Affinage

PSMA3

Proteasome subunit alpha type-3 · UniProt P25788

Round 2 corrected
Length
255 aa
Mass
28.4 kDa
Annotated
2026-04-28
60 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMA3 (alpha7/HC8) is an alpha-type subunit of the 20S proteasome that serves dual roles in proteasome structure and substrate recruitment for ubiquitin-independent degradation. Its C-terminal 69-amino-acid region functions as an 'IDP trapper' that preferentially captures intrinsically disordered proteins—including p21, which it engages via a C-terminal RRLIF degron box—and delivers them for 20S-mediated proteolysis; CRISPR deletion of this degron stabilizes p21, disrupts cell cycle progression, and promotes senescence gene expression after DNA damage [PMID:36291102, PMID:bio_10.1101_2024.08.29.610237]. The PSMA3 C-terminus is also required for 26S proteasome integrity, as its truncation releases free 20S core particles that accumulate in the nucleus (PMID:37371572). Beyond proteolysis, PSMA3 physically interacts with Aurora-B kinase and numerous splicing factors, linking the proteasome to mRNA processing and mitotic regulation (PMID:14674694, PMID:22079093), and its expression is modulated by the antisense lncRNA PSMA3-AS1, which stabilizes PSMA3 mRNA and can confer proteasome-inhibitor resistance in multiple myeloma (PMID:30610101).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1995 Medium

    Isolation and characterization of the PSMA3 gene established that its promoter relies on CAAT and TATA boxes rather than GC boxes, distinguishing its transcriptional regulation from that of other proteasomal subunit genes and mapping the locus to 14q23.

    Evidence Gene isolation with CAT reporter promoter-deletion assays and chromosomal mapping

    PMID:7857283

    Open questions at the time
    • No trans-acting factors for CAAT/TATA-dependent regulation identified
    • Functional consequence of promoter architecture for proteasome stoichiometry not tested
  2. 2003 Medium

    Demonstration that Aurora-B kinase physically binds PSMA3 and accumulates upon proteasome inhibition provided the first evidence that PSMA3 can recruit a specific mitotic regulator for proteasomal degradation.

    Evidence Yeast two-hybrid, GST pull-down, co-immunoprecipitation, and ALLN proteasome inhibitor treatment in HeLa cells

    PMID:14674694

    Open questions at the time
    • Direct ubiquitin-independent versus ubiquitin-dependent degradation of Aurora-B via PSMA3 not distinguished
    • In vivo functional consequence of Aurora-B–PSMA3 interaction for mitosis not assessed
  3. 2011 Medium

    Proteomic identification of PSMA3 interactors enriched for splicing and mRNA-metabolism factors, combined with demonstration that the 20S proteasome regulates SMN2 splicing in vitro, expanded PSMA3's functional scope beyond proteolysis to mRNA processing.

    Evidence 2D gel electrophoresis with MS/MS, in vitro co-immunoprecipitation with splicing factors, in vitro splicing assay

    PMID:22079093

    Open questions at the time
    • Whether splicing regulation requires catalytic proteasome activity or a non-proteolytic PSMA3 scaffold function is unresolved
    • In vivo validation of proteasome-mediated splicing regulation not performed
  4. 2019 Medium

    Discovery that the antisense lncRNA PSMA3-AS1 forms an RNA duplex with pre-PSMA3 mRNA to stabilize it revealed a post-transcriptional feedback that controls 20S proteasome levels and showed that exosomal transfer of this duplex confers proteasome-inhibitor resistance in multiple myeloma.

    Evidence RNA duplex assay, siRNA knockdown, exosome characterization, co-culture, xenograft mouse model

    PMID:30610101

    Open questions at the time
    • Precise RNA duplex structure and regulatory elements within pre-PSMA3 mRNA not mapped at nucleotide resolution
    • Contribution of PSMA3-AS1 to proteasome levels in non-myeloma contexts not explored
  5. 2022 High

    Reconstitution experiments established that the C-terminal 69-amino-acid segment of PSMA3 is an autonomous 'IDP trapper' sufficient to bind intrinsically disordered proteins and competitively inhibit their 20S-mediated degradation, defining the molecular basis of ubiquitin-independent substrate recruitment by the 20S proteasome.

    Evidence Recombinant C-terminal fragment, in vitro degradation and competitive inhibition assays, interactome analysis

    PMID:36291102

    Open questions at the time
    • Structural basis of trapper–IDP recognition (e.g., cryo-EM or crystal structure) not resolved
    • Selectivity determinants distinguishing IDP substrates that use PSMA3 versus other alpha-ring entry routes remain unclear
  6. 2023 High

    CRISPR-based endogenous tagging revealed that the PSMA3 C-terminus is required for 26S proteasome integrity; its truncation liberates free 20S core particles that accumulate in the nucleus while 19S subunits remain cytoplasmic, establishing a structural gatekeeper role beyond substrate recruitment.

    Evidence CRISPR endogenous PSMB6-YFP and PSMD6-mScarlet tagging, live-cell microscopy, PSMA3 C-terminal truncation, PSMD1 siRNA

    PMID:37371572

    Open questions at the time
    • Mechanism by which the C-terminus stabilizes the 19S–20S interface is not defined at the structural level
    • Physiological consequences of nuclear 20S accumulation not characterized
  7. 2024 High

    Identification of the p21 RRLIF box as a ubiquitin-independent degron that docks onto the PSMA3 trapper resolved how a key cell-cycle inhibitor is targeted for 20S degradation and showed that loss of this degron stabilizes p21, disrupts cell cycle, and promotes DNA-damage-induced senescence.

    Evidence Split luciferase binding assay, p21 mutagenesis, CRISPR deletion in HEK293/HeLa, pulse-chase half-life, cell cycle and senescence assays (preprint)

    PMID:bio_10.1101_2024.08.29.610237

    Open questions at the time
    • Peer review pending; awaits independent replication
    • Whether other RRLIF-like degrons exist across the IDP trapper substrate repertoire is unknown
    • In vivo organismal consequence of RRLIF-box disruption not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A structural model of the PSMA3 C-terminal trapper domain engaged with an IDP substrate (e.g., p21 RRLIF box) is missing, and the rules that govern substrate selectivity among the many IDPs captured by this region remain undefined.
  • No high-resolution structure of trapper–substrate complex
  • Relative contribution of 20S (via PSMA3 trapper) versus 26S (ubiquitin-dependent) degradation of shared substrates in physiological settings not quantified
  • Non-proteolytic functions (splicing regulation) lack mechanistic detail

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
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 1
Partners
AURKBCDKN1APSMA3-AS1PSMD1
Complex memberships
20S proteasome26S proteasome

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The PSMA3 (HC8) gene encoding the alpha-type subunit of the human 20S proteasome was isolated and characterized. Its promoter requires CAAT and TATA boxes (but not GC boxes) for activity, distinguishing it from other proteasomal subunit promoters. The HC8 gene was mapped to chromosome 14q23. Gene isolation, chloramphenicol acetyltransferase promoter assay, chromosomal mapping Biochemical and biophysical research communications Medium 7857283
2003 Human Aurora-B kinase physically interacts with PSMA3 (alpha7/HC8), a subunit of the 20S proteasome. Aurora-B protein levels increase when the proteasome is inhibited with ALLN, suggesting Aurora-B undergoes proteasome-dependent degradation mediated by its binding to PSMA3. Yeast two-hybrid screen, GST pull-down assay, co-immunoprecipitation, proteasome inhibitor (ALLN) treatment in HeLa cells Molecular and cellular biochemistry Medium 14674694
2011 Proteomic profiling of PSMA3-interacting proteins in both cytoplasm and nucleus revealed a large set of partners involved in mRNA metabolism and splicing. In vitro biochemical studies confirmed direct interactions between PSMA3 and splicing factors. Furthermore, the 20S proteasome was shown to regulate splicing of the SMN2 gene in vitro, establishing a functional link between the proteasome (via PSMA3) and mRNA processing. 2D gel electrophoresis, tandem mass spectrometry (MS/MS), in vitro co-immunoprecipitation with splicing factors, in vitro splicing assay Biochemical and biophysical research communications Medium 22079093
2019 PSMA3-AS1 (an antisense lncRNA) forms an RNA duplex with pre-PSMA3 mRNA and promotes PSMA3 expression by increasing its mRNA stability, thereby upregulating 20S proteasome levels and conferring proteasome inhibitor resistance in multiple myeloma cells. Exosomal transfer of PSMA3 and PSMA3-AS1 from mesenchymal stem cells to myeloma cells mediates this resistance. Exosome characterization (DLS, TEM, Western blot), co-culture experiments, siRNA knockdown, xenograft mouse model, RNA duplex interaction assay Clinical cancer research Medium 30610101
2022 The C-terminal 69-amino-acid region of PSMA3 (alpha7 subunit of the 20S proteasome) functions as an 'IDP trapper' that preferentially binds intrinsically disordered proteins (IDPs). A recombinant trapper fragment is sufficient to interact with multiple IDPs and competitively blocks their degradation by the 20S proteasome in vitro. Over one-third of PSMA3 trapper-binding proteins are known 20S proteasome substrates, and they display features characteristic of 20S substrates. Protein interactome dataset analysis, in vivo binding assays, cell-free (in vitro) degradation assays with recombinant C-terminal fragment, competitive inhibition experiments Cells High 36291102
2023 The C-terminal region of PSMA3 is critical for 26S proteasome integrity. Truncation of the PSMA3 C-terminus phenocopies knockdown of the 19S regulatory particle subunit PSMD1, resulting in elevated levels of 'free' 20S core particles. Using CRISPR-tagged endogenous PSMB6-YFP and PSMD6-mScarlet, it was shown that free 20S CPs (without 19S caps) accumulate in the nucleus while PSMD6 (19S subunit) remains cytoplasmic under these conditions. CRISPR endogenous tagging (YFP, mScarlet), live-cell fluorescence microscopy, colocalization analysis, PSMA3 C-terminal truncation, PSMD1 siRNA knockdown Biomolecules High 37371572
2024 The IDP p21 interacts with the PSMA3 C-terminal 'Trapper' region via a C-terminal RRLIF box, which acts as a ubiquitin-independent degron. CRISPR deletion or mutation of the p21 RRLIF box in HEK293 and HeLa cells increases p21 half-life, causes aberrant cell cycle patterns, and promotes senescence hallmark gene expression in response to DNA damage. The RRLIF box is positioned adjacent to the known ubiquitin-dependent degron, forming a dual degron module. Split luciferase reporter assay, p21 mutagenesis, CRISPR genome editing (HEK293 and HeLa), pulse-chase/half-life analysis, cell cycle analysis, senescence gene expression assays bioRxivpreprint High bio_10.1101_2024.08.29.610237

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
1996 Structure and functions of the 20S and 26S proteasomes. Annual review of biochemistry 2108 8811196
2002 Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 1924 12167863
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annual review of biochemistry 1398 19489727
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2011 Systematic and quantitative assessment of the ubiquitin-modified proteome. Molecular cell 1334 21906983
2003 Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 1236 12808466
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2003 DNA deamination mediates innate immunity to retroviral infection. Cell 1150 12809610
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex. Science (New York, N.Y.) 1006 14564014
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2003 The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 912 12808465
2013 Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 870 23503661
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2001 The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nature cell biology 829 11146632
2003 The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nature medicine 798 14528300
2008 Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 787 18854154
2003 Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 763 12859895
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Molecular & cellular proteomics : MCP 749 21890473
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2001 The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature cell biology 708 11146634
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2019 Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 110 30610101
2020 Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA. Aging 59 32005028
2011 Characterization of Bacillus subtilis HC8, a novel plant-beneficial endophytic strain from giant hogweed. Microbial biotechnology 41 21366893
2011 Proteomic analysis of the 20S proteasome (PSMA3)-interacting proteins reveals a functional link between the proteasome and mRNA metabolism. Biochemical and biophysical research communications 38 22079093
2022 PSMA3-AS1 induced by transcription factor PAX5 promotes cholangiocarcinoma proliferation, migration and invasion by sponging miR-376a-3p to up-regulate LAMC1. Aging 24 35022330
2020 LncRNA PSMA3-AS1 promotes colorectal cancer cell migration and invasion via regulating miR-4429. European review for medical and pharmacological sciences 22 33275226
2021 LncRNA PSMA3-AS1 promotes cell proliferation, migration, and invasion in ovarian cancer by activating the PI3K/Akt pathway via the miR-378a-3p/GALNT3 axis. Environmental toxicology 19 34520102
2021 Long non-coding RNA PSMA3-AS1 promotes glioma progression through modulating the miR-411-3p/HOXA10 pathway. BMC cancer 18 34294084
2021 lncRNA PSMA3-AS1 promotes the progression of non-small cell lung cancer through targeting miR-17-5p/PD-L1. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 17 34610219
2021 YY1-induced long non-coding RNA PSMA3 antisense RNA 1 functions as a competing endogenous RNA for microRNA 214-5p to expedite the viability and restrict the apoptosis of bladder cancer cells via regulating programmed cell death-ligand 1. Bioengineered 17 34720049
2003 Human aurora-B binds to a proteasome alpha-subunit HC8 and undergoes degradation in a proteasome-dependent manner. Molecular and cellular biochemistry 17 14674694
2020 LncRNA PSMA3-AS1 Promotes Lung Cancer Growth and Invasion via Sponging MiR-4504. Cancer management and research 15 32669876
2014 Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster. Pediatrics and neonatology 14 24875235
2023 Long noncoding RNA PSMA3-AS1 functions as a competing endogenous RNA to promote gastric cancer progression by regulating the miR-329-3p/ALDOA axis. Biology direct 13 37403106
2020 Long noncoding RNA PSMA3‑AS1 functions as a microRNA‑409‑3p sponge to promote the progression of non‑small cell lung carcinoma by targeting spindlin 1. Oncology reports 13 32945481
2023 METTL3 affects FLT3-ITD+ acute myeloid leukemia by mediating autophagy by regulating PSMA3-AS1 stability. Cell cycle (Georgetown, Tex.) 10 37088992
2019 Y75B8A.8 (HC8) protein of Haemonchus contortus: A functional inhibitor of host IL-2. Parasite immunology 9 30883834
1995 Isolation and characterization of the HC8 subunit gene of the human proteasome. Biochemical and biophysical research communications 9 7857283
2023 The Expression Patterns and Implications of MALAT1, MANCR, PSMA3-AS1 and miR-101 in Esophageal Adenocarcinoma. International journal of molecular sciences 7 38203269
2017 Secretomic profiling of cells from hollow fiber bioreactor reveals PSMA3 as a potential cholangiocarcinoma biomarker. International journal of oncology 7 28560424
2014 PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genetic diversity in Latvians, Lithuanians and Taiwanese. Meta gene 7 25606411
2022 The C-Terminus of the PSMA3 Proteasome Subunit Preferentially Traps Intrinsically Disordered Proteins for Degradation. Cells 6 36291102
2022 Long Noncoding RNA PSMA3 Antisense RNA 1 Promotes Cell Proliferation, Migration, and Invasion in Pancreatic Ductal Adenocarcinoma Via Targeting MicroRNA-154-5p to Positively Modulate Karyopherin Subunit Alpha 4. Pancreas 6 36607951
2020 Long non-coding RNA PSMA3-AS1 enhances cell proliferation, migration and invasion by regulating miR-302a-3p/RAB22A in glioma. Bioscience reports 6 32894281
2012 Polyclonal antibodies against human proteasome subunits PSMA3, PSMA5, and PSMB5. Hybridoma (2005) 5 22894781
2023 LncRNA PSMA3-AS1 promotes preterm delivery by inducing ferroptosis via miR-224-3p/Nrf2 axis. Cellular and molecular biology (Noisy-le-Grand, France) 4 38158666
2023 LncRNA PSMA3-AS1 activates the progression of triple-negative breast cancer cells by blocking miR-186-5p-mediated PSME3 inhibition. Cellular and molecular biology (Noisy-le-Grand, France) 3 38279473
2023 Method of Monitoring 26S Proteasome in Cells Revealed the Crucial Role of PSMA3 C-Terminus in 26S Integrity. Biomolecules 2 37371572
2025 Revisiting the Role of Long Non-coding RNA PSMA3-AS1 in Human Cancers: Current Evidence and Future Directions. Current pharmaceutical design 1 39901687
2021 1,4-dihydropyridine derivatives increase mRNA expression of Psma3, Psmb5, and Psmc6 in rats. Arhiv za higijenu rada i toksikologiju 0 34187104