NOX4 NADPH oxidase 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: NOX4provided by HGNC
Official Full Name: NADPH oxidase 4provided by HGNC
Primary source: HGNC:HGNC:7891
See related: Ensembl:ENSG00000086991 MIM:605261; AllianceGenome:HGNC:7891
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: KOX; KOX-1; RENOX
Summary: This gene encodes a member of the NOX-family of enzymes that functions as the catalytic subunit the NADPH oxidase complex. The encoded protein is localized to non-phagocytic cells where it acts as an oxygen sensor and catalyzes the reduction of molecular oxygen to various reactive oxygen species (ROS). The ROS generated by this protein have been implicated in numerous biological functions including signal transduction, cell differentiation and tumor cell growth. A pseudogene has been identified on the other arm of chromosome 11. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]
Expression: Biased expression in kidney (RPKM 23.6) and endometrium (RPKM 1.5) See more
Orthologs: mouse all
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Genomic context

Location:: 11q14.3

Exon count:: 26

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	11	NC_000011.10 (89324353..89589557, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	11	NC_060935.1 (89244014..89509286, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	11	NC_000011.9 (89057521..89322725, complement)

Chromosome 11 - NC_000011.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein.
Title: Deubiquitinating Enzyme USP19 Regulates Ferroptosis and Mitochondrial Damage in SH-SY5Y Cells by Targeting the NOX4 Protein.
Effects of Nox4 upregulation on PECAM-1 expression in a mouse model of diabetic retinopathy.
Title: Effects of Nox4 upregulation on PECAM-1 expression in a mouse model of diabetic retinopathy.
NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration.
Title: NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration.
Comprehensive bioinformatics analysis of NOX4 as a biomarker for pan-cancer prognosis and immune infiltration.
Title: Comprehensive bioinformatics analysis of NOX4 as a biomarker for pan-cancer prognosis and immune infiltration.
DKK3 promotes oxidative stress injury and fibrosis in HK-2 cells by activating NOX4 via beta-catenin/TCF4 signaling.
Title: DKK3 promotes oxidative stress injury and fibrosis in HK-2 cells by activating NOX4 via β-catenin/TCF4 signaling.
NOX4 regulates gastric cancer cell invasion and proliferation by increasing ferroptosis sensitivity through regulating ROS.
Title: NOX4 regulates gastric cancer cell invasion and proliferation by increasing ferroptosis sensitivity through regulating ROS.
CircSTRBP contributes to H2O2-induced lens epithelium cell dysfunction through increasing NOX4 mRNA stability by recruiting IGF2BP1.
Title: CircSTRBP contributes to H(2)O(2)-induced lens epithelium cell dysfunction through increasing NOX4 mRNA stability by recruiting IGF2BP1.
Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans.
Title: Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans.
Tumor-associated macrophage (TAM)-secreted CCL22 confers cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells via regulating the activity of diacylglycerol kinase alpha (DGKalpha)/NOX4 axis.
Title: Tumor-associated macrophage (TAM)-secreted CCL22 confers cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells via regulating the activity of diacylglycerol kinase α (DGKα)/NOX4 axis.
Development and validation of a new diagnostic prediction model of ENHO and NOX4 for early diagnosis of systemic sclerosis.
Title: Development and validation of a new diagnostic prediction model of ENHO and NOX4 for early diagnosis of systemic sclerosis.

Submit: New GeneRIF Correction See all GeneRIFs (361)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See Variation Viewer (GRCh37.p13)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Knockdown of NOX2 and NOX4 by siRNA abrogates HIV-1 gp120-induced reactive oxygen species (ROS), suggesting that NOX2 and NOX4 are involved in ROS production through CYP2E1 in astrocytes	PubMed
	env	HIV-1 gp120 binding to CXCR4 induces NADPH oxidase-mediated production of superoxide radicals in neurons, which is involved in the activation of neutral sphingomyelinase	PubMed
Envelope surface glycoprotein gp160, precursor	env	HIV-1 gp160 inhibits the cellular immune response and enhances oxidative stress mediated by NADPH oxidase	PubMed
Nef	nef	NADPH oxidase is required for HIV-1 Nef-induced ROS production and endothelial apoptosis in human coronary arterial endothelial cells	PubMed
Tat	tat	HIV-1 Tat C downregulates the expression of miR-17 to increase the expression of NOX2 and NOX4; overexpression of miR-17 inhibits NOX2 and NOX4 expression in human microglial cells	PubMed
	tat	HIV-1 Tat C upregulates NOX2 and NOX4 expression and increases ROS production in human brain cells	PubMed
	tat	PDGF-BB inhibits NADPH oxidase-mediated reactive oxygen species production induced by HIV-1 Tat and morphine treatment in neuroblastoma cells	PubMed
	tat	HIV-1 Tat increases CXCL10 expression in IFN-gamma and TNF-alpha stimulated human astrocytes via NADPH oxidase	PubMed
	tat	Knocking down oxidase Nox4 completely suppresses Tat-dependent Ras and ERK activation downstream of Rac1 and RhoA and blocks Tat-dependent proliferation	PubMed
	tat	NOX4-mediated K-Ras activation on the ER endomembrane results in Tat-induced unfolded-protein response	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D11S1326 (e-PCR), detects polymorphism
- UniSTS:85257

D11S1326 (e-PCR), detects polymorphism
- UniSTS:71767

NOX4_8033 (e-PCR)
- UniSTS:467805

G35510 (e-PCR)
- UniSTS:44150

D11S3741 (e-PCR)
- UniSTS:152971

RH92457 (e-PCR)
- UniSTS:89303

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables NAD(P)H oxidase H2O2-forming activity	IDA Inferred from Direct Assay more info	PubMed
enables NAD(P)H oxidase H2O2-forming activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables NAD(P)H oxidase H2O2-forming activity	TAS Traceable Author Statement more info	PubMed
enables NADPH oxidase H202-forming activity	IEA Inferred from Electronic Annotation more info
enables electron transfer activity	TAS Traceable Author Statement more info	PubMed
enables flavin adenine dinucleotide binding	TAS Traceable Author Statement more info	PubMed
enables heme binding	IDA Inferred from Direct Assay more info	PubMed
enables heme binding	TAS Traceable Author Statement more info	PubMed
enables modified amino acid binding	IDA Inferred from Direct Assay more info	PubMed
enables nucleotide binding	TAS Traceable Author Statement more info	PubMed
enables oxygen sensor activity	TAS Traceable Author Statement more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein tyrosine kinase binding	ISS Inferred from Sequence or Structural Similarity more info	PubMed
enables superoxide-generating NAD(P)H oxidase activity	IBA Inferred from Biological aspect of Ancestor more info
NOT enables superoxide-generating NAD(P)H oxidase activity	IDA Inferred from Direct Assay more info	PubMed
enables superoxide-generating NAD(P)H oxidase activity	IDA Inferred from Direct Assay more info	PubMed
enables superoxide-generating NADPH oxidase activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in bone resorption	IEA Inferred from Electronic Annotation more info
involved_in cardiac muscle cell differentiation	IEA Inferred from Electronic Annotation more info
involved_in cell morphogenesis	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in cellular response to glucose stimulus	IEA Inferred from Electronic Annotation more info
involved_in defense response	IBA Inferred from Biological aspect of Ancestor more info
involved_in gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in heart process	IGI Inferred from Genetic Interaction more info	PubMed
involved_in homocysteine metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in inflammatory response	TAS Traceable Author Statement more info	PubMed
involved_in negative regulation of cell population proliferation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in positive regulation of DNA biosynthetic process	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of ERK1 and ERK2 cascade	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of protein tyrosine kinase activity	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in reactive oxygen species biosynthetic process	NAS Non-traceable Author Statement more info	PubMed
involved_in superoxide anion generation	IBA Inferred from Biological aspect of Ancestor more info
involved_in superoxide anion generation	ISS Inferred from Sequence or Structural Similarity more info	PubMed
involved_in superoxide metabolic process	IDA Inferred from Direct Assay more info	PubMed

Component	Evidence Code	Pubs
part_of NADPH oxidase complex	IBA Inferred from Biological aspect of Ancestor more info
located_in endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
located_in endoplasmic reticulum membrane	IDA Inferred from Direct Assay more info	PubMed
located_in endoplasmic reticulum membrane	TAS Traceable Author Statement more info
located_in focal adhesion	IEA Inferred from Electronic Annotation more info
located_in membrane	TAS Traceable Author Statement more info	PubMed
located_in mitochondrion	ISS Inferred from Sequence or Structural Similarity more info	PubMed
located_in nucleolus	IDA Inferred from Direct Assay more info	PubMed
located_in nucleolus	IEA Inferred from Electronic Annotation more info
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed
located_in nucleus	ISS Inferred from Sequence or Structural Similarity more info	PubMed
located_in perinuclear endoplasmic reticulum	ISS Inferred from Sequence or Structural Similarity more info	PubMed
located_in perinuclear region of cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in perinuclear region of cytoplasm	ISS Inferred from Sequence or Structural Similarity more info	PubMed
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in plasma membrane	IDA Inferred from Direct Assay more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: NADPH oxidase 4

Names: kidney oxidase-1; kidney superoxide-producing NADPH oxidase; renal NAD(P)H-oxidase

NP_001137308.2

EC 1.6.3.1

NP_001137309.2

EC 1.6.3.1

NP_001278855.2

EC 1.6.3.1

NP_001278856.1

EC 1.6.3.1

NP_001278858.2

EC 1.6.3.1

NP_001287924.1

EC 1.6.3.1

NP_058627.2

EC 1.6.3.1

XP_016873332.1

EC 1.6.3.1

XP_054224983.1

EC 1.6.3.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001143836.3 → NP_001137308.2 NADPH oxidase 4 isoform b

Status: REVIEWED

Description

Transcript Variant: This variant (NOX4B), lacks an exon in the coding region compared to variant 1. The encoded isoform (b) is shorter compared to isoform a.

Source sequence(s)

AP001815, AP002404

Consensus CDS

CCDS44695.1

UniProtKB/TrEMBL

B3KQ17

Related

ENSP00000436892.1, ENST00000534731.5

Conserved Domains (2) summary

cd06186
Location:319 → 537

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

pfam01794
Location:69 → 204

Ferric_reduct; Ferric reductase like transmembrane component
NM_001143837.2 → NP_001137309.2 NADPH oxidase 4 isoform c

Status: REVIEWED

Description

Transcript Variant: This variant (3) differs in the 5' UTR and coding region compared to variant 1. These differences cause translation initiation at a downstream AUG and result in a protein (isoform c) with a shorter N-terminus compared to isoform a.

Source sequence(s)

AP001815, AP002404, AP003400

Consensus CDS

CCDS44696.1

UniProtKB/TrEMBL

B3KQ17

Related

ENSP00000412446.1, ENST00000424319.5

Conserved Domains (2) summary

cd06186
Location:295 → 553

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

PLN02844
Location:45 → 455

PLN02844; oxidoreductase/ferric-chelate reductase
NM_001291926.2 → NP_001278855.2 NADPH oxidase 4 isoform d

Status: REVIEWED

Description

Transcript Variant: This variant (4) differs in its 5' UTR, and uses a downstream start codon, compared to variant 1. The encoded isoform (d) has a shorter N-terminus, compared to isoform a.

Source sequence(s)

AP001815, AP002404

UniProtKB/TrEMBL

B7Z529

Conserved Domains (2) summary

cd06186
Location:245 → 503

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

pfam01794
Location:17 → 130

Ferric_reduct; Ferric reductase like transmembrane component
NM_001291927.1 → NP_001278856.1 NADPH oxidase 4 isoform e

Status: REVIEWED

Description

Transcript Variant: This variant (5) differs in the 5' UTR and 5' coding region, compared to variant 1. The encoded isoform (e) has a longer and distinct N-terminus, compared to isoform a.

Source sequence(s)

AB041035, AK298328, AP001815, AP002404

UniProtKB/TrEMBL

B7Z523

Conserved Domains (2) summary

cd06186
Location:332 → 598

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

pfam01794
Location:90 → 225

Ferric_reduct; Ferric reductase like transmembrane component
NM_001291929.2 → NP_001278858.2 NADPH oxidase 4 isoform f

Status: REVIEWED

Description

Transcript Variant: This variant (6) differs in the 5' UTR and 5' coding region, compared to variant 1. The encoded isoform (f) has a shorter and distinct N-terminus, compared to isoform a.

Source sequence(s)

AP001815, AP002404

Consensus CDS

CCDS73362.1

UniProtKB/TrEMBL

B7Z529, E9PPP2

Related

ENSP00000436970.1, ENST00000528341.5

Conserved Domains (2) summary

cd06186
Location:294 → 552

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

PLN02844
Location:44 → 454

PLN02844; oxidoreductase/ferric-chelate reductase
NM_001300995.1 → NP_001287924.1 NADPH oxidase 4 isoform g

See identical proteins and their annotated locations for NP_001287924.1

Status: REVIEWED

Description

Transcript Variant: This variant (8) differs in the 5' UTR and coding sequence and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (g) is shorter at the N-terminus and lacks an alternate internal segment compared to isoform a.

Source sequence(s)

AK057189, AK291830, AK298323, AP001815

Consensus CDS

CCDS73361.1

UniProtKB/TrEMBL

B3KQ17

Related

ENSP00000434924.1, ENST00000532825.5

Conserved Domains (2) summary

cd06186
Location:295 → 513

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

pfam01794
Location:45 → 180

Ferric_reduct; Ferric reductase like transmembrane component
NM_016931.5 → NP_058627.2 NADPH oxidase 4 isoform a

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes isoform (a).

Source sequence(s)

AP001815, AP002404

Consensus CDS

CCDS8285.1

UniProtKB/Swiss-Prot

A8K715, B7Z520, E7EMD7, Q5K3R4, Q5K3R5, Q5K3R6, Q5K3R8, Q7Z7G3, Q86V92, Q9NPH5

UniProtKB/TrEMBL

B3KQ17

Related

ENSP00000263317.4, ENST00000263317.9

Conserved Domains (2) summary

cd06186
Location:319 → 577

NOX_Duox_like_FAD_NADP; NADPH oxidase (NOX) catalyzes the generation of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. ROS were originally identified as bactericidal agents in phagocytes, but are now also implicated in cell signaling and metabolism. NOX ...

cl26813
Location:69 → 479

PLN02844; oxidoreductase/ferric-chelate reductase

RNA

NR_120406.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (7) lacks several exons and uses an alternate 3'-terminal exon, compared to variant 1. This variant is represented as non-coding because the predicted protein does not meet RefSeq quality criteria.

Source sequence(s)

AB041035, AP002404, BC051371