PRDX4 (peroxiredoxin 4)

2013-04-01   Murli Mishra , Hedy A Chawsheen , Lisha Wu , Hong Jiang , Qiou Wei 

Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky 40513, USA





Prdx4 gene is ubiquitously expressed in various strata of life in which more than 40 species has been sequenced.
Atlas Image
Map of X-chromosome showing location of PRDX4 gene.


Human PRDX4 gene is located on X chromosome at p22 location.


Transcription of PRDX4 gene generates 5 different transcripts and the length of the longest is 1005 bp containing 7 exons.





Human PRDX4 gene encodes 271 amino acids. It may present in biological system as dimeric and decameric state. The presence of dimeric or decameric state of Prx-4 may be redox regulated (Wood et al., 2002). The crystal structure of the decameric Prx-4 has been resolved. It is also noteworthy that Prx-4 forms heterodimer or multimer with other Prx isoforms.
Atlas Image
Crystal structure of human peroxiredoxin 4 (PDB 2PN8).


Peroxiredoxin 4 is an antioxidant enzyme that belongs to the peroxiredoxin family. The peroxiredoxin family of proteins scavenges hydrogen peroxide and plays a critical role in cellular response to oxidative stress and intracellular signal transduction.


Peroxiredoxin 4 is abundantly expressed in pancreas, liver and heart. It is also expressed in blood, leukocyte and brain (Schulte, 2011).


Prx-4 is mainly localized in the endoplasmic reticulum (ER), but is also present in the cytosol, lysosome, nucleus, or secreted (Leyens et al., 2003).


The antioxidant property of Prx-4 may play an essential role in the redox balance in the ER. The Cysteine residue of Prx-4 is first oxidized to sulfenic acid form and then forms intermolecular disulfide bond with another Prx molecule, which can be reversed by the reducing activity of the thioredoxin-thioredoxin reductase system. Under oxidative stress conditions, however, the Cysteine of Prx-4 undergoes further oxidation to sulfinic/sulfonic acid forms which can only be reduced by sulfiredoxin (Jeong et al., 2012). The hyperoxidized (or overoxidized) form of Prx-4 loses its antioxidant property but may function as molecular chaperone to facilitate protein folding (Rhee and Woo, 2011; Zito et al., 2010). The Prx-4 has also been shown to mediate multiple cell signaling pathways including the phosphorylation of p38α, JNK1/JNK2, GSK3α/GSK3β, MEK1/MEK2, MSK1/MSK2, AMPKα, HSP27, Src, Fyn, etc.


As in other typical 2-Cys peroxiredoxins, Prdx4 also contains a peroxidatic Cysteine and a resolving Cysteine that is separated by 121 amino acids. The overall sequence homology of Prx-4 with other 2-Cys Prx is at least 56% or higher. In particular, sequences surrounding both cysteine residues are highly conserved which may indicate the importance of those motifs for the activity of Prx family of proteins.

Implicated in

Entity name
Lung cancer
Prx-4 along with sulfiredoxin plays very important role in tumor progression and metastasis in lung cancer. The expression of Prx-4 is at least 1.5 fold higher in tumor cells compared to control and this finding applies most frequently to adenocarcinoma and to little bit modestly to squamous cell carcinoma (Lehtonen et al., 2004). Alteration in expression of Prx-4 results in alteration in rate of tumor progression and metastasis which is indicated by anchorage independent colony formation, cell migration and invasion of human lung cancer cells (Wei et al., 2011). This ability of Prx-4 to promote tumor progression and metastasis is supposed to be due to its antioxidant properties. Same study has also shown role of Srx-Prx-4 axis in activation of intracellular phosphokinase signaling including AP-1/MMP-9 axis and MAPK signaling.
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Alteration of Prx-4 expression is proposed to play a role in development of different types of leukemia. In acute myeloid leukemia (AML) patients, the PRDX4 gene is fused with the AML1 gene between exon 5 and 6 of AML1 and exon 2 of Prdx4 (Zhang et al., 2004). This fusion of AML1 gene with the Prdx4 gene is supposed to play a role in altered expression of Prdx 4 in acute myeloid leukemia. In another study, researchers have found that the alteration in genomic sequence and expression level of Prdx4 is rare in acute myeloid leukemia but have found strong reduction in Prdx4 expression in acute promyelocytic leukemia (APL) (Palande et al., 2011). This study has suggested that due to alteration in Prdx4 expression, the signal transduction from a myeloid growth factor receptor i.e. the granulocyte colony stimulating factor receptor is affected. This study have also found the role of histone methylation in transcriptional silencing of Prdx4 in APL.
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Glioblastoma multiforme (GBM)
Prx-4 is supposed to play a role in most aggressive primary brain malignancy i.e. glioblastoma multiforme (Kim et al., 2012). Kim TH et al. have found in this study that the knockdown of Prx-4 results in reduced cell growth and radiation resistance along with increase ROS level, DNA damage and apoptosis in in-vitro models. This study suggests the importance of Prx-4 in radiation resistance and tumor maintenance of GBM. It also proposes the Prx-4 as an important therapeutic target in this disorder which can be persuaded for drug discovery and may result in development of some anti-GBM chemotherapeutic drug in future.
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Oral cavity squamous cell carcinoma (OSCC)
Prx-4 is also studied for its role in tumor progression, cell migration and invasiveness in oral cavity squamous cell carcinoma (Chang et al., 2011). This study proposes that the Prx-4 can act as a good tumor prognostic factor as it is highly overexpressed in OSCC. Along with the prognostic value of Prx-4 suggested in paper, the Prx-4 can also be a good therapeutic target in OSCC by virtue of its ability to mediate cell migration and/or metastasis. The attributes of Prx-4 leading to OSCC should at least be partially due its ability to manage oxidative stress.
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Cardiovascular diseases
Oxidative stress is considered to play major role in the pathological remodeling of arterial wall (Martin-Ventura et al., 2012). As it is an antioxidant protein, the Prx-4 expression level increases in variety of oxidative stress conditions. Also, Prx-4 is secreted into extracellular environment; therefore, its plasma concentration may be used as a molecular indicator of various cardiovascular disease and other disorders involving oxidative stress. The increased serum Prx-4 concentration is considered as a good indicator of risk to cardiovascular disease (Abbasi et al., 2012) because cardiovascular disease have higher level of oxidative stress and Prx-4 is over-expressed in these conditions.
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Hepatic disease
Prx-4 has the ability to act as a hepato-protective protein due to its ability to act as an antioxidant protein, by virtue of which Prx-4 can protect the hepatic tissue against the Hydrogen peroxide as well as other reactive oxygen species causing oxidative stress. A study in rat model of Wilsons disease has demonstrated that this disease have lower level of Prx-4 expression as compared to normal (Ito et al., 2012). The same study has proposed that Prx-4 can be used as a potential biomarker of hepatic diseases as the Prx-4 serum concentration in this model was found to be quite low.
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Non-canonical scurvy
Genomic loss of Prx-4 in mice results in testicular atrophy due to elevated spermatogenic cell death (Iuchi et al., 2009). Depletion of Prx-4 along with ER specific thiol oxidases ERO1α and ERO1β lead to non-canonical scurvy in mice (Zito et al., 2012), which suggests that Prx-4 and other ER thiol oxidases may be critical for protein folding and disulfide bond formation in the ER. In this sense, Prx-4 may also be considered as an alternative to ERO1α and ERO1β in higher organisms (Zito et al., 2010).
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Inflammatory disease
Prx-4 is a secretory antioxidant protein which can be detected in plasma. By virtue of its antioxidant activity, the extracellular Prx-4 can protect the vascular tissue against reactive oxygen species and hence, it has ability to inhibit the oxidative stress induced inflammation in various tissues and it can also reduce the chances of oxidative stress induced diabetes mellitus in animal models (Yamada et al., 2012).


Pubmed IDLast YearTitleAuthors
233162972012Peroxiredoxin 4, a novel circulating biomarker for oxidative stress and the risk of incident cardiovascular disease and all-cause mortality.Abbasi A et al
218591522011Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology.Chang KP et al
226846882012Measurement of peroxiredoxin-4 serum levels in rat tissue and its use as a potential marker for hepatic disease.Ito R et al
191057922009Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress.Iuchi Y et al
226340552012Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression.Jeong W et al
229161642012Suppression of peroxiredoxin 4 in glioblastoma cells increases apoptosis and reduces tumor growth.Kim TH et al
152391282004Peroxiredoxins, a novel protein family in lung cancer.Lehtonen ST et al
146623162003Cloning of bovine peroxiredoxins-gene expression in bovine tissues and amino acid sequence comparison with rat, mouse and primate peroxiredoxins.Leyens G et al
228365582012Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: detoxifying mechanisms and potential therapeutic options.Martin-Ventura JL et al
212837262011The antioxidant protein peroxiredoxin 4 is epigenetically down regulated in acute promyelocytic leukemia.Palande KK et al
209199302011Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H₂O₂, and protein chaperones.Rhee SG et al
221960272011Peroxiredoxin 4: a multifunctional biomarker worthy of further exploration.Schulte J et al
214870002011Sulfiredoxin-Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling.Wei Q et al
155906252005Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-cys peroxiredoxins.Woo HA et al
119694102002Dimers to doughnuts: redox-sensitive oligomerization of 2-cysteine peroxiredoxins.Wood ZA et al
224284562012Peroxiredoxin 4: critical roles in inflammatory diseases.Yamada S et al
151884612004PRDX4, a member of the peroxiredoxin family, is fused to AML1 (RUNX1) in an acute myeloid leukemia patient with a t(X;21)(p22;q22).Zhang Y et al
229818612012Endoplasmic reticulum thiol oxidase deficiency leads to ascorbic acid depletion and noncanonical scurvy in mice.Zito E et al
211454862010Oxidative protein folding by an endoplasmic reticulum-localized peroxiredoxin.Zito E et al

Other Information

Locus ID:

NCBI: 10549
MIM: 300927
HGNC: 17169
Ensembl: ENSG00000123131


dbSNP: 10549
ClinVar: 10549
TCGA: ENSG00000123131


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPKPD20157331


Pubmed IDYearTitleCitations
210574562010Recycling of peroxiredoxin IV provides a novel pathway for disulphide formation in the endoplasmic reticulum.88
180529302008Peroxiredoxin IV is an endoplasmic reticulum-localized enzyme forming oligomeric complexes in human cells.49
239491172013Synergistic cooperation of PDI family members in peroxiredoxin 4-driven oxidative protein folding.47
214870002011Sulfiredoxin-Peroxiredoxin IV axis promotes human lung cancer progression through modulation of specific phosphokinase signaling.46
210314352011Differential expression of peroxiredoxins in prostate cancer: consistent upregulation of PRDX3 and PRDX4.38
218591522011Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology.38
204467672010Overexpression of peroxiredoxin 4 protects against high-dose streptozotocin-induced diabetes by suppressing oxidative stress and cytokines in transgenic mice.34
219949462011Crystal structure of reduced and of oxidized peroxiredoxin IV enzyme reveals a stable oxidized decamer and a non-disulfide-bonded intermediate in the catalytic cycle.30
176013502007A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition.27
202374962010New genetic associations detected in a host response study to hepatitis B vaccine.27


Murli Mishra ; Hedy A Chawsheen ; Lisha Wu ; Hong Jiang ; Qiou Wei

PRDX4 (peroxiredoxin 4)

Atlas Genet Cytogenet Oncol Haematol. 2013-04-01

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