411:SF3; NUCLEAR FACTOR ERYTHROID 2-RELATED FACTOR 2; 1.
DR Pfam; PF03131; bZIP_Maf; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF47454; A DNA-binding domain in eukaryotic transcription factors; 1.
DR SUPFAM; SSF57959; Leucine zipper domain; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; Cytoplasm; DNA-binding; Glycation; Glycoprotein;
KW Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..607
FT /note="Nuclear factor erythroid 2-related factor 2"
FT /id="PRO_0000286396"
FT DOMAIN 499..562
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 42..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 333..363
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 380..451
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 501..520
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 524..531
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 577..607
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 593..598
FT /note="Mediates interaction with CHD6 and is necessary to
FT activate transcription"
FT /evidence="ECO:0000250"
FT MOTIF 29..31
FT /note="DLG motif"
FT /evidence="ECO:0000250|UniProtKB:Q60795"
FT MOTIF 79..82
FT /note="ETGE motif"
FT /evidence="ECO:0000250|UniProtKB:Q60795"
FT COMPBIAS 405..422
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 424..451
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 579..594
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 40
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000250|UniProtKB:O54968"
FT MOD_RES 214
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 598
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT MOD_RES 601
FT /note="N6-acetyllysine; by CREBBP"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 464
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 474
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 489
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 501
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 571
FT /note="N-linked (Glc) (glycation) arginine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CARBOHYD 576
FT /note="N-linked (Glc) (glycation) lysine"
FT /evidence="ECO:0000250|UniProtKB:Q16236"
FT CONFLICT 287
FT /note="A -> T (in Ref. 1; BAD81030)"
FT /evidence="ECO:0000305"
FT CONFLICT 423
FT /note="Q -> H (in Ref. 1; BAD81030)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 607 AA; 67895 MW; E0C576DBAF2A1A21 CRC64;
MMDLELPPPG LPSQQDMDLI DILWRQDIDL GVSREVFDFS QRQKEHELEK QKKLEKERQE
QLQKEQEKAF FAQLQLDEET GEFLPIQPAQ HIPSETSGSA NYSQVAPIPK ADDLYFDDCM
QLLAETFPFV DDNEVSSATF QSLVPDIPSH IESPVFTAPP QAQSPETLIV QVATAVLDDM
QDIEQVWEEL LSIPELQCLN IQNDKLAETS TVPSPETKLT EIDNYHFYSS MPSLDKEVGN
CSPHFLNAFE DSFNSILSTE DSSQLTVNSL NSSATVNTDF GDEFYSAFIA EPSTSNGMPS
SATLSQSLSE LLNGPIDLSD LSLCKAFNQN HPESTTAEFN DSDSGISLNT TSPSMASPDH
SVESSIYGDT LLGFSDSEME EIDSTPGNVK QKGPKTPSVW PPGDPVQPLS SSQGNSAAAR
DSQCENAPKK EVPVSPGHRK TPFTKDKHSS RLEAHLTRDE LRAKALHIPF PVEKIINLPV
EDFNEMMSKE QFNEAQLALI RDIRRRGKNK VAAQNCRKRK LENIVELEQD LDHLKDEKEK
LLKERGENDK SLHLLKKQLS TLYLEVFSML RDENGKPYSP SEYSLQQTSD GNVFLVPKSK
KPDTKKN
//
