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Showing PJA1 — PRAJA1 is a alias.

PJA1

E3 ubiquitin-protein ligase Praja-1 · UniProt Q8NG27

Length
643 aa
Mass
71.0 kDa
Annotated
2026-06-10
26 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PJA1 (Praja1) is a brain-enriched RING-H2 finger E3 ubiquitin ligase that catalyzes substrate ubiquitination and proteasomal degradation in partnership with UbcH5/UbcH5B-family and UBE2E3 E2 conjugating enzymes, with RING-finger integrity required for all of its catalytic activity (PMID:12036302, PMID:11959851, PMID:32686212). Through this activity it controls the abundance of a broad set of substrates governing transcription, differentiation, and protein homeostasis: it degrades the MAGE/Necdin protein Dlxin-1 to restrain Dlx5-dependent transcription (PMID:11959851), targets individual PRC2 subunits EZH2, EED, and SUZ12 (PMID:21513699), and drives EZH2 turnover during skeletal myogenesis in a manner gated by p38α-mediated EZH2 phosphorylation at threonine 372 and by PJA1's own cytoplasmic-to-nuclear translocation upon differentiation (PMID:28067271). PJA1 functions prominently in the nervous system, where it suppresses aggregation and toxicity of neurodegeneration-associated proteins—including TDP-43, tau, and polyglutamine proteins ataxin-3 and huntingtin—by promoting their ubiquitination and clearance (PMID:32686212, PMID:34161122, PMID:41182881), and acts as a negative regulator of synaptic plasticity and memory by turning over substrates such as spinophilin (PMID:40243483). In cancer contexts it degrades phospho-SMAD3 to impair tumor-suppressive TGFβ signaling (PMID:32127355) and ubiquitinates PGAM5 at K88 via K48-linked chains to suppress pyroptosis and confer chemoresistance (PMID:38906860). Its ligase activity is tuned by upstream inputs: 18:0/22:6-phosphatidic acid generated by DGKδ binds the Praja1 N-terminal region (Lys141 critical) to enhance activity and drive serotonin transporter degradation (PMID:32134507, PMID:36528254), while the deubiquitylase OTUB2 stabilizes PJA1 against self-directed turnover (PMID:35611163). Beyond degradation, PJA1 interacts with the SMC5/6 complex to silence episomal and nuclear DNA-virus genomes in an interferon-independent, topoisomerase-dependent manner (PMID:30185588), and its own expression is transcriptionally controlled by nuclear TDP-43 and by astrocytic GPR30/CREB signaling (PMID:38194085, PMID:37712419).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 High

    Established PJA1 as a bona fide RING-H2 E3 ubiquitin ligase by demonstrating both E2 binding and RING-dependent substrate degradation, defining its core biochemical identity.

    Evidence In vitro E2 (UbcH5B) binding and ubiquitination assays, plus GST pull-down, in vivo ubiquitination, RING mutagenesis, and transcription assay on the substrate Dlxin-1

    PMID:11959851 PMID:12036302

    Open questions at the time
    • Did not define the spectrum of physiological substrates beyond Dlxin-1
    • Chain linkage type and processivity not characterized
  2. 2011 High

    Showed PJA1 targets the PRC2 chromatin-repressive machinery and mapped its preferred E2 partners, expanding its role into epigenetic regulation.

    Evidence Cell-free ubiquitination of EZH2/EED/SUZ12 with RING mutant controls; protein microarray E2-panel and substrate profiling identifying UbcH5 family

    PMID:21461837 PMID:21513699

    Open questions at the time
    • Microarray substrate hits largely unvalidated
    • Physiological contexts where PRC2 subunits are degraded not yet defined
  3. 2013 Medium

    Linked PJA1 to neuronal differentiation control by showing it degrades NRAGE and suppresses NGF-induced neurite outgrowth.

    Evidence Overexpression in PC12 cells with co-localization imaging, proteasome rescue, and neurite assays

    PMID:23717400

    Open questions at the time
    • Endogenous role not tested by loss-of-function
    • Direct ubiquitination of NRAGE not reconstituted
  4. 2017 High

    Defined how substrate access is gated, demonstrating that EZH2 degradation during myogenesis requires p38α phosphorylation of EZH2 (T372) and PJA1 nuclear translocation.

    Evidence Ubiquitination assays, T372 phosphosite mutagenesis, p38α inhibition, genetic epistasis in myoblasts, and subcellular fractionation

    PMID:28067271

    Open questions at the time
    • Signal driving PJA1 nuclear translocation not identified
    • Generality of phospho-gating to other substrates unknown
  5. 2018 High

    Revealed a non-degradative function in which PJA1 partners with SMC5/6 to restrict episomal DNA-virus genomes, broadening its activity beyond proteasomal turnover.

    Evidence Reciprocal Co-IP, knockdown/overexpression, chromatin binding, and topoisomerase inhibitor epistasis across HBV/HSV-1 models

    PMID:30185588

    Open questions at the time
    • Whether SMC5/6 or other partners are ubiquitinated unclear
    • Molecular basis of episomal-versus-chromosomal discrimination not resolved
  6. 2020 Medium

    Connected PJA1 to neuronal proteostasis and serotonergic and TGFβ signaling, showing it clears CTF TDP-43, degrades phospho-SMAD3, and is lipid-activated to degrade SERT.

    Evidence Co-IP with UBE2E3 and substrates, in vivo motor-neuron and HCC models, lipid binding/activity assays in DGKδ KO brain, and an HMGA2 interaction screen

    PMID:32127355 PMID:32134507 PMID:32577156 PMID:32686212

    Open questions at the time
    • HMGA2 not shown to be ubiquitinated by PJA1 (Low-confidence interaction only)
    • Direct lipid-to-catalysis mechanism not structurally defined
  7. 2021 High

    Demonstrated broad protective roles against protein aggregation and additional disease substrates, establishing PJA1 as a multi-substrate quality-control ligase.

    Evidence Co-IP, ubiquitination assays, and cross-model rescue (neuronal, yeast, Drosophila) for polyQ proteins; K88/K48-linkage mutagenesis for PGAM5; ubiquitination and pathway readouts for FOXR2

    PMID:33839405 PMID:34161122 PMID:38906860

    Open questions at the time
    • Whether aggregation suppression requires degradation versus binding not fully separated
    • FOXR2 mechanism limited in depth
  8. 2022 Medium

    Distinguished PJA1's aggregation-suppressing activity from mere substrate binding and identified OTUB2 as a stabilizer that controls PJA1 abundance.

    Evidence Co-IP and aggregate assays comparing PJA1 to other TDP-43-binding E3 ligases; OTUB2 Co-IP and cycloheximide chase with rescue; N/C-terminal domain mapping (K141, DGKδ2)

    PMID:35611163 PMID:35701899 PMID:36528254

    Open questions at the time
    • Mechanism by which PJA1 uniquely suppresses aggregation versus other E3s unresolved
    • OTUB2-PJA1 deubiquitylation linkage specificity not defined
  9. 2023 Medium

    Placed PJA1 downstream of astrocytic GPR30/CREB signaling in learning and memory and identified Serpina3n as a binding partner.

    Evidence Conditional knockout, CREB signaling assays in astrocytes, PJA1-Serpina3n Co-IP, and behavioral testing

    PMID:37712419

    Open questions at the time
    • Serpina3n ubiquitination/degradation by PJA1 not demonstrated
    • Cell-type specificity of PJA1 memory effects not fully dissected
  10. 2024 Medium

    Showed PJA1 expression is transcriptionally driven by nuclear TDP-43, creating a feedback loop relevant to TDP-43 proteinopathy neurotoxicity.

    Evidence TDP-43 knockdown with species-specific promoter binding analysis and in vivo PJA1 overexpression rescue in monkey/mouse brain

    PMID:38194085

    Open questions at the time
    • Species-specificity of the regulatory loop limits human extrapolation
    • Direct promoter occupancy mechanism not structurally defined
  11. 2025 High

    Established PJA1 as a negative regulator of synaptic plasticity and memory and confirmed tau as a degradation substrate with an evolutionarily recent origin.

    Evidence In vivo knockdown, LTP electrophysiology, behavior, and spinophilin Co-IP; tau ubiquitination assays with RING mutant and ancestral sequence reconstruction

    PMID:40243483 PMID:41182881

    Open questions at the time
    • Spinophilin ubiquitination not yet reconstituted
    • How LTP triggers proteasomal PJA1 downregulation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PJA1 selects among its very broad substrate set in a given cell and how its localization, lipid activation, and partner complexes are coordinated in vivo remains unresolved.
  • No structural model of PJA1 substrate engagement
  • Endogenous substrate hierarchy and tissue-specific specificity undefined
  • Integration of degradative versus SMC5/6 non-degradative functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 2 R-HSA-168256 Immune System 1
Partners
DGKΔEZH2OTUB2PGAM5SMAD3TDP-43UBCH5BUBE2E3
Complex memberships
SMC5/6 complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 PJA1 (Praja1) binds to the C-terminal necdin homology domain of Dlxin-1 (a MAGE/Necdin family protein) via GST pull-down and co-immunoprecipitation, and acts as an E3 ubiquitin ligase to promote ubiquitination and proteasomal degradation of Dlxin-1 through its RING finger domain, thereby down-regulating Dlx5-dependent transcriptional activity. RING finger mutant Praja1 failed to degrade Dlxin-1, confirming RING-dependent E3 activity. GST pull-down, co-immunoprecipitation, overexpression with proteasome inhibitor, RING finger mutagenesis, in vivo ubiquitination assay, GAL4-dependent transcription assay The Journal of biological chemistry High 11959851
2002 PJA1 is a RING-H2 finger E3 ubiquitin ligase that binds the ubiquitin-conjugating enzyme UbcH5B (E2) and exhibits E2-dependent E3 ubiquitin ligase activity in vitro. PJA1 shares 52.3% identity with PJA2 (NEURODAP1) and is abundantly expressed in the brain. In vitro binding assay, immunoprecipitation, in vitro ubiquitination assay Genomics High 12036302
2011 PRAJA1 directly ubiquitinates individual PRC2 subunits (EZH2, EED, SUZ12) in a cell-free system, leading to their proteasomal degradation. Expression of PRAJA1, but not an inactive RING finger mutant, enhanced degradation of PRC2 subunits in cells. Cell-free ubiquitination assay, overexpression with RING finger mutant, proteasome inhibitor rescue Biochemical and biophysical research communications High 21513699
2011 Protein microarray profiling identified UbcH5 family E2 enzymes as optimal partners for Praja1 in vitro, and revealed a broad repertoire of putative Praja1 substrates consistent with its roles in bone development and brain function. Protein microarray ubiquitination assay, E2 panel profiling Cell biochemistry and biophysics Medium 21461837
2013 Praja1 co-localizes with cytoskeletal components and NRAGE in PC12 cells, and its overexpression promotes proteasome-dependent degradation of NRAGE, thereby suppressing NGF-induced neuronal differentiation and neurite formation. Overexpression in stably transfected PC12 cells, co-localization imaging, proteasome inhibitor rescue, neurite formation assay PloS one Medium 23717400
2017 PJA1 is a MYOD-induced E3 ubiquitin ligase that promotes EZH2 degradation during skeletal myogenesis. p38α kinase phosphorylates EZH2 at threonine 372, which is required for PJA1-mediated ubiquitination and degradation. PJA1 cytoplasmic localization in proliferating myoblasts limits premature EZH2 degradation; nuclear translocation upon differentiation allows EZH2 targeting. Biochemical ubiquitination assays, genetic epistasis (PJA1 knockdown/overexpression in myoblasts), phosphorylation site mutagenesis (T372), p38α inhibition, subcellular fractionation/localization Nature communications High 28067271
2018 PJA1 interacts with the SMC5/6 complex and facilitates its binding to viral and episomal DNAs in the cell nucleus to restrict DNA viruses (HBV, HSV-1) and episomal plasmids, but not RNA viruses or chromosomally integrated genes, in an interferon-independent manner. This restriction requires DNA topoisomerases, as topoisomerase inhibition or knockdown releases PJA1-mediated silencing. Co-immunoprecipitation, knockdown/overexpression experiments, chromatin binding assay, DNA topoisomerase inhibitor treatment, reporter assays Journal of virology High 30185588
2020 PJA1 binds to C-terminal fragment (CTF) TDP-43 and the E2-conjugating enzyme UBE2E3 as shown by co-immunoprecipitation. PJA1 suppresses phosphorylation and cytoplasmic aggregate formation of TDP-43 in neuronal cells and in mouse facial motor neurons in vivo, acting downstream of the HSF1 pathway. Co-immunoprecipitation, adenoviral overexpression in neuronal cells, in vivo mouse motor neuron model, DNA microarray to identify downstream targets Neuropathology : official journal of the Japanese Society of Neuropathology High 32686212
2020 1-Stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA), generated by DGKδ, selectively binds to Praja1 and enhances its E3 ubiquitin ligase activity, which leads to ubiquitination and degradation of the serotonin transporter (SERT) in the brain. Lipid binding assay, DGKδ knockout mouse brain lipidomics, Praja1 activity assay with PA FEBS letters Medium 32134507
2020 PJA1 promotes ubiquitination and proteasomal degradation of phosphorylated SMAD3 and impairs the SMAD3/β2SP-dependent tumor-suppressing TGFβ pathway in HCC cells. In SMAD3-haploinsufficient mice, PJA1 overexpression promoted liver stem cell transformation. Ubiquitination assay in HCC cells, overexpression/knockdown, mouse liver stem cell transformation assay, gene expression analysis Cancer research Medium 32127355
2020 HMGA2 interacts with PJA1 by mass spectrometry, and this interaction is enhanced by TGFβ treatment. PJA1 and HMGA2 co-localize in the nucleus of HCC cells upon TGFβ treatment, suggesting PJA1 regulates HMGA2 levels in the context of TGFβ signaling. Mass spectrometry, co-immunoprecipitation, co-localization imaging Genes & cancer Low 32577156
2021 PJA1 interacts with polyglutamine (polyQ) proteins ataxin-3 and huntingtin, promotes their ubiquitination and degradation, reduces aggregate formation in neuronal cells, and suppresses polyQ toxicity in yeast and rescues eye degeneration in a transgenic Drosophila SCA3 model. Co-immunoprecipitation, ubiquitination assay, knockdown in neuronal cells, yeast toxicity assay, Drosophila in vivo rescue experiment Molecular biology of the cell High 34161122
2021 PJA1 promotes K48-linked ubiquitination of PGAM5 at K88, leading to its proteasomal degradation. This suppresses DRP1 phosphorylation at S637, reduces mitochondrial ROS production, and inhibits GSDME-mediated pyroptosis, conferring docetaxel resistance in nasopharyngeal carcinoma cells. Ubiquitination assay with K88 mutagenesis and K48-linkage specific analysis, knockdown/overexpression, mitochondrial ROS measurement, pyroptosis assay, in vivo xenograft Nature communications High 38906860
2021 PJA1 regulates ubiquitin-mediated degradation of FOXR2 in lung adenocarcinoma cells, and PJA1 overexpression inhibits cell invasion and induces apoptosis through inactivation of the Wnt/β-catenin signaling pathway. Ubiquitination assay, overexpression, invasion assay, apoptosis assay, Wnt/β-catenin pathway analysis Biochemical and biophysical research communications Medium 33839405
2022 PJA1 binds to and suppresses aggregation of multiple aggregate-prone neurodegenerative disease proteins (FUS, SOD1, α-synuclein, ataxin-3, huntingtin polyQ) in neuronal cultures, as shown by co-immunoprecipitation. In contrast, other E3 ligases (Parkin, RNF112, RNF220) bind TDP-43 but fail to suppress its aggregation. Co-immunoprecipitation, adenoviral co-expression in neuronal cells, aggregate formation assay Neuropathology : official journal of the Japanese Society of Neuropathology Medium 35701899
2022 The deubiquitylase OTUB2 stabilizes PJA1 by removing ubiquitin chains from it (deubiquitylation), as shown by co-immunoprecipitation and cycloheximide chase assay, thereby promoting HCC cell proliferation and migration. Co-immunoprecipitation, cycloheximide chase assay, overexpression/knockdown rescue experiments Cellular and molecular bioengineering Medium 35611163
2022 The N-terminal region (aa 1–224) of Praja1 binds 18:0/22:6-phosphatidic acid with Lys141 being critical for this interaction, while the C-terminal catalytic domain (aa 446–615) interacts with DGKδ2. The N-terminal half of the DGKδ2 catalytic domain (aa 309–466) is the primary binding region for Praja1. Domain deletion mapping, mutagenesis (K141), lipid binding assay, pulldown assay Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 36528254
2023 Astrocytic GPR30 positively modulates PJA1 expression through the CREB signaling pathway. PJA1 mediates the effects of astrocytic GPR30 on learning and memory by binding to and presumably targeting Serpina3n, a neuroinflammation marker in astrocytes. Conditional knockout, CREB signaling assay in cultured astrocytes, Co-IP (PJA1-Serpina3n binding), behavioral assays The Journal of clinical investigation Medium 37712419
2024 Loss of nuclear TDP-43 suppresses PJA1 gene transcription in the monkey brain through species-specific binding of nuclear TDP-43 to the PJA1 promoter, reducing PJA1 levels and accelerating neurotoxicity. Conversely, overexpressing PJA1 diminishes neuronal cell death caused by TDP-43 knockdown in vivo. TDP-43 knockdown in monkey brain, promoter binding analysis (species-specific), in vivo PJA1 overexpression rescue Cellular and molecular life sciences : CMLS Medium 38194085
2025 Praja1 ubiquitinates and promotes proteasomal degradation of tau protein in SH-SY5Y neuroblastoma cells in an E3 ligase activity-dependent manner, as shown by in vivo and in vitro ubiquitination assays. Ancestral sequence reconstruction and mutational analysis revealed the Praja1-tau interaction arose after Praja family duplication in placental ancestors. P301L tau mutant is degraded similarly to wild-type tau by Praja1. In vivo/in vitro ubiquitination assay, RING-finger activity mutant, ancestral sequence reconstruction, mutational analysis, P301L tau disease variant testing The FEBS journal High 41182881
2025 PRAJA1 acts as a negative regulator of synaptic plasticity and memory: LTP induction triggers rapid, proteasome-dependent downregulation of PRAJA1 in hippocampal CA1. PRAJA1 knockdown in vivo enhances object recognition and spatial memory. PRAJA1 regulates excitatory/inhibitory balance, and its elevated expression potentiates GABAergic transmission. Spinophilin was identified as a novel substrate of PRAJA1 by co-immunoprecipitation. In vivo PRAJA1 knockdown, LTP electrophysiology, behavioral memory assays, protein biochemistry, co-immunoprecipitation (spinophilin substrate identification) International journal of molecular sciences Medium 40243483

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. The Journal of biological chemistry 93 11959851
2002 PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain. Genomics 51 12036302
2017 Praja1 E3 ubiquitin ligase promotes skeletal myogenesis through degradation of EZH2 upon p38α activation. Nature communications 46 28067271
2011 PRAJA1 is a ubiquitin ligase for the polycomb repressive complex 2 proteins. Biochemical and biophysical research communications 45 21513699
1997 Praja1, a novel gene encoding a RING-H2 motif in mouse development. Oncogene 44 9393880
2007 Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome. Clinical genetics 36 17941886
2018 PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner. Journal of virology 32 30185588
2020 Praja1 RING-finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP-43 aggregate formation. Neuropathology : official journal of the Japanese Society of Neuropathology 30 32686212
2020 1-Stearoyl-2-docosahexaenoyl-phosphatidic acid interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain. FEBS letters 26 32134507
2020 A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders. Annals of clinical and translational neurology 23 32530565
2024 PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma. Nature communications 22 38906860
2020 Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling. Cancer research 22 32127355
2021 Praja1 ubiquitin ligase facilitates degradation of polyglutamine proteins and suppresses polyglutamine-mediated toxicity. Molecular biology of the cell 15 34161122
2013 The ubiquitin ligase Praja1 reduces NRAGE expression and inhibits neuronal differentiation of PC12 cells. PloS one 15 23717400
2023 PJA1 mediates the effects of astrocytic GPR30 on learning and memory in female mice. The Journal of clinical investigation 13 37712419
2022 Praja1 RING-finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease-associated protein aggregation. Neuropathology : official journal of the Japanese Society of Neuropathology 13 35701899
2020 Dysregulated PJA1-TGF-β signaling in cancer stem cell-associated liver cancers. Oncoscience 13 33457451
2020 Alterations in TGF-β signaling leads to high HMGA2 levels potentially through modulation of PJA1/SMAD3 in HCC cells. Genes & cancer 12 32577156
2021 E3 ubiquitin ligase PJA1 regulates lung adenocarcinoma apoptosis and invasion through promoting FOXR2 degradation. Biochemical and biophysical research communications 11 33839405
2011 Protein microarrays for the identification of praja1 e3 ubiquitin ligase substrates. Cell biochemistry and biophysics 10 21461837
2022 OTUB2 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells by PJA1 Deubiquitylation. Cellular and molecular bioengineering 9 35611163
2022 Distinct regions of Praja-1 E3 ubiquitin-protein ligase selectively bind to docosahexaenoic acid-containing phosphatidic acid and diacylglycerol kinase δ. Biochimica et biophysica acta. Molecular and cell biology of lipids 5 36528254
2025 The E3 Ubiquitin Ligase PRAJA1: A Key Regulator of Synaptic Dynamics and Memory Processes with Implications for Alzheimer's Disease. International journal of molecular sciences 4 40243483
2025 E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein tau. The FEBS journal 3 41182881
2024 Loss of TDP-43 mediates severe neurotoxicity by suppressing PJA1 gene transcription in the monkey brain. Cellular and molecular life sciences : CMLS 2 38194085
2025 Praja1 E3 ubiquitin ligase and the role it plays in neurodegeneration. The FEBS journal 0 41466523

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