Affinage

PADI6

Inactive protein-arginine deiminase type-6 · UniProt Q6TGC4

Length
694 aa
Mass
77.7 kDa
Annotated
2026-06-10
27 papers in source corpus 11 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PADI6 is a maternal-effect scaffolding protein essential for the formation and function of oocyte cytoplasmic lattices (CPLs), the storage hubs that organize translation, protein degradation, and epigenetic factor stability during oocyte maturation and early embryogenesis (PMID:18599511). Despite belonging to the peptidylarginine deiminase family, PADI6 has no reported catalytic deiminase activity, and its function is structural rather than enzymatic (PMID:37778376). PADI6 nucleates a conserved ternary complex (MPU) in which it, assisted by UHRF1, sequesters the E2 ubiquitin-conjugating enzyme UBE2D to block ubiquitin transfer to substrates and thereby suppress the ubiquitination cascade; most clinically identified PADI6 missense variants disrupt assembly of this complex (PMID:18599511). Beyond ubiquitin control, PADI6 anchors ribosomal subunits and the mRNA-MSY2 complex within CPLs, and its loss alters ribosomal sedimentation, disrupts maternal mRNA storage and degradation, dysregulates de novo protein synthesis, and impairs embryonic/zygotic genome activation (PMID:18599511, PMID:27929740). PADI6 also controls the cytoplasmic localization and stability of the epigenetic factors UHRF1 and DNMT1, so that its loss causes reduced DNMT1/UHRF1 levels, decreased H3K9me3, and genome-wide hypomethylation at imprinted loci, establishing PADI6 as a regulator of genomic imprinting maintenance through preimplantation development (PMID:38453481, PMID:41998711). During oocyte maturation PADI6 is hyperphosphorylated and binds 14-3-3 (YWHA) proteins in a phosphorylation-dependent manner (PMID:18463355). Loss-of-function mutations in PADI6 cause early embryonic arrest with failed genome activation (PMID:27545678).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2008 High

    Established that PADI6 is structurally required to build cytoplasmic lattices and to store ribosomal machinery, linking its loss to failed protein synthesis and genome activation — defining its core scaffolding role.

    Evidence Padi6 knockout mouse, sucrose gradient sedimentation, ribosome fractionation and metabolic labeling of protein synthesis in oocytes/embryos

    PMID:18599511

    Open questions at the time
    • Did not resolve the molecular basis of how PADI6 builds lattices
    • No structural mechanism for ribosome sequestration
  2. 2008 Medium

    Showed that PADI6 is post-translationally regulated during maturation, becoming a phosphorylation-dependent 14-3-3 binding partner, implying its activity is gated by the meiotic kinase environment.

    Evidence GST-YWHA pulldown and tandem affinity purification/LC-MS with phosphorylation analysis during oocyte maturation

    PMID:18463355

    Open questions at the time
    • Functional consequence of YWHA binding unresolved
    • Phosphorylation sites and responsible kinase not identified
  3. 2016 Medium

    Extended the scaffolding role to RNA storage, showing PADI6 anchors the mRNA-MSY2 ribonucleoprotein complex into the insoluble CPL fraction, providing a mechanism for maternal mRNA sequestration.

    Evidence Padi6 KO mouse, Triton X-100 fractionation, RNase A treatment, immunofluorescence and western blotting

    PMID:27929740

    Open questions at the time
    • Direct vs. indirect PADI6-MSY2 association not distinguished
    • Single-lab biochemical fractionation
  4. 2016 Medium

    Translated the mouse model into human disease, demonstrating that human PADI6 loss-of-function reduces phosphorylated RNA Pol II and impairs zygotic genome activation gene expression in patient embryos.

    Evidence Immunostaining and gene expression analysis in oocytes/embryos from patients carrying PADI6 nonsense/frameshift mutations

    PMID:27545678

    Open questions at the time
    • Limited patient sample size
    • Mechanistic link between PADI6 and Pol II phosphorylation undefined
  5. 2024 High

    Revealed a distinct epigenetic arm: PADI6 controls cytoplasmic localization and levels of UHRF1 and DNMT1, with developmental arrest separable from DNA methylation defects, indicating multiple independent cytoplasmic functions.

    Evidence Knockin mouse, single-cell multiomics (scRNA-seq + scBS-seq), immunofluorescence and 5-azacytidine rescue

    PMID:38453481

    Open questions at the time
    • How PADI6 governs UHRF1/DNMT1 stability mechanistically unresolved
    • Identity of the cytoplasmic function required for development beyond methylation unknown
  6. 2025 Medium

    Single-cell proteomics defined a CPL-enriched proteome connecting lattices to endolysosomal vesicular assembly, positioning CPLs as hubs integrating translation, respiration, and protein degradation.

    Evidence Single-cell transcriptomics and proteomics fractionation with Padi6 null and hypomorphic mouse models (preprint)

    Open questions at the time
    • Preprint, not peer-reviewed
    • Functional significance of CPL-ELVA interconnection not experimentally tested
  7. 2026 High

    Provided the defining mechanistic and structural model: a cryo-EM-resolved PADI6-UHRF1-UBE2D ternary complex (MPU) in which PADI6 sequesters the E2 to suppress ubiquitin transfer, with most clinical variants disrupting complex assembly.

    Evidence Cryo-EM structure determination, co-immunoprecipitation, biochemical reconstitution and mapping of clinical missense variants

    PMID:41772195

    Open questions at the time
    • Specific substrates protected from ubiquitination not enumerated
    • How MPU function integrates with ribosome/mRNA storage roles unclear
  8. 2026 High

    Showed the epigenetic consequence persists through late preimplantation: PADI6 depletion destabilizes UHRF1/DNMT1, lowers H3K9me3, and causes genome-wide and imprinted-locus hypomethylation with implantation failure.

    Evidence Single-blastocyst RNA-seq/BS-seq, immunostaining and Padi6 mutant mouse model

    PMID:41998711

    Open questions at the time
    • Mechanism by which a cytoplasmic scaffold stabilizes nuclear epigenetic factors not resolved
    • Trophoblast sparing vs. ICM sensitivity unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PADI6's distinct activities — ubiquitin-cascade suppression via MPU, ribosomal/mRNA sequestration, and UHRF1/DNMT1 stabilization — are mechanistically unified within a single CPL scaffold, and whether they share or diverge in molecular determinants, remains unresolved.
  • No single study integrates the ubiquitin, translation, and epigenetic functions
  • Catalytic activity absent yet structural determinants of each function only partially mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0003723 RNA binding 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005829 cytosol 4
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2
Partners
DNMT1MSY2NLRP7UBE2DUHRF1YAP1YWHA
Complex memberships
MPU (PADI6-UHRF1-UBE2D)cytoplasmic lattices (CPLs)subcortical maternal complex (SCMC)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 PADI6 forms a conserved ternary complex (MPU: maternal PADI6-UHRF1-UBE2D) that regulates protein ubiquitination during oocyte maturation and early embryogenesis. Cryo-EM structure of MPU was determined. PADI6, assisted by UHRF1, sequesters UBE2D to prevent ubiquitin transfer from E2 to substrate proteins, thereby suppressing the ubiquitination cascade. 86% (25/29) of clinically identified PADI6 missense variants disrupt MPU assembly. Cryo-electron microscopy structure determination, Co-immunoprecipitation, biochemical reconstitution, mutational analysis of clinical variants Nature structural & molecular biology High 41772195
2008 PADI6 is required for cytoplasmic lattice (CPL) formation in oocytes; in Padi6-/- oocytes, CPLs cannot be visualized. Ribosomal small subunit protein S6 sedimentation properties are dramatically altered in Padi6-/- oocytes, indicating that ribosomal components are stored in CPLs via PADI6. Padi6-/- two-cell embryos show reduced abundance and mislocalization of ribosomal components, dysregulated de novo protein synthesis, and defective embryonic genome activation (EGA). Padi6 knockout mouse model, sucrose gradient sedimentation, immunofluorescence, ribosome fractionation, metabolic labeling of protein synthesis Development (Cambridge, England) High 18599511
2016 PADI6 is required to anchor the mRNA-MSY2 complex to oocyte cytoplasmic lattices (CPLs). In Padi6 KO oocytes, rRNAs are dramatically decreased, mRNA abundance and localization are disrupted, and the association of the major RNA-binding protein MSY2 with the insoluble (CPL) fraction is markedly decreased. RNase A treatment impairs PADI6 and MSY2 localization in oocytes, suggesting mRNAs in complex with MSY2 and PADI6 are bound within CPLs. Padi6 knockout mouse model, Triton X-100 fractionation, RNase A treatment, immunofluorescence, western blotting Cell cycle (Georgetown, Tex.) Medium 27929740
2008 PADI6 undergoes a dramatic increase in phosphorylation during oocyte maturation, and this phosphorylation-dependent modification leads to interaction of PADI6 with YWHA (14-3-3) proteins in the mature egg. GST-YWHA pulldown and tandem affinity purification/LC-MS confirmed the YWHA-PADI6 binding interaction. GST pulldown, transgenic tandem affinity purification with LC-MS, phosphorylation analysis during oocyte maturation Biology of reproduction Medium 18463355
2024 A Padi6 missense variant causes defective oocyte maturation including incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, and up-regulation of maternal decay genes. PADI6 controls cytoplasmic localization of epigenetic factors UHRF1 and DNMT1: UHRF1 levels are reduced in mutant oocytes and DNMT1/UHRF1 localization is abnormal in oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue developmental arrest, indicating cytoplasmic functions of PADI6 are separately required. Mouse knockin model, single-cell multiomic analysis (scRNA-seq + scBS-seq), western blotting, immunofluorescence, 5-azacytidine rescue experiment Genes & development High 38453481
2026 Maternal PADI6 depletion (Padi6P620A mutant oocytes) causes dramatic reduction of UHRF1 and DNMT1 protein levels, decreased H3K9me3, and whole-genome hypomethylation including imprinted loci and repetitive elements at the blastocyst stage. PADI6-deficient embryos show deregulation of inner cell mass markers and defective blastocyst implantation, but no effect on trophoblast differentiation. These data establish PADI6 as a key regulator of epigenetic factor stability required for genomic imprinting maintenance in late preimplantation embryos. Combined single-blastocyst RNA-seq/BS-seq, immunostaining, Padi6 mutant mouse model Epigenetics & chromatin High 41998711
2016 Loss-of-function PADI6 mutations in humans cause reduced phosphorylated RNA polymerase II and decreased expression of seven genes involved in zygotic genome activation in affected embryos, consistent with a role for PADI6 in zygotic genome activation. Immunostaining of affected patient oocytes and embryos, gene expression analysis in embryos from patients with PADI6 nonsense/frameshift mutations American journal of human genetics Medium 27545678
2021 PADI6 co-localizes with and physically interacts with YAP1 in human trophoblast cells (cytotrophoblast). PADI6 positively regulates YAP1 expression. Overexpression of PADI6 promotes cell cycle progression, migration, invasion, proliferation, and apoptosis in trophoblast cells; knockdown has opposite effects. PADI6 regulates trophoblast cell behavior through the Hippo/YAP1 pathway. Co-immunoprecipitation, immunocytochemistry, siRNA knockdown, overexpression, wound healing, Transwell migration/invasion assays, EdU staining, flow cytometry, western blot Journal of inflammation research Medium 34326657
2015 Sp1 transcription factor binds directly to the -56/-47 region of the porcine PADI6 promoter and is required for basal PADI6 transcription. Overexpression of Sp1 increases PADI6 promoter activity and gene expression; siRNA-mediated Sp1 knockdown reduces both. Mithramycin A (Sp1 inhibitor) reduces PADI6 transcriptional activity in a dose-dependent manner. 5'-RACE to map transcription start site, promoter deletion constructs, EMSA, Sp1 overexpression/siRNA knockdown, Mithramycin A treatment, luciferase reporter assay Gene Medium 26403316
2025 PADI6 null mutation inhibits embryonic genome activation and causes defective maternal mRNA degradation and disruption of protein storage on cytoplasmic lattices. Single-cell proteomics fractionation defined a CPL-enriched proteome that includes essential components of the endolysosomal vesicular assembly (ELVA), suggesting previously unknown functional interconnections between CPLs and ELVA. PADI6 performs a critical scaffolding function implicating CPLs as regulatory hubs for translation, respiration, and protein degradation in oocytes and early embryos. Single-cell transcriptomics, single-cell proteomics fractionation, Padi6 null and hypomorphic mouse models bioRxivpreprint Medium
2018 PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos, establishing PADI6 as a member of the subcortical maternal complex (SCMC) alongside NLRP7 in humans. Immunofluorescence co-localization in human oocytes and preimplantation embryos European journal of human genetics : EJHG Low 29693651
2023 PADI6 has no reported catalytic (peptidylarginine deiminase) activity despite belonging to the PAD enzyme family; it is less conserved than other PADIs and its molecular mechanisms of function remain unknown according to the review of available literature. Review and synthesis of published literature Philosophical transactions of the Royal Society of London. Series B, Biological sciences Low 37778376

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest. American journal of human genetics 180 27545678
2008 Role for PADI6 and the cytoplasmic lattices in ribosomal storage in oocytes and translational control in the early mouse embryo. Development (Cambridge, England) 165 18599511
2004 Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene, PADI6. Gene 157 15087120
2018 Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. European journal of human genetics : EJHG 79 29693651
2020 Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance. Clinical epigenetics 50 32928291
2019 New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage. Journal of assisted reproduction and genetics 39 31664658
2020 Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family. European journal of human genetics : EJHG 35 33221824
2016 Role for PADI6 in securing the mRNA-MSY2 complex to the oocyte cytoplasmic lattices. Cell cycle (Georgetown, Tex.) 30 27929740
2021 Two novel mutations in PADI6 and TLE6 genes cause female infertility due to arrest in embryonic development. Journal of assisted reproduction and genetics 29 34036456
2024 A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos. Genes & development 24 38453481
2022 Novel Homozygous PADI6 Variants in Infertile Females with Early Embryonic Arrest. Frontiers in cell and developmental biology 19 35433708
2023 PADI6: What we know about the elusive fifth member of the peptidyl arginine deiminase family. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 18 37778376
2008 Phosphorylation-dependent interaction of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHA) with PADI6 following oocyte maturation in mice. Biology of reproduction 16 18463355
2022 A novel homozygous mutation in the PADI6 gene causes early embryo arrest. Reproductive health 14 36088419
2021 Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy. Genes 10 34573423
2021 PADI6 Regulates Trophoblast Cell Migration-Invasion Through the Hippo/YAP1 Pathway in Hydatidiform Moles. Journal of inflammation research 9 34326657
2023 A complex heterozygous mutation in PADI6 causes early embryo arrest: A case report. Frontiers in genetics 6 36704355
2023 A novel homozygous variant in PADI6 is associate with human cleavage-stage embryonic arrest. Frontiers in genetics 6 37712067
2022 Whole genome sequencing identifies a missense polymorphism in PADI6 associated with testicular/ovotesticular XX disorder of sex development in dogs. Genomics 6 35597501
2024 Novel variants in PADI6 genes cause female infertility due to early embryo arrest. Journal of assisted reproduction and genetics 4 39644447
2015 Characterization of the porcine peptidylarginine deiminase type VI gene (PADI6) promoter: Sp1 regulates basal transcription of the porcine PADI6. Gene 4 26403316
2026 The maternal PADI6-UHRF1-UBE2D complex regulates ubiquitination during oocyte maturation and embryogenesis. Nature structural & molecular biology 2 41772195
2025 A novel PADI6 splice-site variant induces non-canonical GC-AG splicing and embryonic arrest in humans. Functional & integrative genomics 2 40830544
2026 Case Report: Biallelic PADI6 frameshift variants contribute to preimplantation embryonic lethality. Frontiers in genetics 0 41884623
2026 Loss of maternal PADI6 disrupts DNA methylation and genomic imprinting maintenance in late preimplantation mouse embryos. Epigenetics & chromatin 0 41998711
2025 [Pathogenicity analysis of a novel PADI6 gene variant associated with female infertility]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 41451497
2024 Padi6 expression patterns in buffalo oocytes and preimplantation embryos. Animal reproduction 0 38562607

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