GPX4 glutathione peroxidase 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: GPX4provided by HGNC
Official Full Name: glutathione peroxidase 4provided by HGNC
Primary source: HGNC:HGNC:4556
See related: Ensembl:ENSG00000167468 MIM:138322; AllianceGenome:HGNC:4556
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: MCSP; SMDS; GPx-4; PHGPx; snGPx; GSHPx-4; snPHGPx
Summary: The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a 'moonlighting' protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization. [provided by RefSeq, Dec 2018]
Expression: Broad expression in fat (RPKM 347.9), testis (RPKM 229.8) and 24 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 19p13.3

Exon count:: 8

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	19	NC_000019.10 (1103994..1106779)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	19	NC_060943.1 (1068660..1071445)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	19	NC_000019.9 (1103993..1106778)

Chromosome 19 - NC_000019.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

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?

Gpx4 Regulates Invariant NKT Cell Homeostasis and Function by Preventing Lipid Peroxidation and Ferroptosis.
Title: Gpx4 Regulates Invariant NKT Cell Homeostasis and Function by Preventing Lipid Peroxidation and Ferroptosis.
KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer.
Title: KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer.
GSTO2 ameliorates human neuroblastoma cell apoptosis, inflammation, ferroptosis, and oxidative stress by upregulating GPX4 expression in intracerebral hemorrhage.
Title: GSTO2 ameliorates human neuroblastoma cell apoptosis, inflammation, ferroptosis, and oxidative stress by upregulating GPX4 expression in intracerebral hemorrhage.
GPX4 restricts ferroptosis of NKp46[+]ILC3s to control intestinal inflammation.
Title: GPX4 restricts ferroptosis of NKp46(+)ILC3s to control intestinal inflammation.
Knockdown of lncRNA NEAT1 suppresses streptococcus pneumoniae-induced ferroptosis in alveolar epithelial cells by regulating the Nrf2-GPX4 pathway.
Title: Knockdown of lncRNA NEAT1 suppresses streptococcus pneumoniae-induced ferroptosis in alveolar epithelial cells by regulating the Nrf2-GPX4 pathway.
Silencing CK19 regulates ferroptosis by affecting the expression of GPX4 and ACSL4 in oral squamous cell carcinoma in vivo and in vitro.
Title: Silencing CK19 regulates ferroptosis by affecting the expression of GPX4 and ACSL4 in oral squamous cell carcinoma in vivo and in vitro.
Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia.
Title: Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia.
PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma.
Title: PLAG1 interacts with GPX4 to conquer vulnerability to sorafenib induced ferroptosis through a PVT1/miR-195-5p axis-dependent manner in hepatocellular carcinoma.
Dipeptidase 1 promotes ferroptosis in renal tubular epithelial cells in diabetic nephropathy via inhibition of the GSH/GPX4 axis.
Title: Dipeptidase 1 promotes ferroptosis in renal tubular epithelial cells in diabetic nephropathy via inhibition of the GSH/GPX4 axis.
PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.
Title: PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.

Submit: New GeneRIF Correction See all GeneRIFs (179)

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

Associated conditions

Description	Tests
Spondylometaphyseal dysplasia, Sedaghatian type MedGen: C1855229 OMIM: 250220 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Knockdown of glutathione peroxidase 4 (GPX4) by shRNA library screening inhibits HIV-1 replication in cultured Jurkat T-cells	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
Tat	tat	HIV-1 Tat causes a greater than 50% decrease in intracellular reduced glutathione (GSH), leading to the extracellular appearance of acidic FGF-1, an effect that is partially mediated through modulation of GSH biosynthetic enzymes	PubMed
	tat	Expression of HIV-1 Tat in HeLa cells downregulates cytoplasmic glutathione peroxidase while upregulating phospholipid hydroperoxide glutathione peroxidase, thereby deregulating intracellular oxidant/antioxidant balance and amplifying UV sensitivity	PubMed

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Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

MARC_7967-7968:996688192:1 (e-PCR)
- UniSTS:269861

RH16004 (e-PCR)
- UniSTS:55373

STS-X71973 (e-PCR)
- UniSTS:63949

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables glutathione peroxidase activity	IBA Inferred from Biological aspect of Ancestor more info
enables glutathione peroxidase activity	IDA Inferred from Direct Assay more info	PubMed
enables glutathione peroxidase activity	IMP Inferred from Mutant Phenotype more info	PubMed
enables identical protein binding	IMP Inferred from Mutant Phenotype more info	PubMed
enables phospholipid-hydroperoxide glutathione peroxidase activity	IBA Inferred from Biological aspect of Ancestor more info
enables phospholipid-hydroperoxide glutathione peroxidase activity	IDA Inferred from Direct Assay more info	PubMed
enables phospholipid-hydroperoxide glutathione peroxidase activity	ISS Inferred from Sequence or Structural Similarity more info
enables phospholipid-hydroperoxide glutathione peroxidase activity	TAS Traceable Author Statement more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables selenium binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in apoptotic process	IEA Inferred from Electronic Annotation more info
involved_in arachidonate metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in cellular oxidant detoxification	IEA Inferred from Electronic Annotation more info
involved_in cerebellum development	IEA Inferred from Electronic Annotation more info
involved_in chromatin organization	IEA Inferred from Electronic Annotation more info
involved_in dendrite development	IEA Inferred from Electronic Annotation more info
involved_in lipoxygenase pathway	IDA Inferred from Direct Assay more info	PubMed
involved_in long-chain fatty acid biosynthetic process	TAS Traceable Author Statement more info
involved_in multicellular organism growth	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of ferroptosis	ISS Inferred from Sequence or Structural Similarity more info
involved_in phospholipid metabolic process	TAS Traceable Author Statement more info	PubMed
involved_in protein polymerization	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to estradiol	IEA Inferred from Electronic Annotation more info
involved_in response to lipopolysaccharide	IEA Inferred from Electronic Annotation more info
involved_in response to oxidative stress	ISS Inferred from Sequence or Structural Similarity more info
involved_in spermatogenesis	ISS Inferred from Sequence or Structural Similarity more info

Component	Evidence Code	Pubs
located_in cytosol	IDA Inferred from Direct Assay more info	PubMed
located_in cytosol	TAS Traceable Author Statement more info
located_in extracellular exosome	HDA more info	PubMed
located_in mitochondrion	HTP more info	PubMed
is_active_in mitochondrion	IBA Inferred from Biological aspect of Ancestor more info
located_in nuclear envelope	IEA Inferred from Electronic Annotation more info
located_in nucleus	HDA more info	PubMed
is_active_in nucleus	IBA Inferred from Biological aspect of Ancestor more info
part_of protein-containing complex	IMP Inferred from Mutant Phenotype more info	PubMed

General protein information

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Preferred Names: phospholipid hydroperoxide glutathione peroxidase GPX4

Names: epididymis secretory sperm binding protein; phospholipid hydroperoxidase; phospholipid hydroperoxide glutathione peroxidase, mitochondrial; selenoprotein GPX4; sperm nucleus glutathione peroxidase

NP_001034936.1

EC 1.11.1.12

EC 1.11.1.9

NP_001034937.1

EC 1.11.1.12

EC 1.11.1.9

NP_001354761.1

EC 1.11.1.12

EC 1.11.1.9

NP_002076.2

EC 1.11.1.12

EC 1.11.1.9

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.

Genomic

NG_050621.1 RefSeqGene

Range

5069..7854

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_001039847.3 → NP_001034936.1 phospholipid hydroperoxide glutathione peroxidase GPX4 isoform B precursor

Status: REVIEWED

Description

Transcript Variant: This variant (2) uses an alternate acceptor splice site in the 3' coding region, which causes a frame-shift, compared to variant 1. The resulting isoform (B) has a longer and a distinct C-terminus compared to isoform A.

Source sequence(s)

AL558552, BC039849

UniProtKB/TrEMBL

K7EJ20

Conserved Domains (1) summary

cd00340
Location:40 → 168

GSH_Peroxidase; Glutathione (GSH) peroxidase family; tetrameric selenoenzymes that catalyze the reduction of a variety of hydroperoxides including lipid peroxidases, using GSH as a specific electron donor substrate. GSH peroxidase contains one selenocysteine residue per ...
NM_001039848.4 → NP_001034937.1 phospholipid hydroperoxide glutathione peroxidase GPX4 isoform C

Status: REVIEWED

Description

Transcript Variant: This variant (3) contains an alternate 5' terminal exon compared to variant 1. The resulting isoform (C) has a longer and a distinct N-terminus compared to isoform A. A similar isoform in rat (snGPx) has been reported to be localized in the sperm nucleus (PMID:11344099).

Source sequence(s)

BC021567, BF740029, BM764133

UniProtKB/TrEMBL

R4GNE4

Related

ENSP00000473614.3, ENST00000585362.7

Conserved Domains (1) summary

cd00340
Location:77 → 230

GSH_Peroxidase; Glutathione (GSH) peroxidase family; tetrameric selenoenzymes that catalyze the reduction of a variety of hydroperoxides including lipid peroxidases, using GSH as a specific electron donor substrate. GSH peroxidase contains one selenocysteine residue per ...
NM_001367832.1 → NP_001354761.1 phospholipid hydroperoxide glutathione peroxidase GPX4 isoform D

Status: REVIEWED

Description

Transcript Variant: This variant (4) uses an alternate promoter, which results in translation initiation from an in-frame downstream AUG start codon compared to variant 1. The encoded isoform (D) has a shorter N-terminus compared to isoform A. A similar isoform in rat (S-form) has been reported to be localized to the cytoplasm (PMID:9988735).

Source sequence(s)

BC039849

Consensus CDS

CCDS92476.1

UniProtKB/TrEMBL

K7ERP4

Related

ENSP00000483655.1, ENST00000611653.4
NM_002085.5 → NP_002076.2 phospholipid hydroperoxide glutathione peroxidase GPX4 isoform A precursor

See identical proteins and their annotated locations for NP_002076.2

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the predominant transcript and encodes the canonical isoform A. A similar isoform in rat (L-form) has been shown to be localized to the mitochondria (PMID:9988735).

Source sequence(s)

BC039849

Consensus CDS

CCDS42457.1

UniProtKB/Swiss-Prot

O43381, P36969, Q6PJ59, Q9UPK2

UniProtKB/TrEMBL

Q6PI42

Related

ENSP00000346103.7, ENST00000354171.13

Conserved Domains (1) summary

cd00340
Location:40 → 193

GSH_Peroxidase; Glutathione (GSH) peroxidase family; tetrameric selenoenzymes that catalyze the reduction of a variety of hydroperoxides including lipid peroxidases, using GSH as a specific electron donor substrate. GSH peroxidase contains one selenocysteine residue per ...