NFE2L1

Summary

NFE2L1 (NFE2 like bZIP transcription factor 1, HGNC:7781) is a protein-coding gene on chromosome 17q21.32, encoding Endoplasmic reticulum membrane sensor NFE2L1 (Q14494). Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor.

This gene encodes a protein that is involved in globin gene expression in erythrocytes. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene, NFE2L1, and for “nuclear respiratory factor 1” which has an official symbol of NRF1.

Source: NCBI Gene 4779 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Limited, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 158 total
• MANE Select transcript: NM_003204

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7781
Approved symbol	NFE2L1
Name	NFE2 like bZIP transcription factor 1
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	NRF1, LCR-F1, FLJ00380, NRF-1
Ensembl gene	ENSG00000082641
Ensembl biotype	protein_coding
OMIM	163260
Entrez	4779

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 28 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000357480, ENST00000361665, ENST00000362042, ENST00000536222, ENST00000577411, ENST00000577431, ENST00000579481, ENST00000579537, ENST00000579889, ENST00000580037, ENST00000580050, ENST00000581319, ENST00000581441, ENST00000582155, ENST00000582574, ENST00000583060, ENST00000583210, ENST00000583378, ENST00000584137, ENST00000584634, ENST00000585062, ENST00000585291, ENST00000585299, ENST00000880070, ENST00000880071, ENST00000880072, ENST00000880073, ENST00000880074, ENST00000880075, ENST00000937364, ENST00000937365, ENST00000937366

RefSeq mRNA: 3 — MANE Select: NM_003204 NM_001330261, NM_001330262, NM_003204

CCDS: CCDS11524, CCDS82150, CCDS82151

Canonical transcript exons

ENST00000362042 — 6 exons

Exon	Start	End
ENSE00001340556	48050607	48051628
ENSE00001421631	48048359	48048462
ENSE00003491156	48057032	48057121
ENSE00003521831	48056386	48056598
ENSE00003628114	48057344	48057502
ENSE00003845988	48058295	48061545

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 128.4122 / max 2351.3799, expressed in 1825 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161407	68.7155	1748
161406	51.2517	1817
161405	3.2806	1502
161414	1.4211	542
161415	1.0445	383
161408	0.6555	373
161418	0.5445	295
161416	0.4036	200
161417	0.3195	141
161413	0.3018	136

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	99.62	gold quality
gastrocnemius	UBERON:0001388	99.53	gold quality
muscle of leg	UBERON:0001383	99.52	gold quality
muscle organ	UBERON:0001630	99.45	gold quality
diaphragm	UBERON:0001103	99.43	gold quality
skeletal muscle tissue	UBERON:0001134	99.39	gold quality
tibialis anterior	UBERON:0001385	99.37	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.33	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.32	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.31	gold quality
calcaneal tendon	UBERON:0003701	99.30	gold quality
triceps brachii	UBERON:0001509	99.28	gold quality
deltoid	UBERON:0001476	99.26	gold quality
tendon	UBERON:0000043	99.25	gold quality
muscle tissue	UBERON:0002385	99.24	gold quality
body of tongue	UBERON:0011876	99.19	gold quality
quadriceps femoris	UBERON:0001377	99.18	gold quality
vastus lateralis	UBERON:0001379	99.18	gold quality
biceps brachii	UBERON:0001507	99.17	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.10	gold quality
left ventricle myocardium	UBERON:0006566	99.07	gold quality
cranial nerve II	UBERON:0000941	98.99	gold quality
apex of heart	UBERON:0002098	98.94	gold quality
stromal cell of endometrium	CL:0002255	98.90	gold quality
heart left ventricle	UBERON:0002084	98.89	gold quality
cardiac ventricle	UBERON:0002082	98.87	gold quality
olfactory bulb	UBERON:0002264	98.85	gold quality
cardiac atrium	UBERON:0002081	98.84	gold quality
right atrium auricular region	UBERON:0006631	98.81	gold quality
tendon of biceps brachii	UBERON:0008188	98.76	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.98
E-CURD-53	no	375.10
E-CURD-10	no	306.32
E-HCAD-31	no	294.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
CDK11B	Unknown
GCLC	Unknown
HBB	Activation
LPIN1	Activation
NFE2L1
NOS2	Activation
NQO1	Activation
PPARGC1B	Activation
SP7	Unknown

Upstream regulators (CollecTRI, top): E2F4, MAFG, NFE2L1, NRF1

miRNA regulators (miRDB)

116 targeting NFE2L1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-4731-5P	99.89	67.23	2537

Literature-anchored findings (GeneRIF, showing 40)

• A nuclear export signal (NES) localised in the N-terminus of TCF11 is responsible for the active nuclear export of the protein. (PMID:12729924)
• p65Nrf1 has the potential to play an important role in modulating the response to oxidative stress by functioning as a transdominant repressor of Nrf2-mediated activation of ARE-dependent gene transcription (PMID:17609210)
• Data show that nuclear factor erythroid-derived 2-related factor 1 (Nrf1), but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts. (PMID:20385086)
• Data show that Nrf1 can adopt several topologies within membranes that are determined by its NTD. (PMID:20629635)
• Report that proteasome inhibition can be anticipated by TCF11-dependent activation of human proteasome gene expression, which in turn is controlled by a HRD1-p97-ERAD feedback circle. (PMID:20932482)
• Fbw7 as a regulator of Nrf1 expression and reveal a novel function of Fbw7 in cellular stress response. (PMID:21953459)
• data suggests that Nrf1 is controlled by several post-translational mechanisms, including ubiquitination, proteolytic processing and proteasomal-mediated degradation as well as by its phosphorylation status (PMID:22216197)
• results indicate a novel role of Nrf1 in UVB-induced DNA damage repair and suggest Nrf1 as a tumor suppressor in the skin (PMID:22500024)
• A proteasome inhibitor-stimulated Nrf1 protein-dependent compensatory increase in proteasome subunit gene expression reduces polycomb group protein level (PMID:22932898)
• findings suggest that nuclear-related factor erythroid 2 transcription factor (Nrf1) may play a role in maintaining genomic integrity, and that Nrf1 dysregulation may induce tumorigenesis (PMID:22971132)
• Data indicate both Nrf1a and Nrf1b isoforms transcripts were detected in different mouse and human cell lines, and in various mouse tissues. (PMID:23144760)
• GSK3 regulates Nrf1 expression and cell survival function in response to stress activation. (PMID:23623971)
• The study identifies casein kinase 2 as an NRF1-binding protein and finds that the knockdown of casein kinase 2 enhances the NRF1-dependent expression of the proteasome subunit genes. (PMID:23816881)
• Nrf1 knockout resulted in the increased expression of GCLC and GCLM in human bronchial epithelial (HBE1) cells. (PMID:24024152)
• Data uncover an unexpected role for p97 in activation of transcription factor Nrf1 by relocalizing it from the endoplasmic reticulum lumen to the cytosol. (PMID:24448410)
• while Nrf2 is crucial for MRE/ARE-mediated transcription in response to copper, Nrf1 may activate MT-1 expression by a mechanism different from that Nrf2 employs. (PMID:24462598)
• Nrf1 physically interacts with androgen receptor and enhances it’s DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential androgen receptor coactivator. (PMID:24466341)
• The treatment with E2, Res, or VC significantly increased mRNA and protein expression levels of Nrf1. (PMID:25130429)
• The results indicate that Nrf1 is a transcriptional activator of Herpud1 expression during ER stress, and they suggest Nrf1 is a key player in the regulation of the ER stress response in cells. (PMID:25637874)
• Nrf1 is negatively regulated by its O-GlcNAcylation status that depends on the glucose concentrations (PMID:26231763)
• This review outlines Nrf1 structure, function, regulation and its links to insulin resistance, diabetes and inflammation. (PMID:26254094)
• Importantly, Nrf1 activity is positively and/or negatively regulated by distinct doses of proteasome and calpain inhibitors (PMID:26268886)
• Together with molecular expression results, the authors thus suppose requirement of Nrf1alpha (and major derivates) for gene regulatory mechanisms repressing cancer cell process and malignant behaviour. (PMID:27065079)
• our investigation shows that the ER membrane protein TCF11/Nrf1 is an essential component of the cellular stress response mechanism. In response to cytotoxic stress, TCF11/Nrf1 is retrotranslocated and transferred to the nucleus where it induces proteasome subunit expression via binding to the ARE region of the relevant promoter. (PMID:27345029)
• These results uncover a new regulatory mechanism that USP15 activates Nrf1 against the beta-TrCP inhibition to maintain proteostasis. (PMID:27416755)
• Here the authors show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. (PMID:27528193)
• Nrf1 is regulated by O-GlcNAc transferase. (PMID:28625484)
• These findings indicate that NFE2L1(L) functions as a negative regulator of M1 polarization and pro-inflammatory response in macrophages (PMID:29421237)
• study identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes (PMID:29941490)
• Here, we tested the hypothesis that calpain-1 or -2 cleave TCF11/Nrf1. However, we did not find a role for calpain-1 or -2 in the activation of TCF11/Nrf1 after proteasome inhibition neither by using chemical inhibitors nor siRNA-mediated knockdown or overexpression of calpain subunits (PMID:30177525)
• The nascent Nrf1alpha (NFE2L1)/TCF11 polypeptide (non-glycosylated) is transiently translocated into the endoplasmic reticulum (ER). (PMID:30287392)
• Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in high-risk diffuse large B cell lymphomas treated with R-CHOEP (PMID:30755497)
• Distinct isoforms of Nrf1 diversely regulate different subsets of its cognate target genes. (PMID:30814566)
• analysis provides a comprehensive description of differential and overlapping gene regulation by the transcriptional regulators NFE2L1(NRF1), NFE2L2 (NRF2), and NFE2L3 (NRF3). (PMID:31628195)
• High nuclear immunohistochemical NRF1(NFE2L1) expression in pigment cells associated with a worse survival (p = 0.048) in patients with N0 disease at the time of diagnosis, and high nuclear NRF2 (NFE2L2) expression in pigment cells associated with a worse survival. (PMID:31687076)
• Overexpression of NRF1-742 or NRF1-772 Reduces Arsenic-Induced Cytotoxicity and Apoptosis in Human HaCaT Keratinocytes. (PMID:32188015)
• NFE2L1 and NFE2L3 Complementarily Maintain Basal Proteasome Activity in Cancer Cells through CPEB3-Mediated Translational Repression. (PMID:32366381)
• DDI2 Is a Ubiquitin-Directed Endoprotease Responsible for Cleavage of Transcription Factor NRF1. (PMID:32521225)
• Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration. (PMID:32924844)
• Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks. (PMID:33376579)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nfe2l1a	ENSDARG00000030616
danio_rerio	nfe2l1b	ENSDARG00000076533
mus_musculus	Nfe2l1	ENSMUSG00000038615
rattus_norvegicus	Nfe2l1	ENSRNOG00000008830

Paralogs (3): NFE2L3 (ENSG00000050344), NFE2L2 (ENSG00000116044), NFE2 (ENSG00000123405)

Protein

Protein identifiers

Endoplasmic reticulum membrane sensor NFE2L1 — Q14494 (reviewed: Q14494)

Alternative names: Locus control region-factor 1, Nuclear factor erythroid 2-related factor 1, Nuclear factor, erythroid derived 2, like 1, Protein NRF1, p120 form, Transcription factor 11

All UniProt accessions (16): Q14494, A0A0G2JLG9, B4DYE1, F5H1B7, J3KRF3, J3KSE0, J3KSR3, J3KTG6, J3QKY3, J3QLQ1, J3QQH8, J3QQQ1, J3QQY8, J3QR31, J3QRG7, J9JIE5

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum membrane sensor that translocates into the nucleus in response to various stresses to act as a transcription factor. Constitutes a precursor of the transcription factor NRF1. Able to detect various cellular stresses, such as cholesterol excess, oxidative stress or proteasome inhibition. 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. 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. 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. CNC-type bZIP family transcription factor that translocates to the nucleus and regulates expression of target genes in response to various stresses. 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. Activates or represses expression of target genes, depending on the context. 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. 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. 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. 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. 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. Also involved in regulating glucose flux. Together with CEBPB; represses expression of DSPP during odontoblast differentiation. In response to ascorbic acid induction, activates expression of SP7/Osterix in osteoblasts.

Subunit / interactions. Interacts with KEAP1. Interacts (via CPD region) with FBXW7; leading to its ubiquitination and degradation. Interacts with SYVN1/HRD1; leading to its ubiquitination and degradation. Interacts (when ubiquitinated) with DDI2; leading to its cleavage. Interacts (via the bZIP domain) with small MAF protein (MAFF, MAFG or MAFK); required for binding to antioxidant response elements (AREs) on DNA. Interacts (via Destruction motif) with BTRC; leading to its ubiquitination and degradation. Interacts with CEBPB; the heterodimer represses expression of DSPP during odontoblast differentiation. Interacts with MOTS-c, a peptide produced by the mitochondrially encoded 12S rRNA MT-RNR1.

Subcellular location. Endoplasmic reticulum membrane. Endoplasmic reticulum membrane Nucleus.

Post-translational modifications. 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. 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. 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. Ubiquitinated by the SCF(FBXW7) complex and SYVN1/HRD1, leading to its degradation by the proteasome. 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. Phosphorylation by CK2 at Ser-528 inhibits transcription factor activity, possibly by affecting DNA-binding activity. Phosphorylation at Ser-599 is required for interaction with CEBPB. Ubiquitinated by the SCF(BTRC) complex in the nucleus, leading to its degradation by the proteasome.

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

Similarity. Belongs to the bZIP family. CNC subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14494-1	1, TCF11	yes
Q14494-2	2

RefSeq proteins (3): NP_001317190, NP_001317191, NP_003195* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004826	bZIP_Maf	Domain
IPR004827	bZIP	Domain
IPR008917	TF_DNA-bd_sf	Homologous_superfamily
IPR047167	NFE2-like	Family

Pfam: PF03131

UniProt features (31 total): region of interest 7, mutagenesis site 7, glycosylation site 4, compositionally biased region 3, chain 2, modified residue 2, short sequence motif 1, site 1, transmembrane region 1, splice variant 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14494-F1	56.19	0.15

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 103–104 (cleavage; by ddi2)

Post-translational modifications (2): 528, 599

Glycosylation sites (4): 348, 360, 412, 423

Mutagenesis-validated functional residues (7):

Position	Phenotype
101–106	in m1; impaired protein cleavage.
101–103	in m2; impaired protein cleavage.
103–104	in m5; impaired protein cleavage.
103	in m3; impaired protein cleavage.
104–106	in m6; slightly impaired protein cleavage.
104	in m4; slightly impaired protein cleavage.
599	impaired interaction with cebpb.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 526 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_SPINAL_CORD_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MYELOID_CELL_HOMEOSTASIS, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_COLD, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_INFLAMMATORY_RESPONSE, GOBP_STEROL_HOMEOSTASIS, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, AREB6_03, GOBP_ERYTHROCYTE_HOMEOSTASIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (31): protein polyubiquitination (GO:0000209), fructose 6-phosphate metabolic process (GO:0006002), regulation of transcription by RNA polymerase II (GO:0006357), glutathione metabolic process (GO:0006749), heme biosynthetic process (GO:0006783), regulation of mitotic nuclear division (GO:0007088), cholesterol metabolic process (GO:0008203), anatomical structure morphogenesis (GO:0009653), regulation of glucose metabolic process (GO:0010906), regulation of fatty acid metabolic process (GO:0019217), cellular homeostasis (GO:0019725), spinal cord motor neuron differentiation (GO:0021522), glial cell fate commitment (GO:0021781), erythrocyte differentiation (GO:0030218), response to endoplasmic reticulum stress (GO:0034976), cholesterol homeostasis (GO:0042632), L-cysteine transport (GO:0042883), regulation of inflammatory response (GO:0050727), glucose 6-phosphate metabolic process (GO:0051156), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to cold (GO:0070417), cellular response to copper ion (GO:0071280), cellular response to cholesterol (GO:0071397), regulation of nucleus organization (GO:1903353), regulation of response to endoplasmic reticulum stress (GO:1905897), regulation of DNA-templated transcription (GO:0006355), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), regulation of gene expression (GO:0010468), regulation of lipid metabolic process (GO:0019216), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (13): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), cholesterol binding (GO:0015485), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), chromatin binding (GO:0003682), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), protein-containing complex (GO:0032991), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	4
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
organophosphate metabolic process	2
carbohydrate derivative metabolic process	2
regulation of DNA-templated transcription	2
regulation of small molecule metabolic process	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
protein ubiquitination	1
transcription by RNA polymerase II	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
sterol metabolic process	1
secondary alcohol metabolic process	1
developmental process	1
anatomical structure development	1
glucose metabolic process	1
regulation of carbohydrate metabolic process	1
fatty acid metabolic process	1
regulation of ketone metabolic process	1
regulation of lipid metabolic process	1
homeostatic process	1
cell differentiation in spinal cord	1
ventral spinal cord development	1
central nervous system neuron differentiation	1
glial cell differentiation	1
cell fate commitment	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
cellular response to stress	1
sterol homeostasis	1

Protein interactions and networks

STRING

1585 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NFE2L1	MAFG	O15525	993
NFE2L1	MAF	O75444	964
NFE2L1	MAFK	O60675	933
NFE2L1	MAFF	Q9ULX9	885
NFE2L1	DDI2	Q5TDH0	719
NFE2L1	PPARGC1A	Q9UBK2	718
NFE2L1	HHAT	Q5VTY9	697
NFE2L1	GCLC	P48506	676
NFE2L1	NGLY1	Q96IV0	664
NFE2L1	GSTM3	P21266	614
NFE2L1	KEAP1	Q14145	614
NFE2L1	GCLM	P48507	612
NFE2L1	TFAM	Q00059	599
NFE2L1	FOXO3	O43524	582
NFE2L1	NRF1	Q16656	564

IntAct

68 interactions, top by confidence:

A	B	Type	Score
NFE2L1	MAFG	psi-mi:“MI:0407”(direct interaction)	0.710
MAFG	NFE2L1	psi-mi:“MI:0407”(direct interaction)	0.710
NFE2L1	MAFG	psi-mi:“MI:2364”(proximity)	0.710
KEAP1	NFE2L1	psi-mi:“MI:0407”(direct interaction)	0.700
KEAP1	NFE2L1	psi-mi:“MI:0915”(physical association)	0.700
NFE2L1	KEAP1	psi-mi:“MI:0915”(physical association)	0.700

BioGRID (72): NFE2L1 (Affinity Capture-MS), NFE2L1 (Affinity Capture-MS), NFE2L1 (Affinity Capture-MS), NFE2L1 (Proximity Label-MS), RUSC2 (Affinity Capture-MS), WDFY3 (Affinity Capture-MS), C8orf33 (Affinity Capture-MS), BRD9 (Affinity Capture-MS), NFE2L1 (Affinity Capture-MS), NFE2L1 (Affinity Capture-MS), NFE2L1 (Affinity Capture-Western), NFE2L1 (Affinity Capture-MS), NFE2L1 (Two-hybrid), NFE2L1 (Affinity Capture-Western), NFE2L1 (Affinity Capture-Western)

ESM2 similar proteins: A0JMD2, A5D7E9, A6NMN3, A7XW16, F1QDF8, F1RDM5, O00716, O09139, O35261, O35668, O42367, O43151, O54968, P14607, P59054, P59598, P97691, Q00175, Q01094, Q08050, Q14209, Q14494, Q16254, Q4V8F1, Q5DU28, Q5NUA6, Q5RA25, Q5W1J6, Q5ZL67, Q60664, Q60795, Q61321, Q61501, Q61985, Q63449, Q66IG8, Q6DJE5, Q6JPI3, Q76N89, Q7TS75

Diamond homologs: A5D7E9, O14867, O54968, P20482, P34707, P97302, P97303, Q07279, Q14494, Q16236, Q16621, Q5EAD3, Q5NUA6, Q5RA25, Q5ZL67, Q60795, Q61985, Q6AYT2, Q9BYV9, Q9Y4A8, A0JN76, A1L2U9, A1YPR0, B1WAZ8, B1WBU4, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, E1B932, F1LZF0, O15062, O15156, O15209

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GSK3B	down-regulates	NFE2L1	phosphorylation
NFE2L1	“up-regulates quantity by expression”	NQO1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 33 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular responses to stress	5	9.7×	3e-03
Cellular responses to stimuli	5	8.3×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
integrated stress response signaling	7	175.5×	2e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

158 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	129
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3763 predictions. Top by Δscore:

Variant	Effect	Δscore
17:48048456:C:G	donor_gain	1.0000
17:48048459:AGCA:A	donor_gain	1.0000
17:48048460:GCA:G	donor_gain	1.0000
17:48048460:GCAG:G	donor_gain	1.0000
17:48048462:AGT:A	donor_loss	1.0000
17:48048463:G:GG	donor_gain	1.0000
17:48056381:TTCA:T	acceptor_loss	1.0000
17:48056384:A:AG	acceptor_gain	1.0000
17:48056384:AG:A	acceptor_gain	1.0000
17:48056385:G:GG	acceptor_gain	1.0000
17:48056385:GG:G	acceptor_gain	1.0000
17:48056385:GGAC:G	acceptor_gain	1.0000
17:48056594:CACAG:C	donor_loss	1.0000
17:48056595:ACAGG:A	donor_loss	1.0000
17:48056596:CAGG:C	donor_loss	1.0000
17:48056597:AGGTA:A	donor_loss	1.0000
17:48056598:GGTAC:G	donor_loss	1.0000
17:48056599:G:T	donor_loss	1.0000
17:48056600:T:G	donor_loss	1.0000
17:48057342:A:AG	acceptor_gain	1.0000
17:48057343:G:GG	acceptor_gain	1.0000
17:48057343:GT:G	acceptor_gain	1.0000
17:48057498:TGCAG:T	donor_loss	1.0000
17:48057500:CAGGT:C	donor_loss	1.0000
17:48057501:AG:A	donor_loss	1.0000
17:48057502:GGT:G	donor_loss	1.0000
17:48057503:G:T	donor_loss	1.0000
17:48057504:T:A	donor_loss	1.0000
7:129611822:GAG:G	donor_gain	1.0000
7:129611824:GGT:G	donor_loss	1.0000

AlphaMissense

5049 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:48056396:T:C	L174P	1.000
17:48056408:T:A	L178H	1.000
17:48056408:T:C	L178P	1.000
17:48056410:T:A	W179R	1.000
17:48056410:T:C	W179R	1.000
17:48056419:G:C	D182H	1.000
17:48056420:A:C	D182A	1.000
17:48056420:A:T	D182V	1.000
17:48056429:T:C	L185P	1.000
17:48057470:T:A	W314R	1.000
17:48057470:T:C	W314R	1.000
17:48059162:G:C	D614H	1.000
17:48059163:A:C	D614A	1.000
17:48059163:A:G	D614G	1.000
17:48059163:A:T	D614V	1.000
17:48059172:G:C	R617P	1.000
17:48059174:G:C	A618P	1.000
17:48059175:C:A	A618D	1.000
17:48059190:T:A	I623N	1.000
17:48059190:T:C	I623T	1.000
17:48059190:T:G	I623S	1.000
17:48059196:T:C	F625S	1.000
17:48059211:T:A	I630N	1.000
17:48059211:T:C	I630T	1.000
17:48059211:T:G	I630S	1.000
17:48059220:T:C	L633P	1.000
17:48059234:T:A	F638I	1.000
17:48059234:T:C	F638L	1.000
17:48059235:T:C	F638S	1.000
17:48059235:T:G	F638C	1.000

dbSNP variants (sampled 300 via entrez): RS1000035676 (17:48059834 G>A,T), RS1000230474 (17:48048334 CGGTAGCA>C), RS1000253068 (17:48056922 G>A,T), RS1000489262 (17:48060664 A>G), RS1000639718 (17:48058311 C>T), RS1000888119 (17:48046558 C>A,T), RS1000989227 (17:48058532 C>T), RS1001011589 (17:48051915 G>A), RS1001202034 (17:48053267 CCT>C), RS1001314532 (17:48060042 C>CA,CG), RS1001662679 (17:48060351 G>A,T), RS1002291810 (17:48051055 G>A), RS1002431420 (17:48057844 A>G), RS1002583656 (17:48051364 G>A,C), RS1002643494 (17:48061067 A>G)

Disease associations

OMIM: gene MIM:163260 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Limited	Autosomal dominant

Mondo (1): syndromic disease (MONDO:0002254)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001662_4	Generalized epilepsy	9.000000e-09
GCST001762_920	Obesity-related traits	2.000000e-06
GCST003813_2	Response to antidepressants and depression	8.000000e-07
GCST004603_46	Platelet count	6.000000e-13
GCST004607_161	Plateletcrit	6.000000e-09
GCST006804_176	Red cell distribution width	2.000000e-08
GCST006979_824	Heel bone mineral density	3.000000e-14
GCST008103_104	Bipolar disorder	4.000000e-06
GCST90002383_72	Hematocrit	5.000000e-15
GCST90002403_361	Red blood cell count	8.000000e-21
GCST90011899_113	Aspartate aminotransferase levels	9.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0009188	Red cell distribution width
EFO:0009270	heel bone mineral density
EFO:0004348	hematocrit
EFO:0004305	erythrocyte count
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

67 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, increases reaction	4
sodium arsenite	affects cotreatment, decreases reaction, increases cleavage, decreases response to substance, increases activity (+7 more)	4
arsenite	decreases expression, increases expression, affects reaction, affects response to substance, affects expression	2
Resveratrol	increases expression	2
Arsenic	increases cleavage, increases reaction, affects localization, increases abundance, decreases expression (+4 more)	2
Doxorubicin	decreases expression, increases expression, affects reaction	2
Estradiol	increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
4-(E)-((p-tolylimino)-methylbenzene-1,2-diol)	increases expression	1
triphenyl phosphate	affects expression	1
3,4-dihydroxyphenylethanol	decreases expression, decreases reaction	1
geraniol	increases expression	1
thallium sulfate	affects reaction, increases expression	1
beta-lapachone	increases expression	1
2-tert-butylhydroquinone	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression, increases reaction, decreases reaction	1
epoxomicin	affects localization, increases expression, affects reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
apicidin	decreases expression	1
deguelin	increases expression	1
entinostat	decreases expression	1
ICG 001	increases expression	1
pyrachlostrobin	increases expression	1
dorsomorphin	decreases expression	1
4-((4-hydroxyphenylimino)methyl)benzene-1,2-diol	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Decitabine	affects methylation	1

Cellosaurus cell lines

7 cell lines: 3 embryonic stem cell, 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4M4	SEES3-1V human NFE2L1, clone1	Embryonic stem cell	Male
CVCL_A4M5	SEES3-1V human NFE2L1, clone2	Embryonic stem cell	Male
CVCL_A4M6	SEES3-1V human NFE2L1, clone3	Embryonic stem cell	Male
CVCL_AW35	K562 eGFP-NFE2L1	Cancer cell line	Female
CVCL_B3CC	Abcam HEK293T NFE2L1 KO	Transformed cell line	Female
CVCL_TA57	HAP1 NFE2L1 (-) 1	Cancer cell line	Male
CVCL_XQ93	HAP1 NFE2L1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

25 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome