Affinage

GLRX3

Glutaredoxin-3 · UniProt O76003

Length
335 aa
Mass
37.4 kDa
Annotated
2026-06-10
56 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLRX3 (PICOT) is a multidomain monothiol glutaredoxin that functions as a [2Fe-2S] cluster chaperone in the cytosolic iron-sulfur cluster assembly (CIA) pathway and as a regulator of cytosolic Fe/S protein maturation and iron homeostasis (PMID:23615448, PMID:26613676). Its Grx domains coordinate bridging [2Fe-2S]2+ clusters together with non-covalently bound glutathione, forming homodimers or, with BOLA2, a heterotrimeric complex that delivers clusters to apo-anamorsin (CIAPIN1) and to NUBP1, where reductive coupling generates [4Fe-4S] clusters (PMID:20226171, PMID:26613676, PMID:32429669); depletion of GLRX3 produces a cellular iron-starvation signature with activated IRP1, reduced ferritin, and impaired hemoglobin maturation, and a single Trx-Grx unit is sufficient to restore this function (PMID:23615448, PMID:40400140). Loss of Grx3 causes embryonic lethality and a G2/M cell-cycle defect with binucleation, linking Fe/S delivery to mitotic exit (PMID:21575136). The conserved cluster-transfer and iron-regulatory role is recapitulated in yeast, where Grx3/Grx4 form [2Fe-2S]-bridged complexes with BolA homologues (Fra2/Bol2) and govern iron-responsive transcription factors (Aft1/Aft2, Php4, Fep1) through cluster-dependent control of their nuclear export and DNA binding (PMID:17074835, PMID:19715344, PMID:31493153, PMID:37923140). In cardiac tissue PICOT acts as a negative regulator of hypertrophy and a positive inotropic factor: it binds muscle LIM protein at the Z-disc to disrupt the MLP-calcineurin interaction and suppress calcineurin-NFAT signaling (PMID:18258855, PMID:18929570), and binds the catalytic domain of PKCζ to inhibit its kinase activity, down-regulating PKCα and PP2A to increase phospholamban/troponin phosphorylation and SERCA2a-driven contractility (PMID:22449794). In the nucleus PICOT binds the PRC2 component EED via its C-terminal Grx domains to modulate H3K27me3 at target promoters including MYT1 and CCND2 (PMID:30595380, PMID:31527584). PICOT additionally serves as a caspase-3 substrate that promotes apoptotic caspase-3 activation (PMID:23415866) and as a positive upstream regulator of ATR-dependent DNA-damage signaling (PMID:31176019). In aged satellite glial cells GLRX3 deglutathionylates HMGB1 at Cys106 through its catalytic Cys148, converting HMGB1 into a TLR4-MD2 agonist that sensitizes nociceptors (PMID:42007893).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 Medium

    Established the first molecular partner and a candidate signaling role by showing PICOT interacts with PKC and dampens stress-kinase/transcription-factor output in T cells.

    Evidence Yeast two-hybrid and overexpression reporter assays in T cells

    PMID:10636891

    Open questions at the time
    • No biochemical demonstration of direct kinase regulation at this stage
    • Iron-sulfur/glutaredoxin function not yet recognized
  2. 2006 High

    Defined the cardiac function of PICOT as an anti-hypertrophic, positive-inotropic factor acting through Ca2+ handling.

    Evidence Adenoviral transfer, cardiac-specific transgenic mice, contractility and Ca2+ handling assays

    PMID:16809552

    Open questions at the time
    • Molecular target mediating the anti-hypertrophic effect unidentified
    • Mechanism for enhanced SERCA reuptake undefined
  3. 2006 Medium

    Connected GLRX3 orthologs to iron homeostasis by showing yeast Grx3/Grx4 control nuclear export of the iron-regulatory factor Aft1.

    Evidence Co-IP, in vitro binding, GFP localization, deletion genetics in S. cerevisiae

    PMID:17074835

    Open questions at the time
    • Chemical basis of iron sensing not established
    • Relevance to human GLRX3 not yet shown
  4. 2008 High

    Identified the molecular mechanism of cardiac anti-hypertrophy: PICOT binds MLP at the Z-disc and competitively disrupts MLP-calcineurin signaling to NFAT.

    Evidence GST pull-down/MS, reciprocal Co-IP, immunofluorescence, pressure-overload transgenic and PICOT(+/-) mice

    PMID:18258855 PMID:18929570

    Open questions at the time
    • Whether glutaredoxin/Fe-S activity contributes to the cardiac role unknown
    • Stoichiometry of MLP-calcineurin displacement not resolved
  5. 2009 High

    Provided the chemical basis for iron sensing, demonstrating Grx3/4 bind bridging [2Fe-2S] clusters as homodimers or as Fra2 (BolA) heterodimers coordinated by active-site cysteine, glutathione, and a Fra2 histidine.

    Evidence E. coli reconstitution with multi-spectroscopic characterization and mutagenesis; Co-IP/BiFC/Y2H for Crm1 and Php4 in fission yeast

    PMID:19502236 PMID:19715344

    Open questions at the time
    • Direction of cluster trafficking (sensing vs. delivery) not yet defined
    • Human protein cluster coordination not yet confirmed
  6. 2010 High

    Confirmed that human GLRX3 binds two bridging [2Fe-2S] clusters via its Grx domains and glutathione, with oxidant-induced cluster loss as a candidate switch.

    Evidence UV-vis/CD/EPR spectroscopy and 55Fe co-IP of human GLRX3

    PMID:20226171

    Open questions at the time
    • Physiological recipients of the clusters not identified
    • In vivo significance of redox-induced cluster dissociation untested
  7. 2011 High

    Linked GLRX3 to cytosolic Fe/S maturation and cell division by establishing essential roles in mitotic exit and a physical link to anamorsin.

    Evidence Embryonic-lethal Grx3 knockout mouse, cell-cycle flow cytometry, siRNA in HeLa; yeast genetic epistasis with Dre2/Rnr; Y2H/Co-IP with anamorsin

    PMID:21513700 PMID:21575136 PMID:21931161

    Open questions at the time
    • Mechanistic basis of G2/M arrest not defined
    • Anamorsin interaction lacked reciprocal/biochemical depth at this stage
  8. 2011 High

    Resolved how the Grx domain controls an iron-responsive repressor, mapping Trx- and Grx-domain interactions and the requirement of Grx Cys172/Fe-S binding for Fep1 regulation.

    Evidence Domain mapping, Co-IP, BiFC, site-directed mutagenesis and transcription assays in S. pombe

    PMID:21421748 PMID:21531205

    Open questions at the time
    • Cluster transfer chemistry to/from Fep1 not yet demonstrated
  9. 2013 High

    Demonstrated that human GLRX3 is required for cytosolic Fe/S protein activity and organismal iron handling, producing an iron-starvation signature when depleted.

    Evidence Zebrafish morpholino, HeLa siRNA, IRP1/ferritin/transferrin-receptor readouts and Fe/S enzyme assays

    PMID:23615448

    Open questions at the time
    • Direct cluster recipients in human cells not yet identified
    • Distinction between chaperone vs. signaling role unresolved
  10. 2013 High

    Defined the biochemical link from PICOT to cardiac contractility and identified PICOT as a caspase-3 substrate that promotes apoptosis.

    Evidence In vitro kinase assays/pull-down for PKCζ with AAV overexpression and contractility; in vitro caspase cleavage assays with cleavage-resistant mutants and knockdown

    PMID:22449794 PMID:23415866

    Open questions at the time
    • Whether Fe-S/glutaredoxin activity contributes to PKCζ inhibition unknown
    • Functional consequence of PICOT cleavage fragments undefined
  11. 2015 High

    Established GLRX3 as a [2Fe-2S] cluster transfer agent in the CIA pathway by showing a GRX3-BOLA2 heterotrimer delivers clusters to apo-anamorsin.

    Evidence NMR and UV-vis/CD spectroscopy with in vitro reconstitution and cluster transfer assays

    PMID:26613676

    Open questions at the time
    • Source of clusters delivered to GRX3-BOLA2 not defined
    • Regulation of transfer directionality unaddressed
  12. 2016 Medium

    Expanded the glutaredoxin enzymatic repertoire, showing Grx3/4 deglutathionylate Sir2 and form Fe-S-bridged complexes with the MAPK Slt2 to regulate oxidative-stress signaling.

    Evidence In vitro/in vivo deglutathionylation, Co-IP, spectroscopy and mutagenesis in yeast

    PMID:27085841 PMID:28007574

    Open questions at the time
    • Human relevance of Sir2/Slt2 regulation not tested
    • Single-lab findings without independent replication
  13. 2018 High

    Provided structural and chromatin-regulatory mechanism, solving Grx3 Trx/Grx domain structures and defining a non-covalent Fra2-Grx3 interface, and linking PICOT to PRC2 via EED.

    Evidence X-ray crystallography, NMR titration, SPR and activity assays (yeast); Y2H, GST pull-down, reciprocal Co-IP and H3K27me3 ChIP (human)

    PMID:29524511 PMID:30595380

    Open questions at the time
    • Functional impact of the non-covalent vs. covalent Fra2-Grx3 interfaces unresolved
    • How PICOT alters PRC2 catalysis mechanistically unknown
  14. 2019 Medium

    Detailed the cluster-dependent mechanism of iron-regulator inactivation and added nuclear and DNA-damage roles for PICOT.

    Evidence In vitro reconstitution/CD with mutagenesis (Php4/Aft2); siRNA with phospho-ATR/Chk1/Chk2/γH2AX readouts and ChIP for CCND2 (human)

    PMID:28725905 PMID:31176019 PMID:31493153 PMID:31527584

    Open questions at the time
    • Mechanism by which PICOT promotes ATR activation undefined
    • Whether DNA-damage and chromatin roles depend on Fe-S binding untested
  15. 2020 High

    Established GLRX3 as an early-CIA cluster chaperone for NUBP1 and connected it to nucleotide-metabolism stress signaling via GMP synthase.

    Evidence In vitro reconstitution/spectroscopy of NUBP1 cluster transfer; yeast humanization complementation and interaction assays for GMP synthase

    PMID:32414791 PMID:32429669

    Open questions at the time
    • In-cell hierarchy among GLRX3 recipients (anamorsin, NUBP1) not defined
    • Physiological control of [2Fe-2S]→[4Fe-4S] coupling unknown
  16. 2023 High

    Resolved the directionality of cluster trafficking in iron sensing, showing unidirectional [2Fe-2S] removal from Fep1 by the Grx4-Fra2 heterodimer.

    Evidence In vitro reconstitution, CD spectroscopy, mutagenesis and in vivo transcription/growth assays in S. pombe

    PMID:37923140

    Open questions at the time
    • Whether human GLRX3 performs analogous extraction from a target unknown
  17. 2025 Medium

    Mapped the minimal functional unit for human iron metabolism, showing a single Trx-Grx domain pair is sufficient to rescue the iron-starvation phenotype.

    Evidence CRISPR/Cas9 GLRX3 knockout with systematic domain-rescue and IRP1 activity readout in HeLa

    PMID:40400140

    Open questions at the time
    • Role of the second Grx domain in other functions not addressed
    • Quantitative cluster occupancy of rescue constructs not measured
  18. 2026 Medium

    Defined a glutaredoxin catalytic role in disease, showing GLRX3 deglutathionylates HMGB1 to generate a TLR4 agonist that drives nociceptor sensitization in aged mice.

    Evidence snRNA-seq, redox proteomics, Cys148 mutagenesis, in vivo glial knockdown and behavioral pain assays

    PMID:42007893

    Open questions at the time
    • Single-lab finding not independently replicated
    • Whether Fe-S binding modulates the deglutathionylase activity in this context untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GLRX3's distinct activities — Fe/S cluster chaperone, cardiac signaling regulator, PRC2 modulator, DNA-damage signaling, and substrate deglutathionylase — are coordinated within one cell, and whether each depends on its iron-sulfur cluster, remains unresolved.
  • No integrated model linking Fe/S chaperone activity to the cardiac, chromatin, and nociceptive roles
  • Upstream cluster donor to human GLRX3 not identified
  • Regulatory switch controlling which function dominates in a given tissue unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 3 GO:0016491 oxidoreductase activity 2 GO:0098772 molecular function regulator activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 R-HSA-4839726 Chromatin organization 2 R-HSA-1640170 Cell Cycle 1
Partners
BOLA2CIAPIN1EEDGMPSHMGB1MLPNUBP1PRKCZ
Complex memberships
GRX3-BOLA2 [2Fe-2S] heterotrimerPRC2 (via EED)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 PICOT (GLRX3) was identified as a PKCθ-interacting protein via yeast two-hybrid; its N-terminal thioredoxin homology domain is required for the interaction with PKC. Overexpression of full-length PICOT (but not N- or C-terminal fragments alone) inhibited JNK activation and AP-1/NF-κB transcription in T cells. Yeast two-hybrid, colocalization, transient overexpression with reporter assays The Journal of biological chemistry Medium 10636891
2006 Yeast Grx3 and Grx4 interact with Aft1 both in vivo and in vitro, and their Grx domains are required for promoting Aft1 nuclear export; the grx3grx4 double mutant accumulates intracellular iron and constitutively activates Aft1 target genes. Co-immunoprecipitation, in vitro binding, GFP localization, genetic deletion analysis Journal of cell science Medium 17074835
2006 PICOT (GLRX3) overexpression in cardiomyocytes blocked hypertrophic responses to endothelin-1 and phenylephrine; transgenic mice with cardiac-specific PICOT overexpression showed increased ventricular function and cardiomyocyte contractility associated with increased myofilament Ca2+ responsiveness and enhanced SERCA Ca2+ reuptake. Adenoviral gene transfer, transgenic mouse model, cardiomyocyte contractility assays, Ca2+ handling analysis Circulation research High 16809552
2008 PICOT directly interacts with muscle LIM protein (MLP) via its C-terminal half (PICOT-C), colocalizes with MLP at the Z-disc, and disrupts MLP-calcineurin interaction in a dose-dependent manner, thereby abrogating calcineurin-NFAT signaling and inhibiting cardiac hypertrophy. GST pull-down, mass spectrometry, coimmunoprecipitation, immunofluorescence, reporter assays, transgenic mouse pressure overload model Circulation research High 18258855
2008 PICOT(+/-) mice show exacerbated pressure-overload cardiac hypertrophy with enhanced calcineurin-NFAT signaling, reduced cardiomyocyte contractility, hypophosphorylation of phospholamban, and reduced SERCA activity, confirming PICOT as a negative regulator of cardiac hypertrophy and a positive inotropic regulator in vivo. Gene trap knockout mouse, pressure overload model, signaling assays, contractility measurements Journal of molecular and cellular cardiology High 18929570
2009 Yeast Grx3 and Grx4, upon coexpression with Fra2 (BolA homologue), form a [2Fe-2S]-bridged heterodimeric complex; the cluster is coordinated by the active site cysteine of Grx3/4, glutathione, and a histidine residue from Fra2. Without Fra2, Grx3/4 forms a [2Fe-2S]-bridged homodimer. This complex can serve as a signal to control the iron regulon. Reconstitution in E. coli, UV-visible absorption/CD, resonance Raman, EPR, ENDOR, Mossbauer, EXAFS spectroscopy, mutagenesis Biochemistry High 19715344
2009 Fission yeast Grx4 physically interacts with Crm1 (exportin) and with the iron regulatory protein Php4; deletion of grx4 renders Php4 constitutively nuclear and active. Grx4 and Crm1 are required for iron-dependent nuclear export of Php4. Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), two-hybrid assays, leptomycin B treatment, GFP imaging The Journal of biological chemistry High 19502236
2010 Human GLRX3 (PICOT) binds two bridging [2Fe-2S]2+ clusters in a homodimeric complex, coordinated by active site cysteinyl residues of its two Grx domains and non-covalently bound glutathione. The [2Fe-2S]2+ clusters are lost upon treatment with ferricyanide or S-nitroso glutathione, suggesting redox-induced cluster dissociation as a potential activation mechanism. Co-immunoprecipitation of 55-iron confirmed iron binding under physiological conditions. UV-visible spectroscopy, CD, EPR, 55Fe co-immunoprecipitation, treatment with oxidants Biochemical and biophysical research communications High 20226171
2011 S. pombe Grx4 is required for iron-dependent inhibition of Fep1 transcription factor under low-iron conditions. Grx4's TRX domain interacts strongly and constitutively with Fep1's C-terminal region (requiring Cys35), while the GRX domain interacts weakly and iron-dependently with Fep1's N-terminal region (requiring Cys172). Deletion mapping, co-immunoprecipitation, yeast genetics, chromatin binding assays Eukaryotic cell High 21421748
2011 S. cerevisiae Grx3/Grx4 and Fe-S cluster protein Dre2 contribute to in vivo diferric tyrosyl radical (Fe2(III)-Tyr•) cofactor assembly in ribonucleotide reductase subunit Rnr2; growth defects of rnr4 mutants are enhanced by grx3/grx4 deficiency, placing Grx3/4 in the pathway of iron loading into Rnr2. Genetic epistasis, EPR-based Tyr• measurement, iron loading assays, spheroplast complementation The Journal of biological chemistry Medium 21931161
2011 Mouse Grx3 knockout results in embryonic lethality at E12.5; Grx3-deficient MEFs and HeLa knockdown cells show impaired cell cycle progression at G2/M with increased binucleated cells, establishing a direct role in mitotic exit. Knockout mouse (embryonic lethal), flow cytometry cell cycle analysis, siRNA knockdown, immunofluorescence The FEBS journal High 21575136
2011 PICOT (GLRX3) physically interacts with anamorsin (CIAPIN1/AM) via the N-terminal regions of both proteins; inhibition of this interaction impairs cell growth. Yeast two-hybrid, co-immunoprecipitation, cell growth assays Biochemical and biophysical research communications Low 21513700
2011 Fission yeast Grx4 physically interacts with Fep1 in vivo, and mutation of Cys172 (active site of GRX domain) abolishes iron-dependent gene regulation and the Grx4-Fep1 interaction detected by BiFC, indicating that Fe-S cofactor binding in the GRX domain is critical for Fep1 modulation. Co-immunoprecipitation, BiFC, site-directed mutagenesis, transcription assays Biochemical and biophysical research communications Medium 21531205
2012 PICOT directly binds the catalytic domain of PKCζ via its N-terminal thioredoxin-like domain; purified PICOT inhibits PKCζ kinase activity in vitro. PICOT-mediated PKCζ inhibition down-regulates PKCα and PP2A activities, leading to increased phosphorylation of phospholamban (PLB) and troponin I/T, enhancing SERCA2a activity and cardiomyocyte contractility. Protein pull-down, in vitro kinase assay, PKCζ inhibitor peptide, AAV-mediated overexpression, cardiomyocyte contractility measurements Journal of molecular and cellular cardiology High 22449794
2013 PICOT is a caspase-3 cleavage substrate; in vitro cleavage assays show specific cleavage at DRLD(101)/G and EELD(226)/T. Endogenous PICOT is cleaved by caspase-3 during staurosporine- and etoposide-induced apoptosis. PICOT overexpression (WT or cleavage-resistant D101A/D226A) accelerates etoposide-induced caspase-3 activation, while PICOT knockdown blocks it. In vitro caspase cleavage assay, site-directed mutagenesis, pan-caspase inhibitor treatment, siRNA knockdown Biochemical and biophysical research communications High 23415866
2013 Zebrafish depletion of Grx3 severely impairs hemoglobin maturation. Silencing human GLRX3 in HeLa cells decreases activities of cytosolic Fe/S proteins including iron regulatory protein 1 (IRP1), leading to decreased ferritin and increased transferrin receptor levels, a signature of cellular iron starvation despite unimpaired iron uptake. Zebrafish morpholino knockdown, siRNA in HeLa cells, enzyme activity assays, Western blot for IRP1/ferritin/transferrin receptor Molecular biology of the cell High 23615448
2015 Human GRX3 and apo BOLA2 form a heterotrimeric complex (two BOLA2 molecules + one GRX3 molecule) that binds two [2Fe-2S]2+ clusters, each bridged between one BOLA2 and one GRX3 Grx domain; this complex transfers both [2Fe-2S]2+ clusters to apo anamorsin to produce its mature holo form, establishing GRX3-BOLA2 as a [2Fe-2S] cluster transfer component in cytosolic Fe/S protein maturation. NMR spectroscopy, UV-visible/CD spectroscopy, in vitro reconstitution and cluster transfer assays Journal of the American Chemical Society High 26613676
2016 Yeast Grx3/4 physically interact with Sir2 sirtuin in vivo and can reverse S-glutathionylation of Sir2 (at cysteines in the catalytic domain) in vitro and in vivo, restoring Sir2 deacetylase activity after disulfide stress; this establishes Grx3/4 as Sir2 thiol-reductases that regulate telomeric silencing via S-deglutathionylation. In vitro deglutathionylation assay, in vivo S-glutathionylation detection, co-immunoprecipitation, site-directed mutagenesis, silencing assay Free radical biology & medicine Medium 27085841
2016 Yeast Grx3 and Grx4 physically interact with the MAPK Slt2 in vivo and in vitro, forming Fe/S-bridged complexes where cysteines of Grx3/4 active sites, glutathione, and specific Slt2 cysteines provide ligands. Loss of Grx3/4 impairs Slt2 phosphorylation and Rlm1 transcription upon oxidative stress; Grx4 is the predominant regulator of Slt2 phosphorylation under oxidative conditions. Co-immunoprecipitation (in vivo and in vitro), spectroscopic analysis, mutagenesis, viability and kinase activity assays Free radical biology & medicine Medium 28007574
2017 S. pombe Grx4 and its partner Fra2 form a [2Fe-2S]-bridged heterodimer with specific spectroscopic properties; conserved cysteines in Grx4 (Cys172) and Php4 (Cys221, Cys227) are necessary for Fe-S cluster binding and stable Grx4-Php4 complex formation. Grx4 controls Php4 function through binding of a bridging [2Fe-2S] cluster. UV-visible/CD/EPR spectroscopy, in vitro reconstitution, mutagenesis, size exclusion chromatography, in vitro titration Metallomics High 28725905
2018 Crystal structures of the Trx domain (Grx3Trx) and Grx domain (Grx3Grx) of yeast Grx3 were solved; structural analyses revealed that the Trx domain contributes to glutathione S-transferase activity via an inter-domain disulfide between Cys37 and Cys176. NMR titration, pull-down, and SPR assays showed that Fra2 forms a noncovalent heterodimer with Grx3 via an interface between Fra2's helix-turn-helix motif and Grx3Grx's C-terminal segment, independent of the Fe-S-covalent heterodimer. X-ray crystallography, NMR spectroscopy, GST pull-down, surface plasmon resonance, activity assays Journal of molecular biology High 29524511
2018 PICOT interacts with EED (a PRC2 core component) via each of its two C-terminal PICOT/Grx homology domains; PICOT and EED co-immunoprecipitate from Jurkat T cell nuclear extracts and partially colocalize in nuclei. PICOT knockdown reduces H3K27me3 at the MYT1 gene promoter, indicating PICOT modulates PRC2-dependent chromatin silencing. Yeast two-hybrid, GST pull-down, reciprocal coimmunoprecipitation, immunofluorescence/confocal microscopy, ChIP (H3K27me3) Biochemical and biophysical research communications Medium 30595380
2019 The conserved CDC motif cysteines of yeast Aft2 are essential for [2Fe-2S] cluster binding and Aft2 dimerization, and one of the two cysteines is required for interaction with the [2Fe-2S]-Grx3-Bol2 (Bol2=Fra2 homolog) complex; cluster transfer from Grx3-Bol2 to Aft2 likely occurs through a ligand exchange mechanism. Size exclusion chromatography, circular dichroism spectroscopy, mutagenesis, in vitro cluster transfer assays Journal of biological inorganic chemistry Medium 31493153
2019 PICOT-deficient Jurkat T cells show impaired γH2AX foci formation and reduced phosphorylation of ATR, Chk1, and Chk2 in response to genotoxic drugs and radiation; partial localization of PICOT at γH2AX foci at DNA double-strand break sites was observed. PICOT acts as a positive upstream regulator of ATR-dependent DNA damage signaling, independent of ROS levels. siRNA knockdown, immunofluorescence/confocal microscopy, flow cytometry, Western blot for phospho-ATR/Chk1/Chk2/γH2AX Cellular signalling Medium 31176019
2019 PICOT knockdown in Jurkat T cells reduces H3K27me3 at the CCND2 gene promoter, decreases EED and EZH2 occupancy at CCND2, and leads to increased CCND2 (cyclin D2) mRNA and protein expression, establishing PICOT binding to chromatin-associated EED as a modulator of PRC2-mediated repression of CCND2. Coimmunoprecipitation, ChIP (H3K27me3, EED, EZH2), siRNA knockdown, RT-PCR, Western blot Cell death & disease Medium 31527584
2020 Human GLRX3 transfers its [2Fe-2S]2+ clusters to monomeric apo NUBP1 (CIA machinery component); in the presence of glutathione as reductant, the clusters are reductively coupled to form [4Fe-4S]2+ clusters on both N-terminal (CX13CX2CX5C) and C-terminal (CPXC) motifs of NUBP1. Cluster binding at the C-terminal motif promotes NUBP1 dimerization; GLRX3 acts as a [2Fe-2S] cluster chaperone in the early CIA pathway. In vitro reconstitution, UV-visible/CD/EPR spectroscopy, size exclusion chromatography, cluster transfer assays Journal of the American Chemical Society High 32429669
2020 Human GLRX3 (PICOT) interacts with human GMP synthase (hGMPs) via conserved residues that bridge Fe/S clusters and glutathione; this interaction downregulates the Gcn2/ISR stress pathway. The interaction and pathway function are conserved in yeast (Grx3/Grx4 with GUA1/ScGMPs) and human GLRX3/hGMPs can functionally complement yeast Grx3/Grx4. Yeast humanization complementation, two-hybrid, co-expression, genetic pathway assays (Gcn2 readouts) Applied and environmental microbiology Medium 32414791
2023 S. pombe Grx4-Fra2 heterodimer facilitates [2Fe-2S] cluster removal from the Fep1 transcription repressor via unidirectional cluster transfer from Fep1 to Grx4-Fra2 in the presence of GSH; Fra2 His66 and Cys29 serve as Fe-S cluster ligands in the Grx4-Fra2 complex. This defines the Fe-S cluster-dependent mechanism of Fep1 inactivation under low iron. In vitro reconstitution, CD spectroscopy, mutagenesis, in vivo transcription assays, growth assays The Journal of biological chemistry High 37923140
2025 In HeLa cells with CRISPR/Cas9 GLRX3 knockout, IRP1 is activated (indicating iron starvation due to impaired iron metabolism). Rescue experiments show that only a Trx-GrxA construct (first Trx-like domain + first Grx domain) restores the phenotype to wild-type levels; the individual domains alone are insufficient, and the second Grx domain (GrxB) is not required for this function. CRISPR/Cas9 knockout, domain rescue transfection, IRP1 activity assay FEBS letters Medium 40400140
2026 In satellite glial cells of aged mice, GLRX3 upregulation catalyzes deglutathionylation of HMGB1 at Cys106 via its catalytic Cys148 residue; this converts HMGB1 into a TLR4-MD2 agonist, triggering neuronal NF-κB signaling and upregulation of TRPA1 and TRPV2 channels in nociceptors, sustaining neuropathic pain. Satellite glial cell-targeted knockdown of GLRX3 restored HMGB1 glutathionylation and reversed pain phenotype in aged mice. Single-nucleus RNA sequencing, redox proteomics, site-directed mutagenesis (Cys148), in vivo knockdown, behavioral pain assays, TLR4 signaling assays Brain Medium 42007893

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation. Biochemistry 168 19715344
2006 Glutaredoxins Grx3 and Grx4 regulate nuclear localisation of Aft1 and the oxidative stress response in Saccharomyces cerevisiae. Journal of cell science 157 17074835
2000 Inhibition of the c-Jun N-terminal kinase/AP-1 and NF-kappaB pathways by PICOT, a novel protein kinase C-interacting protein with a thioredoxin homology domain. The Journal of biological chemistry 154 10636891
2005 A novel monothiol glutaredoxin (Grx4) from Escherichia coli can serve as a substrate for thioredoxin reductase. The Journal of biological chemistry 120 15833738
2013 Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation. Molecular biology of the cell 84 23615448
2001 Plasmodium falciparum possesses a classical glutaredoxin and a second, glutaredoxin-like protein with a PICOT homology domain. The Journal of biological chemistry 83 11479312
2010 Characterization of the human monothiol glutaredoxin 3 (PICOT) as iron-sulfur protein. Biochemical and biophysical research communications 79 20226171
2006 PICOT inhibits cardiac hypertrophy and enhances ventricular function and cardiomyocyte contractility. Circulation research 73 16809552
2008 PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circulation research 70 18258855
2009 Both Php4 function and subcellular localization are regulated by iron via a multistep mechanism involving the glutaredoxin Grx4 and the exportin Crm1. The Journal of biological chemistry 68 19502236
2023 A Redox Homeostasis Modulatory Hydrogel with GLRX3+ Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence. ACS nano 66 37432866
2004 Analysis of the interaction between piD261/Bud32, an evolutionarily conserved protein kinase of Saccharomyces cerevisiae, and the Grx4 glutaredoxin. The Biochemical journal 61 14519092
2008 PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility. Journal of molecular and cellular cardiology 59 18929570
2015 Elucidating the Molecular Function of Human BOLA2 in GRX3-Dependent Anamorsin Maturation Pathway. Journal of the American Chemical Society 58 26613676
2005 Molecular mapping of functionalities in the solution structure of reduced Grx4, a monothiol glutaredoxin from Escherichia coli. The Journal of biological chemistry 52 15840565
2011 Grx4 monothiol glutaredoxin is required for iron limitation-dependent inhibition of Fep1. Eukaryotic cell 51 21421748
2011 A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis. The FEBS journal 51 21575136
2018 The Monothiol Glutaredoxin Grx4 Regulates Iron Homeostasis and Virulence in Cryptococcus neoformans. mBio 50 30514787
2011 Investigation of in vivo diferric tyrosyl radical formation in Saccharomyces cerevisiae Rnr2 protein: requirement of Rnr4 and contribution of Grx3/4 AND Dre2 proteins. The Journal of biological chemistry 46 21931161
2011 Multi-domain CGFS-type glutaredoxin Grx4 regulates iron homeostasis via direct interaction with a repressor Fep1 in fission yeast. Biochemical and biophysical research communications 33 21531205
2010 Glutaredoxins Grx4 and Grx3 of Saccharomyces cerevisiae play a role in actin dynamics through their Trx domains, which contributes to oxidative stress resistance. Applied and environmental microbiology 32 20889785
2017 Schizosaccharomyces pombe Grx4 regulates the transcriptional repressor Php4 via [2Fe-2S] cluster binding. Metallomics : integrated biometal science 27 28725905
2011 PICOT is a molecule which binds to anamorsin. Biochemical and biophysical research communications 27 21513700
2012 PICOT increases cardiac contractility by inhibiting PKCζ activity. Journal of molecular and cellular cardiology 23 22449794
2019 The conserved CDC motif in the yeast iron regulator Aft2 mediates iron-sulfur cluster exchange and protein-protein interactions with Grx3 and Bol2. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 20 31493153
2017 PICOT alleviates myocardial ischemia-reperfusion injury by reducing intracellular levels of reactive oxygen species. Biochemical and biophysical research communications 20 28257842
2020 GLRX3 Acts as a [2Fe-2S] Cluster Chaperone in the Cytosolic Iron-Sulfur Assembly Machinery Transferring [2Fe-2S] Clusters to NUBP1. Journal of the American Chemical Society 19 32429669
2016 The Escherichia coli BolA Protein IbaG Forms a Histidine-Ligated [2Fe-2S]-Bridged Complex with Grx4. Biochemistry 19 27951647
2020 TRIM16 protects human periodontal ligament stem cells from oxidative stress-induced damage via activation of PICOT. Experimental cell research 18 33091421
2008 PICOT, protein kinase C theta-interacting protein, is a novel regulator of FcepsilonRI-mediated mast cell activation. Cellular immunology 17 18479680
2020 Proteomic profiling of the monothiol glutaredoxin Grx3 reveals its global role in the regulation of iron dependent processes. PLoS genetics 16 32525871
2021 The monothiol glutaredoxin Grx4 influences thermotolerance, cell wall integrity, and Mpk1 signaling in Cryptococcus neoformans. G3 (Bethesda, Md.) 15 34542604
2013 Caspase-3-mediated cleavage of PICOT in apoptosis. Biochemical and biophysical research communications 15 23415866
2018 Structural and Biochemical Insights into the Multiple Functions of Yeast Grx3. Journal of molecular biology 14 29524511
2016 Reversible glutathionylation of Sir2 by monothiol glutaredoxins Grx3/4 regulates stress resistance. Free radical biology & medicine 14 27085841
2016 Physical interaction between the MAPK Slt2 of the PKC1-MAPK pathway and Grx3/Grx4 glutaredoxins is required for the oxidative stress response in budding yeast. Free radical biology & medicine 14 28007574
2019 PICOT (GLRX3) is a positive regulator of stress-induced DNA-damage response. Cellular signalling 13 31176019
2017 Function of glutaredoxin 3 (Grx3) in oxidative stress response caused by iron homeostasis disorder in Candida albicans. Future microbiology 13 29039220
2022 LncRNA FGF7-5 and lncRNA GLRX3 together inhibits the formation of carotid plaque via regulating the miR-2681-5p/ERCC4 axis in atherosclerosis. Cell cycle (Georgetown, Tex.) 12 36071684
2010 Determinants of activity in glutaredoxins: an in vitro evolved Grx1-like variant of Escherichia coli Grx3. The Biochemical journal 11 20604742
2021 GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma. BMC cancer 10 34794402
2020 Interactions of GMP with Human Glrx3 and with Saccharomyces cerevisiae Grx3 and Grx4 Converge in the Regulation of the Gcn2 Pathway. Applied and environmental microbiology 9 32414791
2010 Widespread expression of PICOT in mouse and human tissues with predominant localization to epithelium. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 8 20498481
2019 PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter. Cell death & disease 7 31527584
2018 PICOT binding to the polycomb group protein, EED, alters H3K27 methylation at the MYT1 PRC2 target gene. Biochemical and biophysical research communications 7 30595380
2023 Iron homeostasis proteins Grx4 and Fra2 control activity of the Schizosaccharomyces pombe iron repressor Fep1 by facilitating [2Fe-2S] cluster removal. The Journal of biological chemistry 5 37923140
2023 Structural conservation in the glutathione binding in Sphingomonas sp. glutaredoxin Grx3 and variations for cold adaptation. Biochimica et biophysica acta. Proteins and proteomics 5 37935252
2024 Integrating multi-omics techniques and in vitro experiments reveals that GLRX3 regulates the immune microenvironment and promotes hepatocellular carcinoma cell proliferation and invasion through iron metabolism pathways. Frontiers in immunology 3 39654899
2023 The Monothiol Glutaredoxin Grx4 Influences Iron Homeostasis and Virulence in Ustilago maydis. Journal of fungi (Basel, Switzerland) 2 37998917
2022 Schizosaccharomyces pombe Grx4, Fep1, and Php4: In silico analysis and expression response to different iron concentrations. Frontiers in genetics 2 36568394
2025 The thioredoxin-like and one glutaredoxin domain are required to rescue the iron-starvation phenotype of HeLa GLRX3 knock out cells. FEBS letters 1 40400140
2024 Schizosaccharomyces pombe Grx4 is subject to autophagic degradation under nitrogen- and iron- starvation and ER-stress. Archives of biochemistry and biophysics 1 39603377
2020 Yeast glutaredoxin, GRX4, functions as a glutathione S-transferase required for red ade pigment formation in Saccharomyces cerevisiae. Journal of biosciences 1 32098918
2026 Functional significance of highly conserved residues in dithiol glutaredoxin (Grx3) of cyanobacterium Synechococcus elongatus PCC 7942. Computational biology and chemistry 0 41935503
2026 Satellite glial GLRX3 drives ageing-biased neuropathic pain via HMGB1. Brain : a journal of neurology 0 42007893
2025 Structural Adaptations of Bacterial Grx3 to Temperature: Pro29 Is Essential for Cold Adaptation in Sphingomonas sp. Grx3. ACS omega 0 40521461

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