| 2004 |
GPX7 (NPGPx) was identified as a cytoplasmic ~22 kDa protein that incorporates cysteine instead of selenocysteine at the conserved catalytic motif, exhibits little detectable glutathione peroxidase activity in vitro, and protects against oxidative stress generated from polyunsaturated fatty acid (EPA) metabolism in breast cancer cells. |
In vitro GPx activity assay, siRNA knockdown, ectopic overexpression, cell viability assays |
The Journal of biological chemistry |
High |
15294905
|
| 2011 |
GPX7 and GPX8 were shown to be ER-resident PDI peroxidases: in vitro, addition of GPX7 or GPX8 together with PDI and peroxide enables efficient oxidative refolding of reduced denatured protein; both proteins interact with Ero1α in vivo, and GPX7 significantly increases oxygen consumption by Ero1α in vitro. |
In vitro oxidative refolding assay, co-immunoprecipitation (in vivo), oxygen consumption assay |
Journal of molecular biology |
High |
21215271
|
| 2011 |
GPX7 exhibits H2O2-neutralizing activity independent of glutathione; reconstitution of GPX7 expression in Barrett's esophagus cells conferred resistance to H2O2-induced oxidative DNA damage, double-strand breaks, ROS-dependent JNK/p38 signaling, and apoptosis following acidic bile acid exposure. |
GPx enzymatic activity assay, Amplex UltraRed H2O2 assay, CM-H2DCFDA ROS assay, 8-oxoguanine and phospho-H2AX assays, siRNA knockdown, ectopic overexpression |
Gut |
High |
22157330
|
| 2012 |
NPGPx (GPX7) acts as an oxidative stress sensor/transmitter: upon ROS accumulation, it forms an intramolecular disulfide bond between Cys57 and Cys86; this oxidized form then forms covalent disulfide intermediates with GRP78 (Cys86 of NPGPx to Cys41/Cys420 of GRP78), which subsequently promotes formation of the Cys41–Cys420 disulfide in GRP78, enhancing its chaperone activity. NPGPx-deficient cells accumulate ROS, misfolded proteins, and display impaired GRP78 chaperone activity. |
Mutagenesis of active-site cysteines, co-immunoprecipitation, disulfide bond trapping, chaperone activity assay, NPGPx knockout mice |
Molecular cell |
High |
23123197
|
| 2011 |
Under non-targeting siRNA stress, NPGPx (GPX7) is selectively induced and covalently binds exoribonuclease XRN2 via disulfide bonding, facilitating XRN2-mediated degradation of accumulated non-targeting siRNA and thereby releasing cellular stress. |
Co-immunoprecipitation, siRNA knockdown, apoptosis assay, G1 phase cell cycle analysis |
Nucleic acids research |
Medium |
21908404
|
| 2013 |
GPX7 utilizes Ero1α-generated H2O2 to promote oxidative protein folding. Mechanistically, H2O2 oxidizes Cys57 of GPX7 to sulfenic acid, which is resolved by Cys86 to form an intramolecular disulfide bond; both the sulfenic acid form and disulfide form of GPX7 can oxidize PDI. GPX7 preferentially interacts with the a-domain of PDI, and the Ero1α/GPX7/PDI triad generates two disulfide bonds per O2 molecule consumed. |
In vitro oxidative folding assay, site-directed mutagenesis (Cys57, Cys86), biochemical trapping of sulfenic acid intermediate, in vivo co-IP, oxygen consumption assay |
Antioxidants & redox signaling |
High |
23919619
|
| 2013 |
GPX7 uses a one-Cys catalytic mechanism in which the peroxidatic Cys (CP) is rapidly oxidized by phospholipid hydroperoxide; GSH and PDI are alternative reducing substrates for re-reduction of oxidized CP. PDI-GPX7 interaction was quantified with KD = 5.2 μM by surface plasmon resonance; thioredoxin does not serve as a reducing substrate. |
Steady-state kinetic analysis, site-directed mutagenesis, molecular docking, surface plasmon resonance |
Biochimica et biophysica acta |
High |
23454490
|
| 2013 |
GPX7 functions as a tumor suppressor in esophageal adenocarcinoma: reconstitution of GPX7 suppresses cell growth, impairs G1/S progression, increases cellular senescence, and elevates p73, p27, p21, p16 while decreasing phospho-RB. GPX7 is silenced by location-specific promoter DNA hypermethylation (+13 to +64 region) in 69% of OAC cases. |
Growth curve, colony formation, EdU proliferation assay, cell cycle analysis, senescence assay, western blot, mouse xenograft model, pyrosequencing of CpG methylation |
Gut |
High |
23580780
|
| 2014 |
Loss of GPX7 promotes TNF-α-induced NF-κB activation in esophageal cells. GPX7 suppresses NF-κB by promoting proteasomal degradation of TNFR1 and TRAF2 upstream regulators; this suppression is independent of ROS levels and GPX7 antioxidant function. |
Western blot, immunofluorescence, luciferase reporter assay, siRNA knockdown, ectopic overexpression, protein degradation assays |
Carcinogenesis |
Medium |
24692067
|
| 2015 |
NPGPx (GPX7) forms a disulfide bond with translational regulator CPEB2, which maintains CPEB2 binding to HIF-1α mRNA and suppresses HIF-1α translation under basal conditions. High oxidative stress disrupts this NPGPx–CPEB2 disulfide, releasing CPEB2 from HIF-1α mRNA and elevating HIF-1α translation. |
Co-immunoprecipitation, disulfide trapping, RNA-protein interaction assay, western blot for HIF-1α translation, NPGPx-deficient cell lines |
Nucleic acids research |
Medium |
26446990
|
| 2013 |
NPGPx (GPX7) deficiency leads to obesity in mice via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of C/EBPβ, promoting preadipocyte differentiation into adipocytes. NPGPx is highly expressed in preadipocytes, and NPGPx-knockout mice exhibit increased fat mass and adipocyte hypertrophy reversible by N-acetylcysteine treatment. |
NPGPx knockout mouse model, adipocyte differentiation assays, western blot (PKA regulatory subunit dimerization, C/EBPβ), NAC rescue experiment, SNP association in humans |
EMBO molecular medicine |
High |
23828861
|
| 2017 |
GPX7 and GPX8 are ER-resident antioxidant enzymes; expression of GPX7 in pancreatic INS-1E β-cells attenuates FFA-mediated H2O2 accumulation in the ER, ER stress, and apoptosis without compromising insulin production or oxidative protein folding/disulfide bond formation in insulin. |
Ectopic expression of GPX7/GPX8, H2O2 measurement, ER stress markers (western blot), apoptosis assay, insulin content assay |
Free radical biology & medicine |
Medium |
28751022
|
| 2019 |
NPGPx (GPX7) is activated by oxidative stress and inhibits O-GlcNAcase (OGA) through disulfide bonding, thereby fine-tuning global O-GlcNAcylation. Deficiency of NPGPx in mice causes ALS-like phenotypes (paralysis, muscle denervation, motor neuron loss) and failure to boost O-GlcNAcylation in spinal motor neurons with age; pharmacological OGA inhibition rescues spinal motor neuron loss in aged NPGPx-deficient mice. |
NPGPx knockout mouse model (ALS phenotype characterization), disulfide bond trapping (NPGPx–OGA interaction), proteomic identification, pharmacological rescue (OGA inhibitor), O-GlcNAcylation western blot |
Cell reports |
High |
31747588
|
| 2020 |
Human GPX7 has much higher reactivity with H2O2 than GPX8, attributable to a catalytic tetrad at the redox-active site that stabilizes the sulfenylated Cys57 intermediate. Contrary to prior models, the resolving Cys (not the peroxidatic Cys) regulates PDI oxidation activity of GPX7. GPX7 forms complexes preferentially with PDI and P5 in H2O2-treated cells. |
In vitro H2O2 reactivity assay, PDI oxidation assay, site-directed mutagenesis, co-immunoprecipitation in H2O2-treated cells |
The Journal of biological chemistry |
High |
32719007
|
| 2020 |
GPX7 knockdown in TGF-β/FFA-treated hepatic stellate cells (LX-2) elevated pro-fibrotic and pro-inflammatory gene expression and collagen synthesis; GPX7 overexpression suppressed ROS and these genes. In vivo, GPX7 knockdown accelerated NASH fibrosis in a choline-deficient high-fat diet mouse model. |
siRNA knockdown, ectopic overexpression, western blot/qPCR for fibrotic markers, ROS assay, in vivo mouse NASH model |
BMB reports |
Medium |
32317079
|
| 2021 |
NPGPx (GPX7) modulates T cell homeostasis by restraining ZAP70 activity. Upon TCR stimulation, ROS activates NPGPx, which then forms a disulfide bond with ZAP70, reducing ZAP70 recruitment to the TCR/CD3 complex in membrane lipid rafts and thereby dampening TCR signaling. T cell-specific NPGPx-knockout mice display hyperproliferation, elevated cytokines, and susceptibility to EAE. |
Proteomic identification of NPGPx–ZAP70 disulfide complex, T cell-specific conditional KO mouse, TCR activation assays, lipid raft fractionation, EAE model |
Free radical biology & medicine |
High |
33460768
|
| 2021 |
GPX7 deficiency reduces osteogenesis while increasing adipogenesis in BMSCs via ER stress (not via ROS alone); the osteogenic defect is rescued by ER stress antagonist but not by ROS inhibitor. Mechanistically, Gpx7 deficiency downregulates mTOR signaling during osteogenic differentiation, which is rescued by relief of ER stress. |
siRNA knockdown of Gpx7, osteogenic/adipogenic differentiation assays, ER stress antagonist rescue, ROS inhibitor control, mTOR pathway western blot |
Journal of cellular and molecular medicine |
Medium |
34626080
|
| 2020 |
GPX7 (fused with PDI) mediates disulfide transfer from H2O2 to target proteins; a PDI-GPX7 fusion expressed in E. coli SHuffle cells consumed ER-equivalent H2O2 and enabled efficient disulfide bond formation, resulting in 4-fold improved yield of correctly folded IgG antibody. |
Recombinant fusion protein expression, antibody yield quantification in shake-flask and fermentation, functional disulfide bond formation assay |
Applied microbiology and biotechnology |
Medium |
32997203
|