NMRAL1

Summary

NMRAL1 (NmrA like redox sensor 1, HGNC:24987) is a protein-coding gene on chromosome 16p13.3, encoding NmrA-like family domain-containing protein 1 (Q9HBL8). Redox sensor protein.

This gene encodes an NADPH sensor protein that preferentially binds to NADPH. The encoded protein also negatively regulates the activity of NF-kappaB in a ubiquitylation-dependent manner. It plays a key role in cellular antiviral response by negatively regulating the interferon response factor 3-mediated expression of interferon beta. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 57407 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 79 total
• Druggable target: yes
• MANE Select transcript: NM_020677

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24987
Approved symbol	NMRAL1
Name	NmrA like redox sensor 1
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25918, HSCARG, SDR48A1
Ensembl gene	ENSG00000153406
Ensembl biotype	protein_coding
OMIM	620004
Entrez	57407

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 17 protein_coding, 6 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000283429, ENST00000404295, ENST00000571291, ENST00000571448, ENST00000572110, ENST00000572232, ENST00000572391, ENST00000572559, ENST00000573520, ENST00000573533, ENST00000573571, ENST00000574425, ENST00000574733, ENST00000575002, ENST00000575557, ENST00000575995, ENST00000576176, ENST00000576935, ENST00000906091, ENST00000906092, ENST00000906093, ENST00000906094, ENST00000906095, ENST00000939049, ENST00000939050, ENST00000939051, ENST00000939052, ENST00000939053

RefSeq mRNA: 6 — MANE Select: NM_020677 NM_001305141, NM_001305142, NM_001351994, NM_001351995, NM_001351996, NM_020677

CCDS: CCDS10516

Canonical transcript exons

ENST00000283429 — 6 exons

Exon	Start	End
ENSE00001010609	4463660	4463850
ENSE00001900515	4461694	4461959
ENSE00002662610	4474554	4474625
ENSE00003509454	4474093	4474166
ENSE00003582307	4469227	4469465
ENSE00003650496	4466153	4466402

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 94.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2521 / max 175.2569, expressed in 1779 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156092	25.6014	1779
156091	0.8844	447
156090	0.7663	382

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.99	gold quality
right uterine tube	UBERON:0001302	94.73	gold quality
apex of heart	UBERON:0002098	94.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.50	gold quality
prefrontal cortex	UBERON:0000451	94.44	gold quality
putamen	UBERON:0001874	94.44	gold quality
primary visual cortex	UBERON:0002436	94.41	gold quality
right lobe of liver	UBERON:0001114	94.33	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.29	gold quality
right adrenal gland cortex	UBERON:0035827	94.20	gold quality
substantia nigra	UBERON:0002038	94.17	gold quality
body of pancreas	UBERON:0001150	94.10	gold quality
body of stomach	UBERON:0001161	94.10	gold quality
prostate gland	UBERON:0002367	94.10	gold quality
right adrenal gland	UBERON:0001233	94.07	gold quality
nucleus accumbens	UBERON:0001882	94.02	gold quality
left adrenal gland cortex	UBERON:0035825	93.85	gold quality
frontal cortex	UBERON:0001870	93.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	93.72	gold quality
caudate nucleus	UBERON:0001873	93.69	gold quality
left adrenal gland	UBERON:0001234	93.65	gold quality
telencephalon	UBERON:0001893	93.59	gold quality
cortex of kidney	UBERON:0001225	93.50	gold quality
fundus of stomach	UBERON:0001160	93.46	gold quality
Ammon’s horn	UBERON:0001954	93.46	gold quality
cerebral cortex	UBERON:0000956	93.44	gold quality
temporal lobe	UBERON:0001871	93.40	gold quality
amygdala	UBERON:0001876	93.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.34	gold quality
right lobe of thyroid gland	UBERON:0001119	93.26	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.47
E-CURD-10	no	143.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

4 targeting NMRAL1, 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-671-5P	99.52	67.11	1277
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-3192-5P	96.98	65.76	1926

Literature-anchored findings (GeneRIF, showing 14)

• expression, crystallization and preliminary X-ray crystallographic studies of HSCARG at a resolution of 2.4 A; crystals belong to F23 space group, with unit cell parameters a=b=c=223.30A, alpha=beta=gamma=90 degrees (PMID:17100653)
• One of the functions regulated by HSCARG may be argininosuccinate synthetase that is involved in NO synthesis (PMID:17496144)
• HSCARG regulation of argininosuccinate synthetase activity is crucial for maintaining the intracellular balance between redox state and nitric oxide levels (PMID:18263583)
• In response to the changes in the NADPH/NADP(+) ratio within cells, HSCARG, as a redox sensor, associates and dissociates with NADPH to form a new dynamic equilibrium. (PMID:19254724)
• HSCARG plays critical roles in regulation of NF-kappaB in response to cellular redox changes by promoting ubiquitination and proteolysis of RelA or COMMD1 (PMID:19433587)
• HSCARG is involved in the NF-kappaB signaling pathway, and negatively regulates NF-kappaB activation. (PMID:19843583)
• CRM1 dependent nucleocytoplasmic translocation of HSCARG plays an important role in fine-tuning NF-kappaB signaling (PMID:22348310)
• HSCARG regulated reactive-oxygen-species homeostasis through inhibition of NADPH oxidase activity via regulation of the expression of p47phox. (PMID:23527155)
• HSCARG is involved in DNA damage response through affecting the level of H2A ubiquitination and localization of RAP80 at lesion points. (PMID:24711370)
• After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. (PMID:24763515)
• Data indicate that HSCARG and USP7 function in concert in inhibiting polyubiquination of NEMO, thus inhibiting NF-kappaB activity. (PMID:24832601)
• These findings suggest that the increased susceptibility of the G6PD-knockdown cells to viral infection was due to impaired NF-kappaB signaling and antiviral response mediated by HSCARG. (PMID:26694452)
• Investigated the role of NmrA like redox sensor 1 (HSCARG), a cellular redox sensor. Demonstrated how HSCARG interacts with proliferating cell nuclear antigen (PCNA) in the translesion synthesis pathway, and showed that HSCARG, which is highly expressed in breast carcinoma, promotes accumulation of double stranded breaks and mutations. (PMID:31796584)
• Functional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1. (PMID:35094059)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nmral1	ENSMUSG00000063445
rattus_norvegicus	Nmral1	ENSRNOG00000003794

Protein

Protein identifiers

NmrA-like family domain-containing protein 1 — Q9HBL8 (reviewed: Q9HBL8)

All UniProt accessions (8): Q9HBL8, A0A384P622, I3L0Y6, I3L1Q7, I3L1Y8, I3L2U0, I3L3Z0, I3L543

UniProt curated annotations — full annotation on UniProt →

Function. Redox sensor protein. Undergoes restructuring and subcellular redistribution in response to changes in intracellular NADPH/NADP(+) levels. At low NADPH concentrations the protein is found mainly as a monomer, and binds argininosuccinate synthase (ASS1), the enzyme involved in nitric oxide synthesis. Association with ASS1 impairs its activity and reduces the production of nitric oxide, which subsecuently prevents apoptosis. Under normal NADPH concentrations, the protein is found as a dimer and hides the binding site for ASS1. The homodimer binds one molecule of NADPH. Has higher affinity for NADPH than for NADP(+). Binding to NADPH is necessary to form a stable dimer.

Subunit / interactions. Homodimer. Interacts with ASS1. Interaction is enhanced by low NADPH/NADP(+) ratios, which results in inhibition of ASS1 activity.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus.

Induction. By nitric oxide, cGMP and pro-inflammatory cytokines.

Miscellaneous. Reduced levels of NMRAL1 by RNAi increases nitric oxide production and reduces cell viability. Overexpression of NMRAL1 increases cell viability.

Similarity. Belongs to the NmrA-type oxidoreductase family.

RefSeq proteins (6): NP_001292070, NP_001292071, NP_001338923, NP_001338924, NP_001338925, NP_065728* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008030	NmrA-like	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR051164	NmrA-like_oxidored	Family

Pfam: PF05368

UniProt features (47 total): helix 17, strand 11, binding site 8, mutagenesis site 4, turn 3, sequence variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2WM3	X-RAY DIFFRACTION	1.85
2WMD	X-RAY DIFFRACTION	2
3DXF	X-RAY DIFFRACTION	2.2
2EXX	X-RAY DIFFRACTION	2.4
3E5M	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBL8-F1	96.67	0.97

Functional residue map

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

Ligand- & substrate-binding residues (8): 11–16 (in other chain); 37–41 (in other chain); 58–59 (in other chain); 62; 79–81 (in other chain); 92; 133 (in other chain); 155–158 (in other chain)

Mutagenesis-validated functional residues (4):

Position	Phenotype
37	impairs binding to nadph; abolishes the ability to dimerize; enhances binding to ass1; reduces perinuclear localization.
41	does not impair binding to nadph; maintains the dimerization properties as the wild type; does not affect binding to ass
81	impairs binding to nadph; abolishes the ability to dimerize; enhances binding to ass1; reduces perinuclear localization.
133	impairs binding to nadph; enhances binding to ass1; reduces perinuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-70635	Urea cycle
R-HSA-9956520	ASS1 variants cause citrullinemia

MSigDB gene sets: 99 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, CGTSACG_PAX3_B, ZHAN_MULTIPLE_MYELOMA_MS_DN, MODULE_49, MIKKELSEN_ES_ICP_WITH_H3K4ME3, MIKKELSEN_NPC_ICP_WITH_H3K4ME3, JOHNSTONE_PARVB_TARGETS_2_DN, FEVR_CTNNB1_TARGETS_DN, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_UP, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, REACTOME_DISEASES_OF_METABOLISM, REACTOME_UREA_CYCLE, BANP_TARGET_GENES, DIDO1_TARGET_GENES, DYRK1A_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Diseases of the urea cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	2
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2277 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NMRAL1	USP7	Q93009	735
NMRAL1	OTUB1	Q96FW1	621
NMRAL1	COMMD1	Q8N668	596
NMRAL1	SNX19	Q92543	517
NMRAL1	CYLD	Q9NQC7	507
NMRAL1	NXPH2	O95156	398
NMRAL1	SCRN2	Q96FV2	397
NMRAL1	SUGT1	Q9Y2Z0	374
NMRAL1	OVCH2	Q7RTZ1	357
NMRAL1	C16orf96	A6NNT2	352
NMRAL1	ANKRD55	Q3KP44	348
NMRAL1	PDLIM1	O00151	337
NMRAL1	PRR14L	Q5THK1	335
NMRAL1	C15orf40	Q8WUR7	324
NMRAL1	DCTD	P32321	323

IntAct

17 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
NMRAL1	NMRAL1	psi-mi:“MI:0407”(direct interaction)	0.560
NMRAL1	OPTN	psi-mi:“MI:0915”(physical association)	0.560
PHB2	XIAP	psi-mi:“MI:0914”(association)	0.530
NMRAL1	ASS1	psi-mi:“MI:0915”(physical association)	0.520
FOXJ1	NMRAL1	psi-mi:“MI:0915”(physical association)	0.370
NMRAL1	HSPA8	psi-mi:“MI:0914”(association)	0.350
SEC22A	CGREF1	psi-mi:“MI:0914”(association)	0.350
	NMRAL1	psi-mi:“MI:0915”(physical association)	0.000
aguA	NMRAL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (258): NMRAL1 (Affinity Capture-MS), NMRAL1 (Co-fractionation), NMRAL1 (Co-fractionation), NMRAL1 (Co-fractionation), NMRAL1 (Affinity Capture-MS), NMRAL1 (Affinity Capture-RNA), NMRAL1 (Affinity Capture-MS), NMRAL1 (Proximity Label-MS), NMRAL1 (Affinity Capture-MS), ACTB (Affinity Capture-MS), GNB2 (Affinity Capture-MS), GNB1 (Affinity Capture-MS), HNRNPA1 (Affinity Capture-MS), PPP1CB (Affinity Capture-MS), PPP1CA (Affinity Capture-MS)

ESM2 similar proteins: A0A1C9CX56, A0A1C9CX66, A0A221J5P3, A0A221J5W8, A0A221J5X1, A0A221J5X3, A0A221J5X6, A3R052, B0LL23, B2WSM8, B2WSN0, B2WSN1, B6VRE8, B9HRL7, D0VWT0, E1U332, E6Y2X0, F4HYF3, G9N4A2, K7WDL7, M1T9X3, O81355, P0DKC8, P21334, P46011, P52578, P52581, Q00016, Q18164, Q3LRV4, Q4R0H9, Q4R0I0, Q4WM67, Q5IH14, Q5QGZ8, Q5ZID0, Q6PQJ9, Q8K3F7, Q8MIR0, Q8X0Z0

Diamond homologs: A0A140JWT5, A0A2I1CSG7, A0A2Z5TWF0, A0A7T8F1M6, B8NU00, B8NWW2, E1ACP6, L0E2T7, L0E2U6, L7WRQ4, P0DUL7, Q0VCN1, Q5ZID0, Q8K2T1, Q9HBL8, P86172, B1VN94, Q8KU07, Q54LJ8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	65
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1867 predictions. Top by Δscore:

Variant	Effect	Δscore
16:4463654:GCCCA:G	donor_loss	1.0000
16:4463655:CCCA:C	donor_loss	1.0000
16:4463658:A:AG	donor_loss	1.0000
16:4466148:CTTA:C	donor_loss	1.0000
16:4466149:TTA:T	donor_loss	1.0000
16:4466150:TACTC:T	donor_loss	1.0000
16:4466151:A:AC	donor_gain	1.0000
16:4466151:ACT:A	donor_gain	1.0000
16:4466152:C:CA	donor_loss	1.0000
16:4466152:C:CC	donor_gain	1.0000
16:4466152:CT:C	donor_gain	1.0000
16:4466152:CTC:C	donor_gain	1.0000
16:4466152:CTCA:C	donor_gain	1.0000
16:4466152:CTCAG:C	donor_gain	1.0000
16:4466156:G:C	donor_gain	1.0000
16:4466398:TTCCC:T	acceptor_gain	1.0000
16:4466399:TCCC:T	acceptor_gain	1.0000
16:4466400:CCC:C	acceptor_gain	1.0000
16:4466400:CCCC:C	acceptor_gain	1.0000
16:4466401:CC:C	acceptor_gain	1.0000
16:4466401:CCC:C	acceptor_gain	1.0000
16:4466402:CC:C	acceptor_gain	1.0000
16:4466403:C:CC	acceptor_gain	1.0000
16:4466411:C:CT	acceptor_gain	1.0000
16:4466412:A:T	acceptor_gain	1.0000
16:4469223:TCACC:T	donor_loss	1.0000
16:4469225:AC:A	donor_loss	1.0000
16:4469226:CCTG:C	donor_gain	1.0000
16:4469232:TG:T	donor_gain	1.0000
16:4469237:T:TA	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000031561 (16:4474460 C>A), RS1000063673 (16:4462890 C>G,T), RS1000293974 (16:4470240 G>A,C,T), RS1000405418 (16:4468348 G>A), RS1000491145 (16:4465761 T>A), RS1000772308 (16:4466614 G>A), RS1000825111 (16:4466681 G>A,C), RS1001254384 (16:4473404 C>T), RS1001284972 (16:4464063 C>T), RS1001440578 (16:4468870 C>A), RS1001516494 (16:4469543 C>T), RS1001575273 (16:4477564 A>G), RS1001615747 (16:4474286 G>A), RS1001619716 (16:4464948 C>T), RS1001632395 (16:4474409 C>G)

Disease associations

OMIM: gene MIM:620004 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004946_101	Schizophrenia	5.000000e-09
GCST006956_6	Erectile dysfunction	2.000000e-06
GCST008161_3	Waist circumference adjusted for body mass index	6.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4802017 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
glycidyl methacrylate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Ivermectin	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
NADP	affects binding, increases activity, affects cotreatment	1
Niflumic Acid	affects binding, affects cotreatment	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	affects binding, affects cotreatment	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4724686	Binding	Displacement of (1-(2-aminoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)(4-((1-neopentyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)methanone from NMRAL1 in vorinostat-stimulated human Jurkat 2C4 cells infected with latent HIV-1 by pull-down exp	Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen. — ACS Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TA79	HAP1 NMRAL1 (-) 1	Cancer cell line	Male
CVCL_XR00	HAP1 NMRAL1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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