Affinage

PADI3

Protein-arginine deiminase type-3 · UniProt Q9ULW8

Length
664 aa
Mass
74.7 kDa
Annotated
2026-06-10
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PADI3 is a calcium-dependent peptidylarginine deiminase that catalyzes the post-translational conversion of arginine to citrulline, a modification essential for normal hair-shaft formation: CCCA-associated missense mutations reduce PADI3 enzymatic activity, lower its expression, and mislocalize the protein, establishing loss of deiminase function as the basis of hair-shaft defects (PMID:30763140). In keratinocytes, PADI3 transcription is driven directly by NF-Y and Sp1/Sp3 binding within the proximal promoter (PMID:16671893), and the resulting protein is stabilized by ZDHHC13-mediated palmitoylation (PMID:31669413). Beyond hair biology, PADI3 citrullinates pyruvate kinase M2 (PKM2) at R106, rewiring allosteric regulation to promote glycolysis (PMID:33741961). In cancer cells PADI3 acts as a cytoplasmic tumor suppressor, suppressing the Sirt2/AKT axis to raise p21 and drive G1 arrest, with its C-terminal domain required for antitumor activity (PMID:31908891), and lowering CKS1 to restrain epithelial-mesenchymal transition (PMID:39206995).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 High

    Established how PADI3 expression is controlled in its native keratinocyte context, identifying the transcription factors that set its baseline levels.

    Evidence Luciferase reporter assays, EMSA, ChIP, and siRNA knockdown of Sp1/NF-YA in keratinocytes

    PMID:16671893

    Open questions at the time
    • Does not address signals that modulate NF-Y/Sp1 activity during hair-shaft differentiation
    • No link to enzymatic activity or substrate engagement
  2. 2019 High

    Defined PADI3 loss-of-function as the molecular cause of a hair-shaft disorder by showing disease mutations cripple enzyme activity, expression, and localization.

    Evidence Enzymatic activity assays, immunofluorescence, immunoblotting, and structural modeling of patient-derived mutants across discovery and replication cohorts

    PMID:30763140

    Open questions at the time
    • Specific hair-shaft substrates citrullinated in vivo not directly enumerated here
    • Mechanism by which mislocalization arises from point mutations unresolved
  3. 2019 Medium

    Identified a post-translational control point governing PADI3 protein stability, showing palmitoylation rather than transcription alone sets steady-state protein levels.

    Evidence Quantitative proteomics, biochemical palmitoylation assay, and enzymatically dead ZDHHC13 knock-in mice

    PMID:31669413

    Open questions at the time
    • Palmitoylated residue(s) on PADI3 not mapped
    • Whether palmitoylation regulates PADI3 localization or catalytic activity not addressed
  4. 2019 Medium

    Placed PADI3 as a cytoplasmic tumor suppressor upstream of a Sirt2/AKT/p21 cell-cycle axis, extending its role beyond epidermal biology.

    Evidence Overexpression/knockdown with Sirt2 rescue, flow cytometry, truncation mutants, and xenografts in colon cancer cells

    PMID:31908891

    Open questions at the time
    • Whether the Sirt2/AKT effect depends on PADI3 deiminase activity not established
    • Direct PADI3 substrate in this axis unidentified
  5. 2021 Medium

    Provided the first defined enzymatic substrate-site for PADI3 in a metabolic context, showing citrullination of PKM2-R106 reprograms allosteric regulation toward glycolysis.

    Evidence Mass spectrometry site mapping plus overexpression/knockdown and metabolic assays in cancer cells

    PMID:33741961

    Open questions at the time
    • No in vitro reconstitution with purified PADI3 alone (acts with PADI1)
    • Apparent contradiction between glycolysis-promoting and tumor-suppressive roles not reconciled
  6. 2024 Low

    Connected PADI3 to suppression of EMT through CKS1 downregulation, linking it to migration control in cancer.

    Evidence Migration assays and overexpression/rescue experiments measuring CKS1, Snail, N-cadherin, E-cadherin in colon cancer cells

    PMID:31708688 PMID:39206995

    Open questions at the time
    • Ubiquitin-dependent CKS1 degradation inferred from rescue without direct ubiquitination or proteasome assays
    • No direct PADI3-CKS1/Hsp90 biochemical interaction demonstrated
  7. 2024 Low

    Extended PADI3's cancer relevance to endometrial cells via ERK signaling and glycolysis.

    Evidence siRNA knockdown and overexpression rescue with proliferation, apoptosis, glycolysis, and ERK-pathway readouts

    PMID:38474453

    Open questions at the time
    • Pathway placement based on KD/rescue without direct PADI3-ERK biochemical link
    • Whether deiminase activity drives the ERK effect unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single deiminase reconciles glycolysis promotion via PKM2 citrullination with tumor-suppressive cell-cycle arrest, and whether its cancer-context effects require catalytic activity, remains unresolved.
  • No structure of PADI3 bound to a substrate
  • Catalytic dependence of the Sirt2/AKT and CKS1 effects untested
  • Full in vivo hair-shaft substrate repertoire not enumerated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
NFYAPKM2SP1ZDHHC13

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 PADI3 (together with PADI1) citrullinates pyruvate kinase M2 (PKM2) at arginine residue R106, reprogramming cross-talk between PKM2 ligands: it lowers PKM2 sensitivity to the inhibitors tryptophan, alanine, and phenylalanine and promotes activation by serine, thereby bypassing normal physiological regulation to promote excessive glycolysis. Mass spectrometry identification of citrullination site, cancer cell overexpression/knockdown experiments, metabolic assays measuring glycolysis Nature communications Medium 33741961
2019 CCCA-associated missense mutations in PADI3 result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic (peptidylarginine deiminase) activity, establishing that loss of PADI3 enzymatic function underlies hair-shaft formation defects. Enzymatic activity assay, immunofluorescence for localization, immunoblotting for expression, protein structural modeling of mutants The New England journal of medicine High 30763140
2006 Transcription factors NF-Y and Sp1/Sp3 directly bind the PADI3 promoter region (within 129 bp of the transcription start site) in keratinocytes in vitro and in vivo, and mutation of either binding motif or siRNA knockdown of Sp1 or NF-YA markedly reduces PADI3 promoter activity and expression. Luciferase reporter assays with deletion/mutation constructs, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown The Biochemical journal High 16671893
2019 ZDHHC13 palmitoylates PADI3 protein, and this palmitoylation is critical for PADI3 protein stability in vivo; loss of ZDHHC13 enzymatic activity reduces PADI3 palmitoylation and protein levels. Quantitative proteomics to identify palmitoylation candidates, biochemical palmitoylation assay, knock-in mice bearing enzymatically dead ZDHHC13 mutation The Journal of investigative dermatology Medium 31669413
2019 PADI3 overexpression in colon cancer cells suppresses Sirt2 and AKT phosphorylation, increases p21 expression, and induces G1 cell cycle arrest; Sirt2 overexpression partially reverses these effects, placing PADI3 upstream of the Sirt2/AKT/p21 axis. PADI3 is localized mainly in the cytoplasm, and the C-terminal domain is required for its antitumor activity. Western blot, flow cytometry for cell cycle, CCK-8 proliferation assay, colony formation assay, RNA-seq, truncation mutation experiments, immunocytochemistry, xenograft tumor formation Cancer biology & medicine Medium 31908891
2019 PADI3 decreases Hsp90 and CKS1 expression in colon cancer cells, and Hsp90 is required as an intermediary for PADI3-mediated downregulation of CKS1. Western blot, real-time PCR, CCK-8 proliferation assay, colony formation assay, overexpression and rescue experiments, xenograft mouse model Cancer cell international Low 31708688
2024 PADI3 promotes ubiquitin-dependent degradation of CKS1, thereby suppressing EMT: reduced CKS1 leads to decreased Snail and N-cadherin levels and restored E-cadherin expression, inhibiting colon cancer cell migration. Western blot, Transwell and wound healing migration assays, flow cytometry, overexpression and rescue experiments Journal of cancer research and therapeutics Low 39206995
2024 PADI3 knockdown in endometrial cancer cells inhibits ERK signaling pathway activity, reduces glycolysis, and induces apoptosis; PADI3 overexpression reverses the anti-cancer effects of atractylenolide II, placing PADI3 upstream of ERK in this context. siRNA knockdown, overexpression rescue experiments, proliferation assays, apoptosis assays, glycolysis measurements, Western blot for ERK pathway proteins Molecules (Basel, Switzerland) Low 38474453

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Variant PADI3 in Central Centrifugal Cicatricial Alopecia. The New England journal of medicine 96 30763140
2021 Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation. Nature communications 56 33741961
2006 NF-Y and Sp1/Sp3 are involved in the transcriptional regulation of the peptidylarginine deiminase type III gene (PADI3) in human keratinocytes. The Biochemical journal 32 16671893
2019 Palmitoyl Acyltransferase Activity of ZDHHC13 Regulates Skin Barrier Development Partly by Controlling PADi3 and TGM1 Protein Stability. The Journal of investigative dermatology 21 31669413
2019 PADI3 induces cell cycle arrest via the Sirt2/AKT/p21 pathway and acts as a tumor suppressor gene in colon cancer. Cancer biology & medicine 18 31908891
2003 Thioredoxin motif of Caenorhabditis elegans PDI-3 provides Cys and His catalytic residues for transglutaminase activity. Biochemical and biophysical research communications 14 12684055
2019 PADI3 plays an antitumor role via the Hsp90/CKS1 pathway in colon cancer. Cancer cell international 12 31708688
2024 Atractylenolide II Suppresses Glycolysis and Induces Apoptosis by Blocking the PADI3-ERK Signaling Pathway in Endometrial Cancer Cells. Molecules (Basel, Switzerland) 5 38474453
2024 PADI3 inhibits epithelial-mesenchymal transition by targeting CKS1-induced signal transduction in colon cancer. Journal of cancer research and therapeutics 3 39206995
2023 Pseudogenization of the Hair-Related Genes PADI3 and S100A3 in Cetaceans and Hippopotamus amphibius. Journal of molecular evolution 2 37787841
2023 Citrullinated and MMP-degraded vimentin is associated with chronic pulmonary diseases and genetic variants in PADI3/PADI4 and CFH in postmenopausal women. Scientific reports 1 38155185

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