Affinage

PADI4

Protein-arginine deiminase type-4 · UniProt Q9UM07

Length
663 aa
Mass
74.1 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PADI4 is a Ca2+-dependent peptidylarginine deiminase that catalyzes the post-translational citrullination of arginine residues, acting predominantly in the nucleus where it functions as a chromatin-modifying enzyme and stress-responsive transcriptional effector (PMID:12833157, PMID:22334079). As a stress-induced transcriptional target, PADI4 is transactivated by p53 through an intronic binding site and is required for p53-mediated tumor suppression, an activity dependent on an intact immune system (PMID:19843866, PMID:37140445); it is independently induced by hypoxia in a HIF-dependent manner and recruited to hypoxia response elements where its histone citrullination is required for transcription of HIF target genes and for tumor growth and angiogenesis (PMID:34452909). At chromatin, PADI4 partners with sequence-specific transcription factors including Elk-1 and Tal1 to act as a context-dependent co-activator or co-repressor, citrullinating histone H4 and modulating the balance of arginine methylation marks (counteracting PRMT6-deposited H3R2me2a to augment H3K4me3 at target promoters) (PMID:21655091, PMID:24874575). Beyond histones, PADI4 citrullinates a range of nuclear substrates with downstream functional consequences: it converts NPM1 R197 to drive its nucleolar-to-nucleoplasmic translocation, citrullinates Lamin C and H4R3 to promote chromatin decondensation and an apoptotic nuclear-fragmentation program, and citrullinates DNMT3A and PRMT2 to stabilize these enzymes against ubiquitin-proteasome degradation, thereby increasing DNA methylation and histone arginine methylation respectively (PMID:19843866, PMID:22334079, PMID:24957603, PMID:40078091). PADI4 enters the nucleus via two nuclear localization sequences that bind the major cargo site of importin α3 (PMID:35883608). Genetically, Padi4 is dispensable for steady-state haematopoiesis but is required for radiation-induced thymocyte apoptosis and for innate-immune extracellular trap (NET/MET) formation downstream of cytokine signaling (PMID:22334079, PMID:35603697, PMID:39405117). A functional PADI4 haplotype affecting transcript stability is associated with rheumatoid arthritis, consistent with its citrullination of synovial substrates (PMID:12833157, PMID:15466895).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 2003 Medium

    Established PADI4 as a citrullinating enzyme whose genetic variation links it to autoimmune disease, framing citrullination as a source of autoantigens.

    Evidence Case-control association study with mRNA stability assays in rheumatoid arthritis

    PMID:12833157

    Open questions at the time
    • Mechanism limited to transcript-stability; no protein-level enzymatic mechanism in this study
    • Causal substrates in RA not defined here
  2. 2004 Medium

    Localized PADI4 protein to inflamed synovial cell types and to citrullinated fibrin, implicating it as the citrullinating agent in inflamed tissue.

    Evidence Immunohistochemistry and double immunofluorescence of RA synovial tissue

    PMID:15466895

    Open questions at the time
    • Co-localization is correlative; no knockout or reconstitution to prove fibrin is a direct substrate
  3. 2007 Medium

    Defined the upstream transcriptional control of PADI4, showing hormone and basal transcription factor inputs govern its expression.

    Evidence Luciferase reporter, ChIP, and siRNA knockdown in MCF-7 cells

    PMID:17456793

    Open questions at the time
    • Promoter mapping in one cell line
    • Does not address PADI4 catalytic function
  4. 2009 High

    Connected PADI4 to the p53 DNA-damage axis and identified NPM1 as a direct substrate whose citrullination drives subnuclear relocalization, establishing PADI4 as a stress-responsive enzyme with anti-proliferative activity.

    Evidence p53 transactivation assay, in vivo citrullination, NPM1 R197K mutant localization, siRNA knockdown, growth assays

    PMID:19843866

    Open questions at the time
    • Mechanism by which NPM1 relocalization restrains growth not fully resolved
    • Single lab
  5. 2011 High

    Demonstrated PADI4 acts as a chromatin co-activator at active promoters via physical partnership with Elk-1, expanding its role from substrate modification to transcriptional regulation.

    Evidence Genome-wide ChIP-chip, reciprocal Co-IP, EGF-stimulated reporter assays in MCF-7

    PMID:21655091

    Open questions at the time
    • Direct citrullination target driving co-activation not pinpointed
    • Single cell context
  6. 2012 High

    Showed PADI4 citrullinates histone H4R3 and Lamin C to drive chromatin decondensation and apoptotic nuclear fragmentation, and a knockout phenotype linked it to radiation-induced apoptosis in vivo.

    Evidence In vitro/in vivo citrullination, Padi4-knockout mice, ectopic expression, irradiation model

    PMID:22334079

    Open questions at the time
    • Precise contribution of each substrate to nuclear fragmentation unresolved
    • Tissue scope of apoptotic role limited
  7. 2014 High

    Resolved PADI4's dual transcriptional logic, acting as co-activator (IL6ST) or repressor (CTCF) through Tal1 and antagonism of PRMT6-deposited arginine methylation.

    Evidence Reciprocal Co-IP, ChIP for multiple histone marks, expression analysis in hematopoietic cells

    PMID:24874575

    Open questions at the time
    • What dictates activator-versus-repressor outcome at a given locus is unknown
  8. 2014 High

    Identified DNMT3A as a substrate whose citrullination stabilizes the protein and increases DNA methylation, linking citrullination to the epigenetic methylation machinery.

    Evidence Co-IP, in vitro/in vivo citrullination, pulse-chase stability, Padi4-KO MEFs, bisulfite pyrosequencing

    PMID:24957603

    Open questions at the time
    • Citrullinated residue(s) on DNMT3A not enumerated
    • Genome-wide methylation impact not mapped
  9. 2014 Medium

    Placed PADI4 upstream of NF-κB/AP-1 in TNF-α signaling, broadening its role to inflammatory signal transduction in vascular cells.

    Evidence siRNA knockdown, PADI4 inhibitor, NF-κB/AP-1 translocation and VCAM-1/adhesion assays

    PMID:25494680

    Open questions at the time
    • Direct citrullination substrate in this pathway not identified
    • Single lab and cell type
  10. 2017 Medium

    Detailed PADI4 repression of p21 in synoviocytes via histone arginine mark editing, tying its chromatin activity to apoptosis resistance in disease.

    Evidence siRNA/overexpression, ChIP at p21 promoter, flow cytometry apoptosis

    PMID:28367100

    Open questions at the time
    • Single lab
    • Mechanistic link between H3 modification changes and p21 silencing partly correlative
  11. 2017 Low

    Proposed crosstalk between citrullination and ubiquitination through a PADI4-SYVN1 interaction.

    Evidence Co-IP and overexpression with ubiquitination assays

    PMID:29039504

    Open questions at the time
    • Single Co-IP and overexpression without reconstitution or mutagenesis
    • SYVN1 not shown to be a citrullination substrate
  12. 2021 High

    Established PADI4 as a HIF-recruited co-factor required for histone citrullination at hypoxia response elements and for HIF-driven tumor growth, defining a hypoxia arm of PADI4 function.

    Evidence RNA-seq, ChIP at HREs, siRNA knockdown, mouse xenograft tumor models

    PMID:34452909

    Open questions at the time
    • How HIFs recruit PADI4 mechanistically not defined
    • Histone target residues at HREs not enumerated
  13. 2022 Medium

    Mapped the structural basis of PADI4 nuclear import, identifying two NLSs that engage the importin α3 cargo site.

    Evidence Fluorescence, CD, ITC, molecular docking

    PMID:35883608

    Open questions at the time
    • No cell-based nuclear import functional assay
    • Single lab
  14. 2022 Medium

    Characterized PADI4 quaternary structure and pH/Ca2+ dependence, relating its native dimeric fold to citrullination activity.

    Evidence CD, fluorescence, ITC, molecular dynamics simulations

    PMID:35081374

    Open questions at the time
    • Functional mutagenesis not performed
    • Activity correlation inferred, not directly assayed
  15. 2022 Medium

    Extended PADI4 substrate range into the proteasome system, citrullinating and stabilizing hRpn13 and modulating proteasome peptidase activity.

    Evidence Proteomics, PADI4 inhibitor, proteasome peptidase assay, PROTAC co-depletion in myeloma

    PMID:38151017

    Open questions at the time
    • Citrullinated residues on proteasome subunits not mapped
    • Single lab
  16. 2022 Low

    Identified PKP1 as a direct binding partner of PADI4 by biophysics.

    Evidence Fluorescence, CD, ITC, Western blot, molecular simulation

    PMID:36372391

    Open questions at the time
    • In vitro binding only with no cellular functional validation
    • PKP1 not shown to be a substrate
  17. 2022 Medium

    Linked PADI4 to RUNX2 stabilization and osteoblast mineralization through a circRNA/miRNA-controlled, proteasome-inhibiting mechanism.

    Evidence RNA-seq, miRNA-sponge luciferase, PADI4-RUNX2 Co-IP, proteasome inhibition, knockdown/overexpression

    PMID:33363159

    Open questions at the time
    • Whether RUNX2 stabilization requires citrullination not established
    • Single lab
  18. 2022 Medium

    Provided in vivo evidence linking PAD2/PAD4 to male reproductive function and hormone signaling.

    Evidence Conditional Padi2/Padi4 double-knockout mice, hormone assays, histology, apoptosis quantification

    PMID:36224627

    Open questions at the time
    • PADI4-specific contribution confounded by joint deletion with PADI2
    • Molecular substrate in testis unknown
  19. 2022 High

    Showed PADI4 is dispensable for normal and regenerative haematopoiesis, delimiting where its function is required.

    Evidence Conditional single-gene Padi4 knockout, serial transplantation, steady-state and injury analysis

    PMID:35603697

    Open questions at the time
    • Does not exclude roles under non-hematopoietic stress contexts
  20. 2022 Medium

    Demonstrated PADI4 citrullination of fibronectin remodels the tumor microenvironment to favor proliferation and glycolysis, and that antibody targeting suppresses tumor growth.

    Evidence In vitro fibronectin citrullination, functional cell assays, mouse xenograft with PET-CT, ELISA

    PMID:35772376

    Open questions at the time
    • Citrullinated fibronectin residues not mapped
    • Single lab
  21. 2023 High

    Established PADI4 as a critical, immune-dependent effector of p53 tumor suppression, with a hypomorphic p53 variant selectively failing to induce it.

    Evidence NMR/crystal structures of p53 Y107H, colony formation, Y107H knock-in mouse cancer models, gene-signature analysis

    PMID:37140445

    Open questions at the time
    • Immune effector mechanism downstream of PADI4 not fully resolved
    • Direct citrullination substrate mediating tumor suppression unknown
  22. 2023 Medium

    Identified a nuclear PADI4-NUPR1 complex by structure-guided binding studies, expanding the PADI4 interactome to intrinsically disordered proteins.

    Evidence NMR mapping, mutagenesis, PLA, immunofluorescence, ITC, modelling

    PMID:36858171

    Open questions at the time
    • Functional consequence of the complex not established
    • NUPR1 not confirmed as substrate
  23. 2023 Medium

    Mapped a direct MDM2-PADI4 interaction at the PADI4 active site, hinting MDM2 could be a substrate and integrating PADI4 into the p53/MDM2 axis.

    Evidence IF, PLA, NMR chemical shift perturbation, ITC, docking, GSK484 competition

    PMID:37409874

    Open questions at the time
    • MDM2 citrullination not directly demonstrated
    • Functional outcome of interaction unknown
  24. 2023 Low

    Identified RYBP as a low-micromolar PADI4 binder and showed combined PADI4/PARP inhibition alters proliferation.

    Evidence ITC, fluorescence, PLA, immunofluorescence, AlphaFold2-multimer modelling, combination drug assay

    PMID:37399862

    Open questions at the time
    • RYBP citrullination not directly demonstrated
    • Single lab; mechanism of drug synergy unresolved
  25. 2024 Medium

    Placed PADI4 in a cytokine-driven NET pathway, with IL-33/Akt/mTOR-induced PADI4 driving NET formation and tumor drug resistance.

    Evidence siRNA, Western blot, rapamycin and GSK484 experiments, mouse tumor models, NET-marker ELISA

    PMID:39585643

    Open questions at the time
    • Substrate driving NET formation not defined here
    • Single lab
  26. 2024 Medium

    Extended extracellular-trap function to macrophages, showing IL-4-induced PADI4 drives MET formation and shapes macrophage polarization in sepsis injury.

    Evidence Padi2/Padi4 double KO, scRNA-seq, siRNA, Nlrp3-KO, in vivo sepsis model

    PMID:39405117

    Open questions at the time
    • PADI4-specific contribution confounded by double KO
    • Direct substrate in MET formation not identified
  27. 2025 Medium

    Showed PADI4 citrullinates PRMT2 at R312 to block its ubiquitin-dependent degradation, driving ID1/ID2 transcription, cancer stemness, and chemoresistance.

    Evidence IP, Western blot, RT-PCR, spheroid/CSC assays, cisplatin resistance assay, R312 mutagenesis, GSK484

    PMID:40078091

    Open questions at the time
    • Single lab
    • Generalizability beyond OSCC not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying determinant of PADI4's context-dependent outcomes — how substrate selection and activator-versus-repressor behavior are governed across the p53, HIF, and innate-immune programs — remains undefined.
  • No structural model linking recruitment partners to substrate choice
  • Direct citrullination substrate mediating immune-dependent tumor suppression unknown
  • Mechanism of recruitment to specific promoters by different transcription factors unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-5357801 Programmed Cell Death 1
Partners
DNMT3AELK-1IMPORTIN Α3MDM2NPM1NUPR1RUNX2TAL1

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PADI4 encodes a peptidylarginine deiminase enzyme that catalyzes post-translational citrullination of arginine residues in proteins; a functional haplotype of PADI4 affects mRNA transcript stability and is associated with increased citrullinated peptide autoantigen production in rheumatoid arthritis. Case-control association study with mRNA stability assays Nature genetics Medium 12833157
2004 PADI4 protein is expressed in T cells, B cells, macrophages, neutrophils, fibroblast-like cells, and endothelial cells in RA synovium; it co-localizes with citrullinated fibrin and apoptotic cells in fibrin deposits, suggesting PADI4 is responsible for fibrin citrullination in the inflamed synovium. Immunohistochemistry, double immunofluorescent labelling, and western blotting of synovial tissue Rheumatology (Oxford, England) Medium 15466895
2007 Estrogen receptor-α (ERα) stimulates PADI4 transcription in MCF-7 cells through both classical and non-classical ER-mediated pathways; transcription factors AP-1, Sp1/Sp3, and NF-Y bind the minimal promoter (−348 bp) of PADI4 and cooperatively regulate its expression, as shown by ChIP and siRNA knockdown. Luciferase reporter assays, chromatin immunoprecipitation (ChIP), siRNA knockdown Molecular endocrinology (Baltimore, Md.) Medium 17456793
2009 p53 transcriptionally transactivates PADI4 via an intronic p53-binding site; PADI4 in turn citrullinated the histone chaperone nucleophosmin (NPM1) at arginine 197 in vivo, causing NPM1 translocation from nucleoli to nucleoplasm. Knockdown of PADI4 or p53 inhibited DNA-damage-induced protein citrullination; ectopic PADI4 expression inhibited tumor cell growth. p53 transactivation assay, in vivo citrullination assay, NPM1 R197K mutant localization, siRNA knockdown, cell growth assays Cancer research High 19843866
2011 PADI4 is enriched at gene promoters near transcription start sites of actively transcribed genes in MCF-7 cells; PADI4 physically associates with transcription factor Elk-1, and following EGF stimulation PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation, defining a novel co-activator role for PADI4. ChIP-chip (genome-wide), co-immunoprecipitation, EGF stimulation assays, transcriptional reporter assays PLoS genetics High 21655091
2012 In response to DNA damage, p53 activates PADI4, which citrullinates arginine 3 of histone H4 (cit-H4R3) and also citrullinates Lamin C; cit-H4R3 localizes around fragmented nuclei in apoptotic cells; ectopic PADI4 expression causes chromatin decondensation and promotes DNA cleavage; Padi4-knockout mice show resistance to radiation-induced apoptosis in the thymus. In vivo and in vitro citrullination assays, Padi4 knockout mice, ectopic expression, immunofluorescence, irradiation model Nature communications High 22334079
2014 PADI4 interacts with transcription factor Tal1 and acts as an epigenetic co-activator at the IL6ST gene by counteracting the repressive H3R2me2a mark placed by PRMT6, thereby augmenting the active H3K4me3 mark and increasing IL6ST expression; at the CTCF promoter, PADI4 acts instead as a repressor. Co-immunoprecipitation, ChIP, gene expression analysis in hematopoietic cells Nature communications High 24874575
2014 PADI4 physically interacts with DNMT3A and citrullinates it both in vitro and in vivo; citrullination of the region upstream of the PWWP domain of DNMT3A by catalytically active PADI4 stabilizes the DNMT3A protein, increases DNA methyltransferase activity, and increases CpG methylation at the p21 promoter. Co-immunoprecipitation (endogenous and overexpressed), in vitro and in vivo citrullination assays, pulse-chase protein stability, Padi4-knockout MEFs, bisulfite pyrosequencing Nucleic acids research High 24957603
2017 PADI4 suppresses p21 transcription in RA fibroblast-like synoviocytes by binding to the p21 promoter and altering histone H3 arginine modifications (global H3 citrullination and H3R17 methylation); PADI4 knockdown promotes apoptosis and increases p53 and p21 expression, while ectopic PADI4 inhibits adriamycin-induced apoptosis. siRNA knockdown, overexpression, ChIP for PADI4 and histone marks at p21 promoter, flow cytometry apoptosis International journal of biological sciences Medium 28367100
2017 PADI4 directly interacts with the E3 ubiquitin ligase synoviolin (SYVN1), and overexpression of PADI4 suppresses ubiquitination of cellular proteins, suggesting crosstalk between citrullination and ubiquitination pathways in RA synoviocytes. Co-immunoprecipitation, overexpression, ubiquitination assays Molecular medicine reports Low 29039504
2021 PADI4 expression is induced by hypoxia in a HIF-dependent manner; PADI4 is recruited by HIFs to hypoxia response elements (HREs) and is required for histone citrullination at HREs and transcription of nearly all HIF target genes in breast cancer cells; PADI4 loss reduces breast and liver tumor growth and angiogenesis in mice. RNA sequencing, ChIP, siRNA knockdown, mouse xenograft tumor models, immunohistochemistry Science advances High 34452909
2022 PADI4 binds to importin α3 (Impα3) with an affinity of ~1–5 µM through two nuclear localization sequences (Pro56–Ser83 and Arg495–Ile526); both NLS-containing peptides bind at the major cargo-binding site of importin α3, explaining nuclear translocation of PADI4. Fluorescence, circular dichroism, isothermal titration calorimetry (ITC), molecular docking Cells Medium 35883608
2022 PADI4 citrullinates and stabilizes hRpn13 (proteasome substrate receptor); PADI4 also citrullinates proteasomes (shown by in-cell citrullination), and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. Proteomic analysis, PADI4 inhibitor treatment, proteasome peptidase activity assay, PROTAC co-depletion Molecular cell Medium 38151017
2022 PADI4 exists in a dimeric native structure within a narrow pH range (6.5–8.0) and requires Ca2+ for stability; the protein unfolds through at least one intermediate under guanidinium denaturation, and the native structure is strongly pH-dependent, relevant to its histone citrullination activity. Biophysical characterization (CD, fluorescence, ITC), in silico molecular dynamics simulations Archives of biochemistry and biophysics Medium 35081374
2022 The armadillo-repeat domain of Plakophilin 1 (PKP1) binds to PADI4 with a dissociation constant of ~1 µM, as demonstrated by fluorescence, CD, ITC, and Western blot analyses; molecular modelling predicts the binding hotspot on PADI4. Fluorescence, CD, isothermal titration calorimetry (ITC), Western blot, molecular simulations Biochimica et biophysica acta. Proteins and proteomics Low 36372391
2022 PADI4 promotes osteoblast mineralization indirectly: circ8500 sponges miR-1301-3p, relieving suppression of PADI4; PADI4 then binds to RUNX2 and stabilizes its protein expression by inhibiting the ubiquitin-proteasome pathway, thereby enhancing matrix mineralization. RNA-seq, luciferase reporter (miRNA sponge), co-immunoprecipitation (PADI4-RUNX2), proteasome inhibition assay, overexpression/knockdown Frontiers in cell and developmental biology Medium 33363159
2022 Padi2/Padi4 double knockout (DKO) male mice exhibit delayed puberty, lower testosterone levels, smaller testes, and increased germ cell apoptosis, providing the first in vivo evidence linking PAD2/PAD4 to hormone signaling and male reproductive function. Conditional double knockout mouse model, breeding trials, serum hormone assays, histology, apoptosis quantification Reproductive biology and endocrinology Medium 36224627
2022 Conditional Padi4 knockout (single gene) in mice does not significantly affect hematopoietic stem cell (HSC) self-renewal, differentiation, serial transplantation capacity, or haematopoietic regeneration, demonstrating that PADI4 is cell-autonomously dispensable for normal haematopoiesis. Conditional in vivo Padi4 ablation, acute knockout, serial transplantation, steady-state haematopoiesis analysis Biology open High 35603697
2022 Anti-PADI4 monoclonal antibody suppresses breast tumor growth in mice by inhibiting PADI4-mediated citrullination of fibronectin; citrullinated fibronectin in the tumor microenvironment increases cancer cell proliferation, migration, and glycolytic ATP production while decreasing apoptosis. In vitro citrullination of fibronectin, cell-based functional assays (proliferation, migration, colony formation), mouse xenograft with PET-CT imaging, Western blot and ELISA for citrullination levels Biomedicine & pharmacotherapy Medium 35772376
2023 PADI4 is a key transcriptional target of p53 required for p53-mediated tumor suppression; the p53 Y107H hypomorphic variant selectively fails to transactivate PADI4, and PADI4 itself is tumor-suppressive requiring an intact immune system for this activity. NMR and crystal structures of p53 Y107H, tumor colony formation assays, mouse cancer models (Y107H knock-in), p53-PADI4 gene signature analysis Cancer discovery High 37140445
2023 PADI4 directly binds intrinsically disordered protein NUPR1 (and its paralogue NUPR1L) with a dissociation constant of ~18 µM; the binding region on NUPR1 involves a hydrophobic patch around Ala33, mapped by NMR and confirmed by site-directed mutagenesis; the PADI4–NUPR1 complex forms predominantly in the nucleus. NMR mapping, site-directed mutagenesis, proximity ligation assay (PLA), immunofluorescence, isothermal titration calorimetry, molecular modelling Journal of molecular biology Medium 36858171
2023 MDM2 directly binds PADI4 at the active site region (inhibited by GSK484); the N-terminal domain of MDM2 interacts with PADI4 (residues Thr26, Val28, Phe91, Lys98 most affected), and the interaction occurs in both the nucleus and cytosol; MDM2 may be a substrate for PADI4-mediated citrullination. Immunofluorescence, proximity ligation assay, NMR chemical shift perturbation, ITC, in silico docking, PADI4 inhibitor (GSK484) competition assay Protein science Medium 37409874
2023 The intrinsically disordered protein RYBP binds to PADI4 with low-micromolar affinity (~1 µM) in the nucleus and cytosol; AlphaFold2 modelling predicts that PADI4's catalytic domain contacts Arg53 of RYBP at the active site, suggesting potential citrullination of RYBP; combined PADI4 inhibition and PARP inhibition alters cell proliferation. ITC, fluorescence, proximity ligation assay, immunofluorescence, AlphaFold2-multimer modelling, combination drug assay International journal of biological macromolecules Low 37399862
2024 IL-33, whose secretion from HCC cells is increased by lenvatinib via NDUFA4L2 upregulation, triggers NET formation in neutrophils by increasing PADI4 protein expression through the Akt/mTOR signaling pathway; PADI4 inhibition (GSK484) reduces NETs and reverses HCC resistance to lenvatinib by restoring cuproptosis. siRNA knockdown, Western blot, mTOR inhibitor (rapamycin) experiments, GSK484 PADI4 inhibitor, mouse tumor models, ELISA for NET markers Cellular oncology Medium 39585643
2024 IL-4 triggers macrophage extracellular trap (MET) formation in M2 macrophages by increasing PADI4 (but not PADI2) mRNA and protein expression; loss of Padi2 and Padi4 (double KO) reduces Nlrp3+ proinflammatory macrophages and promotes Chil3+ antiinflammatory macrophage differentiation, alleviating sepsis-induced lung injury. Padi2/Padi4 double KO mouse model, single-cell RNA-seq, siRNA knockdown, Nlrp3-KO experiments, in vivo sepsis model JCI insight Medium 39405117
2025 PADI4 citrullinates PRMT2 at arginine 312, stabilizing PRMT2 protein by preventing its ubiquitin-proteasome-dependent degradation (mediated by disrupted USP7 interaction); stabilized PRMT2 promotes transcription of ID1 and ID2 via histone arginine methylation, increasing cancer stem-like properties and cisplatin resistance in OSCC; PADI4 inhibition (GSK484) or R312 mutation reduces stemness and restores cisplatin sensitivity. Immunoprecipitation, Western blot, RT-PCR, spheroid growth/CSC marker assays, CCK8 cisplatin resistance assay, site-directed mutagenesis (R312), GSK484 inhibitor Clinical and translational medicine Medium 40078091
2014 PADI4 inhibits TNF-α-induced NF-κB and AP-1 activation in vascular smooth muscle cells, and siRNA knockdown of PADI4 or a PADI4-specific inhibitor attenuates TNF-α-induced VCAM-1 expression and monocyte adhesion, placing PADI4 upstream of NF-κB/AP-1 in TNF-α signaling. siRNA knockdown, PADI4-specific inhibitor, NF-κB/AP-1 translocation assay, VCAM-1 expression assay, adhesion assay Bioscience, biotechnology, and biochemistry Medium 25494680

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nature genetics 859 12833157
2005 Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. American journal of human genetics 450 16380915
2009 Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC cancer 217 19183436
2004 Localization of peptidylarginine deiminase 4 (PADI4) and citrullinated protein in synovial tissue of rheumatoid arthritis. Rheumatology (Oxford, England) 160 15466895
2004 A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis and rheumatism 156 15077293
2012 Regulation of histone modification and chromatin structure by the p53-PADI4 pathway. Nature communications 131 22334079
2006 A functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Koreans. Arthritis and rheumatism 128 16385500
2007 PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatology international 126 17265154
2005 Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis and rheumatism 123 16200584
2009 Regulation of protein Citrullination through p53/PADI4 network in DNA damage response. Cancer research 109 19843866
2006 Association between PADI4 and rheumatoid arthritis: a meta-analysis. Rheumatology (Oxford, England) 96 16449362
2011 Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells. PLoS genetics 93 21655091
2005 PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology (Oxford, England) 91 15998632
2004 A family based study shows no association between rheumatoid arthritis and the PADI4 gene in a white French population. Annals of the rheumatic diseases 90 15485997
2021 Histone citrullination by PADI4 is required for HIF-dependent transcriptional responses to hypoxia and tumor vascularization. Science advances 78 34452909
2008 Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking. Arthritis research & therapy 71 18462498
2009 PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Annals of the rheumatic diseases 67 19470526
2005 Genetic and genomic studies of PADI4 in rheumatoid arthritis. Rheumatology (Oxford, England) 61 15814578
2007 Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies. Journal of human genetics 60 18087673
2007 Estrogen-enhanced peptidylarginine deiminase type IV gene (PADI4) expression in MCF-7 cells is mediated by estrogen receptor-alpha-promoted transfactors activator protein-1, nuclear factor-Y, and Sp1. Molecular endocrinology (Baltimore, Md.) 58 17456793
2014 PADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation. Nature communications 56 24874575
2010 PADI4 and tumourigenesis. Cancer cell international 50 20222985
2014 Citrullination of DNMT3A by PADI4 regulates its stability and controls DNA methylation. Nucleic acids research 48 24957603
2012 Citrullinated vimentin stimulates proliferation, pro-inflammatory cytokine secretion, and PADI4 and RANKL expression of fibroblast-like synoviocytes in rheumatoid arthritis. Scandinavian journal of rheumatology 46 22765310
2013 PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: results from the IORRA cohort study. PloS one 45 23577190
2010 PADI4 polymorphism predisposes male smokers to rheumatoid arthritis. Annals of the rheumatic diseases 44 21062850
2005 Peptidylarginine deiminase 4 (PADI4) identified as a conformation-dependent autoantigen in rheumatoid arthritis. Scandinavian journal of rheumatology 43 16134727
2007 Association of anti-cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis and rheumatism 39 17469103
2005 Investigation of polymorphisms in the PADI4 gene in determining severity of inflammatory polyarthritis. Annals of the rheumatic diseases 34 15731287
2022 Berberine regulates PADI4-related macrophage function to prevent lung cancer. International immunopharmacology 33 35764017
2011 Investigating the pathogenic role of PADI4 in oesophageal cancer. International journal of biological sciences 31 21698003
2010 Peptidyl arginine deiminase type IV (PADI4) haplotypes interact with shared epitope regardless of anti-cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis: a case control study. Arthritis research & therapy 30 20537173
2007 Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population. Clinical immunology (Orlando, Fla.) 30 17980669
2015 Association between susceptibility to rheumatoid arthritis and PADI4 polymorphisms: a meta-analysis. Clinical rheumatology 29 26474773
2013 Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) β up-regulation. Journal of ethnopharmacology 29 23665163
2008 A functional haplotype and expression of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in Chinese. Tissue antigens 29 18764812
2009 The expression of PADI4 in synovium of rheumatoid arthritis. Rheumatology international 28 19199100
2009 A functional haplotype of PADI4 gene in rheumatoid arthritis: positive correlation in a French population. The Journal of rheumatology 26 19332633
2023 An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression. Cancer discovery 25 37140445
2005 Functional haplotypes of PADI4: relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies. Annals of the rheumatic diseases 25 15760928
2015 Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis. Archives of medical research 24 26043831
2014 Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways. Bioscience, biotechnology, and biochemistry 24 25494680
2010 Contribution of anti-CCP antibodies, proximal interphalangeal joint involvement, HLA-DRB1 shared epitope, and PADI4 as risk factors for the development of rheumatoid arthritis in palindromic rheumatism. Scandinavian journal of rheumatology 24 20476860
2012 PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Modern rheumatology 23 22552437
2021 The regulation of macrophage polarization by hypoxia-PADI4 coordination in Rheumatoid arthritis. International immunopharmacology 21 34333356
2017 PADI4 Epigenetically Suppresses p21 Transcription and Inhibits Cell Apoptosis in Fibroblast-like Synoviocytes from Rheumatoid Arthritis Patients. International journal of biological sciences 21 28367100
2010 The PADI4 gene does not contribute to genetic susceptibility to rheumatoid arthritis in Chinese Han population. Rheumatology international 21 20563870
2022 PADI4 promotes epithelial-mesenchymal transition(EMT) in gastric cancer via the upregulation of interleukin 8. BMC gastroenterology 20 35045833
2019 PADI4‑mediated epithelial‑mesenchymal transition in lung cancer cells. Molecular medicine reports 20 30816464
2015 Polymorphisms and functional haplotype in PADI4: further evidence for contribution on rheumatoid arthritis susceptibility and anti-cyclic citrullinated peptide antibodies in a western Mexican population. Immunology letters 19 25562673
2022 Biochemical and biophysical characterization of PADI4 supports its involvement in cancer. Archives of biochemistry and biophysics 18 35081374
2021 PADI4 mediates autophagy and participates in the role of ganoderic acid A monomers in delaying the senescence of Alzheimer's cells through the Akt/mTOR pathway. Bioscience, biotechnology, and biochemistry 18 33963744
2021 PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking. Frontiers in immunology 18 34733271
2019 Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans. International journal of molecular sciences 18 31242568
2018 PADI4 stimulates esophageal squamous cell carcinoma tumor growth and up-regulates CA9 expression. Molecular carcinogenesis 18 30242913
2016 Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases. Lung 18 27372294
2024 Lenvatinib-activated NDUFA4L2/IL33/PADI4 pathway induces neutrophil extracellular traps that inhibit cuproptosis in hepatocellular carcinoma. Cellular oncology (Dordrecht, Netherlands) 17 39585643
2022 Human Enzyme PADI4 Binds to the Nuclear Carrier Importin α3. Cells 17 35883608
2018 Hypoxia‑induced autophagy is inhibited by PADI4 knockdown, which promotes apoptosis of fibroblast‑like synoviocytes in rheumatoid arthritis. Molecular medicine reports 17 29393388
2011 PADI4 polymorphisms and related haplotype in rheumatoid arthritis patients. Joint bone spine 17 21981985
2019 One-Step ARMS-PCR for the Detection of SNPs-Using the Example of the PADI4 Gene. Methods and protocols 16 31349745
2014 Association between PADI4 gene polymorphisms and anti-cyclic citrullinated peptide antibody positive rheumatoid arthritis in a large Chinese Han cohort. Clinical and experimental rheumatology 16 24564960
2012 Association of single nucleotide polymorphisms (SNPs) of PADI4 gene with rheumatoid arthritis (RA) in Indian population. Genes & genetic systems 16 22976394
2020 PADI4 modulates the invasion and migration of osteosarcoma cells by down-regulation of epithelial-mesenchymal transition. Life sciences 15 32544462
2013 Antistress effect of red ginseng in brain cells is mediated by TACE repression via PADI4. Journal of ginseng research 15 24198657
2023 Intrinsically Disordered Chromatin Protein NUPR1 Binds to the Enzyme PADI4. Journal of molecular biology 14 36858171
2023 Molecular Factors in PAD2 (PADI2) and PAD4 (PADI4) Are Associated with Interstitial Lung Disease Susceptibility in Rheumatoid Arthritis Patients. Cells 14 37759458
2023 hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50. Molecular cell 14 38151017
2020 CircRNA hsa_circ_0008500 Acts as a miR-1301-3p Sponge to Promote Osteoblast Mineralization by Upregulating PADI4. Frontiers in cell and developmental biology 14 33363159
2017 PADI4 polymorphisms and the functional haplotype are associated with increased rheumatoid arthritis susceptibility: A replication study in a Southern Mexican population. Human immunology 14 28551357
2015 Expression of PADI4 in patients with ankylosing spondylitis and its role in mediating the effects of TNF-α on the proliferation and osteogenic differentiation of human mesenchymal stem cells. International journal of molecular medicine 14 26082376
2004 High variability of peptidylarginine deiminase 4 (PADI4) in a healthy white population: characterization of six new variants of PADI4 exons 2-4 by a novel haplotype-specific sequencing-based approach. Journal of molecular medicine (Berlin, Germany) 14 15338034
2024 Sorafenib-induced macrophage extracellular traps via ARHGDIG/IL4/PADI4 axis confer drug resistance through inhibiting ferroptosis in hepatocellular carcinoma. Biology direct 13 39529192
2020 Analysis of Polymorphisms rs7093069-IL-2RA, rs7138803-FAIM2, and rs1748033-PADI4 in the Group of Adolescents With Autoimmune Thyroid Diseases. Frontiers in endocrinology 13 33193078
2013 Decreased PADI4 mRNA association with global hypomethylation in hepatocellular carcinoma during HBV exposure. Cell biochemistry and biophysics 13 22907585
2013 PADI4 haplotypes in association with RA Mexican patients, a new prospect for antigen modulation. Clinical & developmental immunology 13 24454473
2003 Association of PADI4 and rheumatoid arthritis: a successful multidisciplinary approach. Trends in molecular medicine 13 14557050
2024 Loss of PADI2 and PADI4 ameliorates sepsis-induced acute lung injury by suppressing NLRP3+ macrophages. JCI insight 12 39405117
2017 NLRP1, PTPN22 and PADI4 gene polymorphisms and rheumatoid arthritis in ACPA-positive Singaporean Chinese. Rheumatology international 12 28653215
2023 Neutrophil extracellular traps in rheumatoid arthritis and periodontitis: Contribution of PADI4 gene polymorphisms. Journal of clinical periodontology 10 38115803
2021 Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy. Genes 10 34573423
2022 PADI4 Haplotypes Contribute to mRNA Expression, the Enzymatic Activity of Peptidyl Arginine Deaminase and Rheumatoid Arthritis Risk in Patients from Western Mexico. Current issues in molecular biology 9 36135205
2021 Novel functional polymorphism on PADI-4 gene and its association with arthritis onset. Saudi journal of biological sciences 9 35197789
2018 Lack of Association among Peptidyl Arginine Deiminase Type 4 Autoantibodies, PADI4 Polymorphisms, and Clinical Characteristics in Rheumatoid Arthritis. The Journal of rheumatology 9 29858238
2017 PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis. PloS one 9 28182665
2017 Inhibitory effects of ubiquitination of synoviolin by PADI4. Molecular medicine reports 9 29039504
2013 [Association of polymorphisms of PTPN22 and PADI4 genes with rheumatoid arthritis in Yunnan]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 9 23450494
2023 The intrinsically disordered, epigenetic factor RYBP binds to the citrullinating enzyme PADI4 in cancer cells. International journal of biological macromolecules 8 37399862
2023 New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4. Protein science : a publication of the Protein Society 8 37409874
2022 The armadillo-repeat domain of Plakophilin 1 binds to human enzyme PADI4. Biochimica et biophysica acta. Proteins and proteomics 8 36372391
2020 PADI4 (rs2240340), PDCD1 (rs10204525), and CTLA4 (231775) gene polymorphisms and polyarticular juvenile idiopathic arthritis. British journal of biomedical science 8 32163016
2019 Stimulation of DC-CIK with PADI4 Protein Can Significantly Elevate the Therapeutic Efficiency in Esophageal Cancer. Journal of immunology research 8 30944835
2006 PADI4 gene in multiple sclerosis: a family-based association study. Journal of neuroimmunology 8 16828881
2022 Anti-PADI4 antibody suppresses breast cancer by repressing the citrullinated fibronectin in the tumor microenvironment. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 7 35772376
2022 Delayed puberty, gonadotropin abnormalities and subfertility in male Padi2/Padi4 double knockout mice. Reproductive biology and endocrinology : RB&E 7 36224627
2025 PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma. Clinical and translational medicine 6 40078091
2022 Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis. Biology open 6 35603697
2022 The lack of association between PADI4_94 or PADI4_104 polymorphisms and RF, ACPA and anti-PAD4 in patients with rheumatoid arthritis. Scientific reports 6 35831381
2022 A Screening of Epigenetic Therapeutic Targets for Non-Small Cell Lung Cancer Reveals PADI4 and KDM6B as Promising Candidates. International journal of molecular sciences 6 36233212
2021 PADI4, negatively regulated by miR-335-5p, participates in regulating the proliferation, migration, invasion and radiosensitivity of nasopharyngeal carcinoma cells. Journal of biological regulators and homeostatic agents 6 33593046

Missed literature

Know a paper Affinage missed for PADI4? Flag it for the maintainers and the community.

No submissions yet.