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Showing PSMC3 — RPT5 is a alias.

PSMC3

26S proteasome regulatory subunit 6A · UniProt P17980

Length
439 aa
Mass
49.2 kDa
Annotated
2026-06-10
25 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMC3 (TBP-1/Rpt5) is an AAA-ATPase subunit of the 19S regulatory cap of the 26S proteasome, harboring an N-terminal heptad leucine zipper and conserved ATPase motifs, and its substrate-translocation function is essential for protein homeostasis and mammalian development (PMID:9266764, PMID:10945464). Genetic ablation of Psmc3 causes pre-implantation embryonic lethality with defective blastocyst development, and PSMC3 loss in zebrafish reproduces inner ear and lens (cataract) anomalies, establishing a non-redundant requirement in early embryogenesis and sensory/CNS organogenesis (PMID:10945464, PMID:32500975). Beyond bulk degradation, PSMC3 acts as a positive regulator of selected substrates: it directly binds and stabilizes the tumor suppressor p14ARF against ubiquitin-independent 20S degradation through ARF's N-terminal residues (PMID:17334400), and it stabilizes AGO2 by binding it RNA-independently via its N-terminal coiled-coil and recruiting the deubiquitylase USP14 to reverse AGO2 ubiquitination, thereby promoting RNAi activity (PMID:36528617). PSMC3 also functions as a transcriptional co-activator of the androgen receptor, where both its ATPase domain and leucine zipper are required and it is recruited ligand-dependently to the PSA promoter ARE together with the partner TBPIP (PMID:9345291, PMID:19325002). Disease-associated PSMC3 variants impair 26S substrate translocation and trigger proteotoxic stress: a deep intronic variant constitutively activates the TCF11/Nrf1 proteasome-recovery pathway in patient fibroblasts (PMID:32500975), and de novo missense variants drive a PKR-dependent type I interferon response and alter neuronal dendrite development and learning, linking PSMC3 dysfunction to neurodevelopmental pathology (PMID:37256937).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Medium

    Establishing PSMC3/TBP-1 as a 19S proteasome cap subunit with defined sequence architecture answered what class of molecule it is and where it acts in the cell.

    Evidence cDNA cloning, immunofluorescence and immunogold EM with biochemical fractionation in rat spermatids; FISH chromosomal mapping

    PMID:9048938 PMID:9266764

    Open questions at the time
    • ATPase/helicase motifs identified by sequence but enzymatic activity not directly assayed
    • functional contribution of the leucine zipper untested
  2. 1998 Medium

    Tissue and subcellular localization plus retention of HIV Tat-transactivation inhibition placed PSMC3 in germ-cell nuclei and hinted at a transcription-modulating activity beyond degradation.

    Evidence Immunohistochemistry, in situ hybridization, RT-PCR in mouse testis with Tat transactivation assay

    PMID:9714759

    Open questions at the time
    • mechanism of Tat inhibition not resolved
    • relationship between nuclear localization and proteasome function unclear
  3. 1997 Medium

    Identification of TBPIP as a direct PSMC3 partner that synergizes Tat inhibition provided the first physical interactor and a functional readout.

    Evidence Yeast two-hybrid, co-immunoprecipitation, co-localization, in vitro transactivation assay

    PMID:9345291

    Open questions at the time
    • interaction interface not mapped
    • physiological context of TBPIP synergy beyond Tat unknown
  4. 2000 High

    Knockout established that PSMC3 is non-redundantly essential in vivo, ruling out functional compensation by paralogs during early development.

    Evidence Gene-targeted Psmc3 knockout mice with embryological phenotyping

    PMID:10945464

    Open questions at the time
    • does not separate proteasome-dependent from proteasome-independent roles in the lethal phenotype
    • cell-type-specific requirements not addressed
  5. 2007 High

    Demonstrating that PSMC3 binds and protects p14ARF from 20S degradation revealed a substrate-stabilizing function opposite to canonical proteolysis.

    Evidence Co-IP, in vitro 20S degradation assay, deletion mutagenesis

    PMID:17334400

    Open questions at the time
    • how a proteasome subunit shields rather than feeds a substrate is mechanistically unresolved
    • in vivo consequences for ARF tumor-suppressor signaling not established
  6. 2009 High

    Identifying PSMC3 as a domain-dependent AR co-activator recruited to AREs defined a direct transcriptional role for the subunit at hormone-responsive promoters.

    Evidence Y2H, Co-IP, GST pulldown, reporter assay, ChIP, domain deletion in LNCaP cells

    PMID:19325002

    Open questions at the time
    • whether co-activation requires assembled proteasome or free PSMC3 unknown
    • genome-wide AR target scope not mapped
  7. 2009 Medium

    Co-localization and interaction with the ligase RNF19a connected PSMC3 to ubiquitin-proteasome activity during acrosome biogenesis and spermatid head shaping.

    Evidence Co-IP, immunofluorescence, immunogold EM in rat spermatids

    PMID:19517565

    Open questions at the time
    • functional requirement of PSMC3 in spermiogenesis not tested by loss-of-function
    • substrates at the acroplaxome unidentified
  8. 2011 Medium

    Placing PSMC3 in an Akt/MDM2 feedback loop linked its levels to proliferation, migration, and apoptosis control in fibroblasts.

    Evidence shRNA knockdown, proliferation/migration/apoptosis assays, Akt phosphorylation immunoblotting, Co-IP

    PMID:21991300

    Open questions at the time
    • direct vs indirect regulation of PSMC3 by Akt not fully resolved
    • phenotypes not validated in non-fibroblast systems
  9. 2020 High

    A pathogenic deep intronic variant tied PSMC3 dysfunction to proteotoxic stress and constitutive TCF11/Nrf1 activation, and zebrafish knockout defined inner ear, lens, and CNS developmental requirements.

    Evidence Whole-genome sequencing, patient fibroblast proteasome/ubiquitin assays, Nrf1 reporter assays, CRISPR zebrafish knockout

    PMID:32500975

    Open questions at the time
    • how loss of proteasome capacity yields tissue-specific developmental defects unclear
    • link between TCF11/Nrf1 activation and phenotype not directly tested
  10. 2022 High

    Demonstrating PSMC3-dependent stabilization of AGO2 via USP14 recruitment, and of HBx via VCPIP1, generalized PSMC3's role as a recruiter of deubiquitylases that rescue substrates from degradation.

    Evidence Y2H screens, Co-IP, domain mapping, in vitro 20S degradation with purified PSMC3, RNAi reporter, ubiquitination and cycloheximide-chase assays

    PMID:35695579 PMID:36528617

    Open questions at the time
    • whether DUB recruitment occurs in the context of the assembled proteasome unknown
    • selectivity rules for which substrates PSMC3 stabilizes vs degrades undefined
  11. 2023 High

    Showing that de novo missense variants impair substrate translocation and trigger PKR-dependent type I interferon plus neuronal phenotypes established a causal mechanism linking proteasome dysfunction to neurodevelopmental disease.

    Evidence Patient variant analysis, structural modeling, proteomics/transcriptomics of patient T cells, mouse neuronal dendrite assays, Drosophila Rpt5 behavioral assay, PKR inhibitor rescue

    PMID:37256937

    Open questions at the time
    • upstream trigger sensed by PKR not molecularly defined
    • translatability of PKR inhibition to patient neurodevelopment untested
  12. 2024 Medium

    Identifying PSMC3-mediated ubiquitin-dependent NRF2 degradation, promotable by procyanidin B1, added a context where PSMC3 drives substrate turnover and ferroptosis in glioblastoma.

    Evidence Docking, SPR, Co-IP, mass spectrometry, orthotopic GBM mouse model

    PMID:39293861

    Open questions at the time
    • mechanism partly reliant on docking
    • specificity of PSMC3 for NRF2 vs general proteasome activity not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular determinants dictate whether PSMC3 routes a given substrate toward stabilization (via DUB recruitment) versus degradation, and how this switch is regulated across tissues.
  • no unifying model for substrate-fate selection
  • structural basis of PSMC3-DUB-substrate ternary complexes unknown
  • in vivo balance of these activities uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 3 GO:0140657 ATP-dependent activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 1
Partners
AGO2ARHBXNFE2L2RNF19ATBPIPUSP14VCPIP1
Complex memberships
26S proteasome 19S regulatory cap

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PSMC3/TBP-1 is a component of the 19S regulatory cap of the 26S proteasome, contains a heptad leucine zipper at the N-terminus and conserved ATPase/DNA-RNA helicase motifs, and localizes to the manchette of elongating rat spermatids, as well as cytoplasmic granular bodies, paraaxonemal mitochondria, and outer dense fibers of the spermatid tail. cDNA cloning, indirect immunofluorescence, immunogold electron microscopy, chromatofocusing fractionation, immunoblotting Molecular reproduction and development Medium 9266764
1992 The yeast homolog of PSMC3/TBP-1 (TBPY) encodes a protein with a leucine-zipper-like heptad repeat and helicase sequence motifs, suggesting capacity for self-dimerization or heterodimerization via the hydrophobic region. cDNA cloning, sequence analysis, secondary structure prediction DNA and cell biology Low 1388730
1997 PSMC3 (TBP-1) maps to human chromosome 11p12-p13, with a probable processed pseudogene locus on chromosome 9p. Fluorescence in situ hybridization (chromosomal mapping) Human genetics Medium 9048938
1998 Mouse PSMC3/TBP-1 protein is localized predominantly to the nuclei of spermatogonia and spermatocytes in the testis, and its mRNA is robustly expressed in testis with heterogeneous distribution across other tissues; it retains inhibitory activity on HIV Tat-mediated transactivation. Immunohistochemistry, in situ hybridization, RT-PCR, cDNA cloning Biochimica et biophysica acta Medium 9714759
1997 A novel TBP-1-interacting protein (TBPIP) was cloned; it physically interacts with PSMC3/TBP-1 and co-localizes with it in vivo. TBPIP enhances the inhibitory action of TBP-1 on HIV Tat-mediated transactivation in a synergistic manner. Yeast two-hybrid, co-immunoprecipitation, co-localization assay, in vitro transactivation assay Biochemical and biophysical research communications Medium 9345291
2000 Both Psmc3 and Psmc4 are essential for early embryogenesis; Psmc3-deficient mice die before implantation with defective blastocyst development, establishing a non-redundant, essential role for Psmc3 in vivo. Gene targeting (knockout mice), embryological phenotyping Genomics High 10945464
2007 PSMC3/TBP-1 physically binds p14ARF and stabilizes it against proteasomal degradation; this requires an intact N-terminal 39 amino acids of ARF. In vitro, p14ARF can be degraded by the 20S proteasome in a ubiquitin-independent manner, and TBP-1 counteracts this degradation. Co-immunoprecipitation, in vitro 20S proteasome degradation assay, deletion mutagenesis, western blotting Oncogene High 17334400
2009 PSMC3/TBP-1 directly binds androgen receptor (AR) and TBPIP (TBP-1-interacting protein) in vitro and in LNCaP cells. TBP-1 augments AR-mediated transcription additively with TBPIP, and both the ATPase domain and leucine zipper of TBP-1 are required for transcriptional enhancement. TBP-1 is transiently recruited to the proximal androgen response element (ARE) of the PSA gene promoter in a ligand-dependent manner. Yeast two-hybrid, co-immunoprecipitation, GST pulldown, transient transfection reporter assay, chromatin immunoprecipitation (ChIP), domain deletion mutagenesis Endocrinology High 19325002
2009 During rat spermatid development, PSMC3 and RNF19a (a ubiquitin protein ligase) interact and co-localize in Golgi-derived proacrosomal vesicles, along the cytosolic side of acrosomal membranes and acroplaxome, at the acroplaxome marginal ring, and in the developing sperm head-tail coupling apparatus and tail, implicating the ubiquitin-proteasome system in acrosome biogenesis and spermatid head shaping. cDNA cloning, co-immunoprecipitation, indirect immunofluorescence, immunogold electron microscopy Developmental dynamics Medium 19517565
2011 Stable knock-down of PSMC3/TBP-1 in human fibroblasts increases cell proliferation, migration, and resistance to apoptosis. TBP-1 silencing causes activation of the Akt/PKB kinase, and TBP-1 is itself a downstream target of Akt/PKB; MDM2, a known Akt target, plays a major role in this regulatory loop, suggesting a negative feedback mechanism modulating TBP-1 levels in proliferating cells. shRNA knockdown, cell proliferation/migration/apoptosis assays, western blotting for Akt phosphorylation, co-immunoprecipitation PloS one Medium 21991300
2020 A deep intronic homozygous variant in PSMC3 causes transcription of a cryptic exon, leading to impaired protein homeostasis with accumulation of ubiquitinated proteins (proteotoxic stress) in patient fibroblasts; the TCF11/Nrf1 transcriptional pathway for proteasome recovery after proteasomal inhibition is constitutively activated but cannot be further induced upon chemical proteasome inhibition. Zebrafish PSMC3 knockout reproduces inner ear development anomalies and cataracts, establishing an essential role for PSMC3/Rpt5 in inner ear, lens, and CNS development. Whole-genome sequencing, patient fibroblast functional assays (ubiquitin accumulation, proteasome activity), TCF11/Nrf1 pathway reporter assays, CRISPR zebrafish knockout with phenotypic analysis EMBO molecular medicine High 32500975
2022 PSMC3 physically interacts with AGO2 in an RNA-independent manner via its N-terminal coiled-coil motif. PSMC3 promotes RNAi activity by stabilizing AGO2 at the post-translational level: depletion of PSMC3 increases AGO2 ubiquitination and turnover via the 26S proteasome, whereas PSMC3 facilitates the interaction between AGO2 and the deubiquitylase USP14, leading to USP14-mediated deubiquitination and stabilization of AGO2. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, truncation mutagenesis, RNAi/EGFP reporter assay, cycloheximide chase, ubiquitination assay, western blotting Cellular & molecular biology letters High 36528617
2022 PSMC3 forms a ternary complex with VCPIP1 (a deubiquitinating enzyme) and HBx (hepatitis B virus X protein). Purified His-tagged PSMC3 rescues HBx degradation induced by the 20S proteasome in vitro; VCPIP1 synergizes this stabilization in vivo, acting through a ubiquitin-independent pathway to stabilize HBx. 74-DUB yeast two-hybrid screen, co-immunoprecipitation, in vitro proteasome degradation assay with purified proteins, ubiquitination site mutant plasmids, western blotting Journal of virology High 35695579
2023 De novo missense variants in PSMC3 (encoding the AAA-ATPase proteasome subunit Rpt5) disrupt substrate translocation by the 26S proteasome, inducing proteotoxic stress and alterations in proteins controlling developmental and innate immune programs. PSMC3 variants in patient T cells activate a type I interferon (IFN) response mediated by the intracellular stress sensor PKR, which could be blocked by PKR inhibition. Expression of PSMC3 variants in mouse neuronal cultures alters dendrite development; deletion of the PSMC3 Drosophila ortholog Rpt5 impairs reversal learning. Patient variant analysis, structural modeling, proteomic and transcriptomic analyses of patient T cells, mouse neuronal culture dendrite morphology assay, Drosophila Rpt5 knockout behavioral assay, PKR inhibitor rescue experiment Science translational medicine High 37256937
2024 PSMC3 mediates ubiquitin-dependent proteasomal degradation of NRF2 in glioblastoma cells. The small molecule procyanidin B1 binds NRF2 and promotes the interaction between PSMC3 and NRF2, facilitating ubiquitin-dependent NRF2 degradation and inducing ferroptosis through H₂O₂ accumulation. Protein-small molecule docking, surface plasmon resonance, laser confocal z-stack assay, co-immunoprecipitation, mass spectrometry, western blotting, intracranial GBM orthotopic mouse model Phytotherapy research Medium 39293861

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Specificity and biomineralization activities of Ti-binding peptide-1 (TBP-1). Langmuir : the ACS journal of surfaces and colloids 145 15779989
2020 Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress. EMBO molecular medicine 53 32500975
2009 Rnf19a, a ubiquitin protein ligase, and Psmc3, a component of the 26S proteasome, tether to the acrosome membranes and the head-tail coupling apparatus during rat spermatid development. Developmental dynamics : an official publication of the American Association of Anatomists 47 19517565
1997 A protein associated with the manchette during rat spermiogenesis is encoded by a gene of the TBP-1-like subfamily with highly conserved ATPase and protease domains. Molecular reproduction and development 46 9266764
2000 Mouse proteasomal ATPases Psmc3 and Psmc4: genomic organization and gene targeting. Genomics 39 10945464
1994 Identification of a novel mammalian member of the NSF/CDC48p/Pas1p/TBP-1 family through heterologous expression in yeast. FEBS letters 39 8082782
2023 PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. Science translational medicine 31 37256937
1992 Isolation of a yeast gene encoding a protein homologous to the human Tat-binding protein TBP-1. DNA and cell biology 25 1388730
2009 Tat-binding protein-1 (TBP-1), an ATPase of 19S regulatory particles of the 26S proteasome, enhances androgen receptor function in cooperation with TBP-1-interacting protein/Hop2. Endocrinology 22 19325002
1993 AFG2, an essential gene in yeast, encodes a new member of the Sec18p, Pas1p, Cdc48p, TBP-1 family of putative ATPases. Yeast (Chichester, England) 22 8109176
2007 TBP-1 protects the human oncosuppressor p14ARF from proteasomal degradation. Oncogene 20 17334400
1997 Molecular cloning and characterization of a novel TBP-1 interacting protein (TBPIP):enhancement of TBP-1 action on Tat by TBPIP. Biochemical and biophysical research communications 20 9345291
1995 Structure and expression of LeMA-1, a tomato protein belonging to the SEC18-PAS1-CDC48-TBP-1 protein family of putative Mg(2+)-dependent ATPases. Plant molecular biology 15 7766893
2022 Hepatitis B Virus X Protein Is Stabilized by the Deubiquitinating Enzyme VCPIP1 in a Ubiquitin-Independent Manner by Recruiting the 26S Proteasome Subunit PSMC3. Journal of virology 14 35695579
1997 Localization of genes encoding two human one-domain members of the AAA family: PSMC5 (the thyroid hormone receptor-interacting protein, TRIP1) and PSMC3 (the Tat-binding protein, TBP1). Human genetics 14 9048938
2020 Circ PSMC3 inhibits prostate cancer cell proliferation by downregulating DGCR8. European review for medical and pharmacological sciences 11 32196577
1998 Cloning and heterogeneous in vivo expression of Tat binding protein-1 (TBP-1) in the mouse. Biochimica et biophysica acta 10 9714759
2024 Procyanidin B1 Promotes PSMC3-NRF2 Ubiquitination to Induce Ferroptosis in Glioblastoma. Phytotherapy research : PTR 9 39293861
2011 A regulatory mechanism involving TBP-1/Tat-Binding Protein 1 and Akt/PKB in the control of cell proliferation. PloS one 5 21991300
2021 Prioritization of human well-being spectrum related GWAS-SNVs using ENCODE-based web-tools predict interplay between PSMC3, ITIH4, and SERPINC1 genes in modulating well-being. Journal of psychiatric research 4 34883412
1996 Genomic structure of the maize TATA-box binding protein 1 (TBP-1): conserved exon/intron structure in eukaryotic TBP genes. Gene 4 8863736
2022 PSMC3 promotes RNAi by maintaining AGO2 stability through USP14. Cellular & molecular biology letters 3 36528617
1998 Distribution of mRNA encoding Tat-binding protein-1 (TBP-1), a component of 26S proteasome, in the rat brain. Brain research. Molecular brain research 3 9473711
2026 Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 0 41732108
2025 Neuroimaging PheWAS and molecular phenotyping implicate PSMC3 in Alzheimer's Disease. medRxiv : the preprint server for health sciences 0 41001458

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