Affinage

PSMD12

26S proteasome non-ATPase regulatory subunit 12 · UniProt O00232

Length
456 aa
Mass
52.9 kDa
Annotated
2026-06-10
17 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMD12 (Rpn5) is a conserved lid subunit of the 19S regulatory particle of the 26S proteasome, required for proper proteasome assembly and localization around the inner nuclear membrane; its loss causes accumulation of polyubiquitinated substrates and mitotic defects, and the human protein functionally substitutes for the yeast ortholog (PMID:12783882). Consistent with a dosage-sensitive role in proteasome integrity, PSMD12 haploinsufficiency impairs proteasome activity in patient cells and knockdown models and drives elevated type I interferon signaling as part of a proteasome-associated autoinflammatory syndrome (PMID:35080150). Beyond its structural role in the proteasome, PSMD12 controls the stability of specific cell-cycle regulators: it binds CDK1 and CDKN3 and reduces their ubiquitination to stabilize them, accelerating G2/M progression and promoting proliferation in hepatocellular and pancreatic cancer cells (PMID:37037907, PMID:40534847, PMID:41496578). PSMD12 also raises Nrf2 protein levels and promotes Nrf2 nuclear translocation, activating downstream transcriptional programs including TrxR1 to drive tumor progression (PMID:33987398, PMID:38243044), and its depletion induces pro-apoptotic gene expression in breast cancer cells (PMID:32222279). In a distinct, non-proteasomal context, PSMD12 interacts with influenza A virus M1 and promotes K63-linked ubiquitination of M1 at K102 to facilitate viral budding (PMID:35861516). The structural basis of its interactions resides in an N-terminal α-solenoid domain (PMID:30177392).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 High

    Established PSMD12/Rpn5 as a bona fide lid subunit whose loss disrupts proteasome assembly and substrate turnover, and demonstrated cross-species functional conservation of the human protein.

    Evidence Genetic deletion, fluorescence localization, lid/base epistasis, and human PSMD12 complementation in fission yeast

    PMID:12783882

    Open questions at the time
    • Does not define human-specific proteasomal interactions
    • Substrate specificity of the human proteasome not addressed
  2. 2018 Medium

    Resolved the structural architecture of the Rpn5 N-terminal domain, defining an α-solenoid fold with candidate protein-interaction surfaces.

    Evidence Solution NMR structure of yeast Rpn5 NTD (residues 1–136) with cryo-EM comparison

    PMID:30177392 PMID:30229448

    Open questions at the time
    • Identified interaction sites not functionally validated
    • Rpn11 inhibition claim referenced but not directly tested
    • Full-length human structure not determined
  3. 2020 Medium

    Connected PSMD12 levels to cell survival by showing that its depletion derepresses a pro-apoptotic transcriptional program in breast cancer cells.

    Evidence siRNA knockdown with RNA-seq, RT-qPCR/Western validation, GeCKO screen, and xenografts

    PMID:32222279

    Open questions at the time
    • Pathway placement rests on transcriptomic correlation
    • Direct mechanism linking PSMD12 to each pro-apoptotic gene unresolved
  4. 2021 Medium

    Linked PSMD12 to a transcription-factor stabilization axis, showing it elevates Nrf2 and promotes its nuclear translocation to drive tumor cell proliferation and invasion.

    Evidence siRNA/overexpression, Western blot, invasion assays, xenograft, and Nrf2 rescue in glioma cells

    PMID:33987398

    Open questions at the time
    • Direct vs indirect mechanism of Nrf2 regulation not biochemically resolved
    • Whether proteasomal activity mediates the effect unclear
  5. 2022 High

    Revealed a non-proteasomal, E3-like writer function: PSMD12 directs K63-linked ubiquitination of influenza M1 to enable viral budding.

    Evidence IP/MS, reciprocal Co-IP, M1-K102 mutagenesis, VLP release, TEM, reverse-genetics virus, and mouse virulence

    PMID:35861516

    Open questions at the time
    • Whether PSMD12 acts catalytically or as an adaptor for an E3 not defined
    • Generality of K63-ubiquitination activity to host substrates unknown
  6. 2022 Medium

    Tied PSMD12 dosage to human disease, showing haploinsufficiency impairs proteasome activity and triggers type I interferon–driven autoinflammation.

    Evidence Whole-exome sequencing, proteasome activity assays in patient PBMCs and knockdown HEK293T, and single-cell RNA-seq

    PMID:35080150

    Open questions at the time
    • Mechanistic link from reduced proteasome activity to interferon induction not fully traced
    • Single-lab cohort
  7. 2025 High

    Defined a substrate-stabilizing role in cell-cycle control, showing PSMD12 binds and deubiquitinates CDK1 (and CDKN3) to accelerate proliferation in cancer cells.

    Evidence Co-IP, ubiquitination assays, cycloheximide chase, MG132, CRISPR knockout, and xenografts (CDK1 replicated in two studies; CDKN3 in pancreatic cancer)

    PMID:37037907 PMID:40534847 PMID:41496578

    Open questions at the time
    • Whether PSMD12 itself possesses deubiquitinase activity or recruits a DUB is unresolved
    • How a proteasome subunit selectively protects substrates from degradation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how PSMD12 mechanistically toggles between its canonical role as a proteasome lid subunit and its substrate-stabilizing, transcription-factor-modulating, and ubiquitin-writing activities.
  • No reconstituted biochemistry distinguishing direct catalytic vs adaptor roles
  • No structural model of PSMD12 bound to CDK1, CDKN3, M1, or Nrf2

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0005198 structural molecule activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 1 GO:0005635 nuclear envelope 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1
Complex memberships
26S proteasome 19S regulatory particle (lid)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Rpn5 (PSMD12 ortholog in fission yeast) is a lid subunit of the 26S proteasome that associates with the proteasome and is required for proper proteasome assembly and localization around the inner nuclear membrane. Deletion of rpn5 leads to accumulation of polyubiquitinated proteins (e.g., Cut2/securin) and mitotic abnormalities. Nuclear import of Rpn5 requires other lid components, while subsequent assembly into the nuclear membrane requires the base subcomplex. Human Rpn5 rescues rpn5Δ phenotypes and is incorporated into the yeast proteasome, demonstrating functional conservation. Genetic deletion (rpn5Δ), overexpression, fluorescence localization, epistasis with lid/base mutants, complementation with human PSMD12 The Journal of biological chemistry High 12783882
2018 The N-terminal domain (NTD) of yeast Rpn5 (PSMD12 ortholog) adopts an α-solenoid-like fold in a right-handed superhelical configuration formed by multiple α-helices, as determined by NMR spectroscopy. The NTD is conformationally flexible and contains three putative protein-interaction sites. Structural comparisons reveal local differences in the first three helices between yeast and human Rpn5. NMR spectroscopy (solution structure determination of Rpn5 NTD residues 1–136); structural comparison with cryo-EM data Biochemical and biophysical research communications Medium 30177392
2018 The Rpn5 (PSMD12) subunit, located in the lid subcomplex of the 19S regulatory particle, inhibits Rpn11 deubiquitinase activity in the isolated lid. The NTD (α-solenoid domain) is highly flexible in the isolated lid and may participate in interactions with different proteasome subunits. NMR resonance assignment (1H, 13C, 15N backbone and side chain) of Rpn5 NTD; referenced established biochemical knowledge about Rpn11 inhibition Biomolecular NMR assignments Low 30229448
2022 PSMD12 interacts with influenza A virus M1 protein and promotes K63-linked ubiquitination of M1 at the K102 site, thereby facilitating M1-M2 virus-like particle release and viral budding. PSMD12 knockdown or M1-K102 mutation disrupts virus budding and reduces viral replication and virulence in mice. Immunoprecipitation/mass spectrometry (identification of interaction), Co-IP, site-directed mutagenesis of M1-K102, VLP release assay, transmission electron microscopy, reverse-genetics mutant viruses, mouse virulence experiments Journal of virology High 35861516
2022 PSMD12 haploinsufficiency impairs proteasome function in peripheral blood mononuclear cells and in PSMD12-knockdown HEK 293T cells, leading to elevated type I interferon signaling especially in monocytes, as part of a proteasome-associated autoinflammatory syndrome (PRAAS) phenotype. Whole-exome sequencing (variant identification), proteasome activity assays in patient PBMCs and PSMD12-knockdown HEK 293T cells, single-cell RNA sequencing Arthritis & rheumatology (Hoboken, N.J.) Medium 35080150
2023 PSMD12 physically interacts with CDKN3 (cyclin-dependent kinase inhibitor 3) and reduces its ubiquitination level, thereby stabilizing CDKN3 protein and promoting pancreatic cancer cell proliferation. Rescue assays confirmed that CDKN3 regulation mediates the proliferative and anti-apoptotic effects of PSMD12. Co-immunoprecipitation, Western blot (ubiquitination assay), rescue/epistasis assays, xenograft models Cancer gene therapy Medium 37037907
2025 PSMD12 interacts with CDK1, prevents its proteasome-mediated degradation through deubiquitination (reducing CDK1 ubiquitination), thereby stabilizing CDK1 and accelerating G2/M cell cycle progression in hepatocellular carcinoma cells. Co-immunoprecipitation, Western blot, cycloheximide chase, MG132 proteasome inhibition assay, CRISPR-Cas9 knockout, lentiviral overexpression, xenograft experiments Frontiers in immunology / Cancer science (replicated in two independent papers) High 40534847 41496578
2021 PSMD12 increases the protein level of Nrf2 transcription factor and promotes Nrf2 nuclear translocation, which then drives glioma cell proliferation and invasion via Akt signaling-mediated Nrf2 expression. Nrf2 overexpression rescues the inhibitory effects of PSMD12 knockdown. siRNA knockdown, overexpression, Western blot, CCK-8, Transwell invasion assay, xenograft model, epistasis rescue experiments Annals of translational medicine Medium 33987398
2024 PSMD12 elevates Nrf2 protein level and promotes its nuclear translocation, which increases TrxR1 promoter activity and TrxR1 transcription, promoting NSCLC progression. TrxR1 overexpression rescues the suppressive effects of PSMD12 knockdown. siRNA knockdown, overexpression, Western blot, dual luciferase reporter assay (Nrf2 on TrxR1 promoter), immunofluorescence staining, flow cytometry, Transwell assay, rescue experiments Genes & genomics Medium 38243044
2024 RPS27A (ubiquitin-ribosomal protein S27a) regulates PSMD12 expression, and silencing RPS27A in OGD/R-induced microglia and MCAO mice attenuates inflammatory factor release and neutrophil infiltration via modulation of the PSMD12/NF-κB signaling axis. siRNA silencing of RPS27A in OGD/R microglia and MCAO mouse model, high-throughput sequencing, GO/KEGG/PPI analysis, immunological assays for inflammatory factors and immune cell infiltration Molecular medicine (Cambridge, Mass.) Low 39039432
2020 PSMD12 knockdown in breast cancer cells activates the apoptosis pathway by upregulating pro-apoptotic genes TXNIP, GADD45A, GADD45B, RHOB, and CDKN1A, as identified by RNA-seq and validated by RT-qPCR and Western blot. Restoration of PSMD12 expression decreases expression of these pro-apoptotic genes. siRNA knockdown, RNA-seq, RT-qPCR, Western blot, flow cytometry, GeCKO screen, mouse xenograft Biochemical and biophysical research communications Medium 32222279

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2025 PSMD12 promotes hepatocellular carcinoma progression by stabilizing CDK1. Frontiers in immunology 43 40534847
2018 PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 37 30421579
2003 Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly. The Journal of biological chemistry 32 12783882
2022 Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation. Arthritis & rheumatology (Hoboken, N.J.) 27 35080150
2022 PSMD12-Mediated M1 Ubiquitination of Influenza A Virus at K102 Regulates Viral Replication. Journal of virology 26 35861516
2020 PSMD12 promotes breast cancer growth via inhibiting the expression of pro-apoptotic genes. Biochemical and biophysical research communications 20 32222279
2021 PSMD12 promotes glioma progression by upregulating the expression of Nrf2. Annals of translational medicine 17 33987398
2023 PSMD12 interacts with CDKN3 and facilitates pancreatic cancer progression. Cancer gene therapy 15 37037907
2024 Modulating the RPS27A/PSMD12/NF-κB pathway to control immune response in mouse brain ischemia-reperfusion injury. Molecular medicine (Cambridge, Mass.) 10 39039432
2022 PSMD12 promotes the activation of the MEK-ERK pathway by upregulating KIF15 to promote the malignant progression of liver cancer. Cancer biology & therapy 10 36137220
2024 PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway. Genes & genomics 3 38243044
2025 Integrating multi-omics to unveil PSMD12 as a critical gene in promoting brain metastases of lung adenocarcinoma. Journal of translational medicine 2 40528170
2023 [Clinical characteristics and genetic analysis of a patient with STISS syndrome due to variant of PSMD12 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 36854413
2018 Solution structure of the N-terminal domain of proteasome lid subunit Rpn5. Biochemical and biophysical research communications 1 30177392
2018 NMR 1H, 13C, 15N backbone and side chain resonance assignment of the N-terminal domain of yeast proteasome lid subunit Rpn5. Biomolecular NMR assignments 1 30229448
2026 PSMD12 Overexpression Promotes Lung Adenocarcinoma Progression via Ubiquitin-Proteasome Pathway Dysregulation. Cancer science 0 41496578
2025 [Clinical features and genetic analysis of a child with STISS syndrome due to variant of PSMD12 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 41811043

Missed literature

Know a paper Affinage missed for PSMD12? Flag it for the maintainers and the community.

No submissions yet.