Affinage

PSMD4

26S proteasome non-ATPase regulatory subunit 4 · UniProt P55036

Length
377 aa
Mass
40.7 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMD4 (S5a/Rpn10) is the intrinsic ubiquitin receptor of the 26S proteasome's 19S regulatory particle, providing one of the principal modes by which polyubiquitinated substrates are recognized and delivered for degradation (PMID:15117949, PMID:12584246). Its two ubiquitin-interacting motifs (UIMs) directly engage both Lys48- and Lys63-linked polyubiquitin chains—preferring longer chains—through mechanistically distinct binding surfaces, with UIM binding driving a conformational opening of the Lys48 interdomain interface (PMID:15826667, PMID:17368669). The same UIM surface recruits UBL-domain shuttle factors including hHR23A/B and ubiquilins/Plic proteins, whose binding opens their own closed UBL–UBA conformation and links indirect substrate delivery to the proteasome (PMID:10488153, PMID:14557549, PMID:26222436); Rpn10 acts redundantly and cooperatively with Rad23, Dsk2, and the second proteasomal receptor Rpn13 such that combined loss causes massive ubiquitin conjugate accumulation and failure of shuttle-factor docking (PMID:15117949, PMID:12051757, PMID:26222436). Beyond ubiquitin binding, the von Willebrand factor type A (VWA) domain provides a distinct interaction surface that mediates ubiquitin-independent recognition of FAT10/NUB1L-conjugated substrates (PMID:22434192), and the VWA domain controls incorporation into the proteasome via Rpn12 (PMID:22906049). Rpn10 activity is autoregulated by monoubiquitination at a conserved lysine catalyzed by the NEDD4-family E3 Rsp5 and reversed by Ubp2; this modification inhibits the UIM, dissociates Rpn10 from the proteasome by sterically clashing with Rpn9, and switches the receptor landscape from an Rpn10-high to a Dsk2-high state, enabling cyclic receptor usage (PMID:20542005, PMID:27698474, PMID:26450923). The free extraproteasomal pool of Rpn10 additionally filters Dsk2 access and prevents formation of nondegradable forked ubiquitin chains during E3-mediated assembly (PMID:19387488, PMID:18995839). Rpn10 mediates selective degradation of specific substrates—including p53 (but not Mdm2), PTEN, and PARP1—linking it to Akt and Nrf2 signaling axes in cancer, where it is required for tumor cell viability and is a therapeutic target in multiple myeloma (PMID:24121268, PMID:30673593, PMID:36630605, PMID:28316110). In neurons it localizes to centrosomes where it is essential for local proteasomal activity and dendrite arbor elaboration, an activity antagonized by Id1 (PMID:23831032).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 Medium

    Establishing that the S5a-like protein is a bona fide proteasome component answered whether this ubiquitin-binding subunit was physically and functionally integrated into the 26S particle.

    Evidence Genetic suppressor screen, ubiquitin-lysozyme conjugate binding, and glycerol gradient co-sedimentation in yeast (Sun1p)

    PMID:9017604

    Open questions at the time
    • Did not define which proteasome subunits anchor Rpn10
    • No structural basis for ubiquitin recognition
  2. 1999 High

    Identifying the hHR23A/B UBL domain as an S5a-binding partner defined the indirect (shuttle-factor) route of substrate delivery alongside the direct ubiquitin receptor.

    Evidence Yeast two-hybrid, co-precipitation with deletion mutants, and glycerol gradient co-sedimentation with 26S proteasomes

    PMID:10488153

    Open questions at the time
    • UBL-binding surface on S5a not yet structurally mapped
    • Functional consequence for substrate turnover unresolved
  3. 2000 High

    Genetic and splice-variant analyses established that Rpn10's polyubiquitin-binding site becomes essential when other proteasome subunits are compromised and that alternative isoforms generate functionally distinct proteasome populations.

    Evidence Synthetic lethality and polyubiquitin-binding mutagenesis in fission yeast; isoform cloning and Xenopus egg extract cyclin degradation assays

    PMID:10809753 PMID:10921894

    Open questions at the time
    • Mechanism distinguishing isoform-specific cyclin effects unknown
    • Role under unstressed wild-type conditions limited
  4. 2002 High

    Structural and genetic work answered how shuttle UBL domains engage S5a and demonstrated redundancy among Rad23, Dsk2, and Rpn10 in clearing polyubiquitinated proteins.

    Evidence NMR structure/homology modeling of UBL–S5a complexes; triple-deletion yeast genetics with chain-binding assays

    PMID:11827521 PMID:12051757

    Open questions at the time
    • Quantitative hierarchy among receptors not resolved
    • Distinct surfaces for different UBLs only partly mapped
  5. 2003 High

    A series of NMR studies established the molecular logic of how S5a UIM binding opens the closed UBL–UBA conformation of hHR23 and how intramolecular contacts regulate ubiquitin access.

    Evidence NMR structure determination, residual dipolar coupling, and chemical shift perturbation of S5a–HR23 complexes

    PMID:12832454 PMID:14557549 PMID:14585839

    Open questions at the time
    • Did not connect conformational switching to substrate flux at the proteasome
    • Single-lab NMR models
  6. 2003 High

    Loss-of-function in Drosophila established Rpn10's essential organismal role and showed its loss causes mitotic defects and ubiquitin conjugate accumulation without disrupting proteasome assembly.

    Evidence Drosophila genetic deletion with immunofluorescence and proteasome assembly analysis

    PMID:12584246

    Open questions at the time
    • Substrates underlying mitotic defects not identified
    • Tissue-specific requirements not dissected
  7. 2005 High

    The crystal structure of S5a bound to monoubiquitin defined the two UIMs as mechanistically distinct, chain-length-preferring modules that bind both K48 and K63 linkages.

    Evidence X-ray crystallography, NMR, and polyubiquitin chain binding assays of S5a(196-306)

    PMID:15826667

    Open questions at the time
    • Did not address full-length context or proteasome-assembled conformation
    • Chain-linkage selectivity in vivo unresolved
  8. 2007 Medium

    Quantitative proteomics and NMR jointly answered the breadth of Rpn10's substrate influence and how UIM accommodates diubiquitin, showing UIM contributes only part of Rpn10's total turnover role.

    Evidence 14N/15N metabolic-labeling MS in yeast rpn10Δ and uimΔ mutants; NMR mapping of UIM–diUb binding

    PMID:17368669 PMID:17644757

    Open questions at the time
    • Non-UIM contributions to substrate turnover mechanistically undefined
    • NMR diUb study lacked mutagenesis validation
  9. 2009 High

    Reconstitution experiments revealed that free S5a edits ubiquitin chain topology—preventing nondegradable forked chains—and that S5a is itself ubiquitinated by diverse E3s in a UIM-dependent manner.

    Evidence In vitro ubiquitination/degradation assays with E3/E2 panels, mass spectrometry chain analysis, UIM deletion mutagenesis

    PMID:19240029 PMID:19387488

    Open questions at the time
    • Physiological significance of fork prevention in cells not established
    • Identity of in vivo E3 not defined here
  10. 2010 High

    Identification of Rsp5 and Ubp2 as the writer/eraser of Rpn10 monoubiquitination, plus the SpRpn10 structure, established autoregulation of the UIM and a role for Rpn12 in tuning receptor activity.

    Evidence In vivo ubiquitination and genetic E3/DUB identification; crystallography/NMR/ITC of S. pombe Rpn10

    PMID:20542005 PMID:20739285

    Open questions at the time
    • Structural basis of how modification blocks UIM not yet shown
    • Stress-signal triggering demonstrated only correlatively
  11. 2012 High

    Domain-resolved studies separated Rpn10's functions—the VWA domain mediates ubiquitin-independent FAT10/NUB1L recognition and Rpn12-dependent proteasome incorporation—while a C-terminal lysine cluster carries regulatory ubiquitylation that gates shuttle binding.

    Evidence Co-IP, domain reconstitution in yeast, siRNA in human cells; Rpn12 crystallography; in vivo ubiquitylation site mapping and transgenic rescue in Drosophila

    PMID:22364263 PMID:22434192 PMID:22906049

    Open questions at the time
    • Coordination between VWA and UIM functions unclear
    • Drosophila lysine-cluster mutant only partially rescues, leaving roles undefined
  12. 2013 Medium

    Multiple studies established substrate-selective and tissue-specific roles: Rpn10 selectively governs p53 (not Mdm2) degradation, localizes to neuronal centrosomes for dendrite elaboration, and is itself a Ube3a substrate.

    Evidence siRNA/dominant-negative and protein stability assays; in vivo rodent brain knockdown with centrosome fractionation; in vitro ubiquitination and Drosophila genetics

    PMID:23831032 PMID:24121268 PMID:24292889

    Open questions at the time
    • Basis of p53 vs Mdm2 selectivity unresolved
    • Centrosomal targeting mechanism single-lab
  13. 2015 High

    In vivo and biochemical work established the receptor hierarchy (Rpn10/Rpn13 as the main UBL-UBA docking sites) and how monoubiquitination switches the proteasome between Rpn10-high and Dsk2-high states.

    Evidence Liver-specific Rpn10/Rpn13 double-knockout mice with biochemical fractionation; yeast genetics and co-IP of monoubiquitinated Rpn10

    PMID:26222436 PMID:26450923

    Open questions at the time
    • Mammalian counterpart of the Rpn10/Dsk2 switch not directly shown
    • Substrate-specific consequences of receptor switching undefined
  14. 2016 High

    Structural and functional work resolved how Rpn10 monoubiquitination drives its dissociation—conjugated ubiquitin sterically clashes with Rpn9—and extended Rpn10's roles to antigen processing and Nrf2/p53 cancer signaling.

    Evidence Crystallography of ubiquitylated Rpn10 with EM superimposition and in vivo K84R mutagenesis; antigen-presentation assays; Nrf2 localization cell and xenograft models

    PMID:26903513 PMID:27033953 PMID:27698474

    Open questions at the time
    • Cyclic re-association kinetics in vivo unmeasured
    • Mechanistic link from PSMD4 to CRM1/p53 only partly resolved
  15. 2019 Medium

    Cancer studies defined Rpn10 as a driver of proliferation through targeted substrate degradation (PTEN, PARP1), connecting it to Akt signaling and PARP-inhibitor sensitivity.

    Evidence siRNA knockdown, overexpression rescue, protein stability assays, ChIP (HIF1α promoter); array-CGH and viability assays in breast cancer

    PMID:28316110 PMID:30673593

    Open questions at the time
    • Direct vs indirect role in PTEN/PARP1 degradation not distinguished
    • Single-lab correlative genomics
  16. 2023 High

    Genetic and chemical targeting established Rpn10 as a therapeutic vulnerability in multiple myeloma, where its loss triggers proteotoxic stress, cell cycle arrest, and apoptosis.

    Evidence Inducible knockout/knockdown, proteomics, flow cytometry, xenograft models, and AlphaScreen-identified small-molecule inhibitor (SB699551)

    PMID:36630605

    Open questions at the time
    • Inhibitor selectivity over other receptors not fully defined
    • Resistance mechanisms unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse regulatory inputs (monoubiquitination, Rpn12 incorporation, VWA vs UIM partitioning, isoform usage) are integrated to set substrate-selective degradation in specific tissues remains unresolved.
  • No unified model linking receptor cycling to substrate choice in mammals
  • Determinants of p53/PTEN/PARP1 selectivity unknown
  • Centrosomal and sperm-acrosomal functions mechanistically isolated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2
Partners
DSK2FAT10HHR23AHHR23BNUB1LRAD23RPN12RSP5
Complex memberships
26S proteasome (19S regulatory particle)

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Rpn10/S5a directly binds polyubiquitin chains at the proteasome, serving as an intrinsic ubiquitin receptor; a block substitution in the chain-binding UIM of RPN10 combined with a RAD23 null mutation causes a synthetic defect in protein degradation, indicating redundancy between direct (Rpn10) and indirect (Rad23) ubiquitin chain recognition modes. Purified biochemical reconstitution, genetic epistasis (double mutant yeast), in vitro ubiquitin chain binding assays The Journal of biological chemistry High 15117949
1999 The ubiquitin-like (UBL) domain of hHR23A and hHR23B interacts specifically with S5a (PSMD4), a subunit of the human 26S proteasome; this interaction was mapped by deletion mutagenesis and co-precipitation experiments, and hHR23B-S5a complexes co-sediment with 26S proteasomes in glycerol gradients. Yeast two-hybrid, co-precipitation with deletion mutants, glycerol gradient centrifugation The Journal of biological chemistry High 10488153
2002 NMR structure of the UBL domain of hPLIC-2 and homology model of hHR23a bound to S5a were determined; the S5a-binding surface on the UBL domain of hPLIC-2 was identified and shown to be required for proteasome interaction, with ubiquitin, SUMO-1, and various UBL domains each engaging S5a through distinct surfaces. NMR spectroscopy, homology modeling, binding assays with point mutants Biochemistry High 11827521
2005 Crystal structure of S5a (residues 196–306) alone and bound to two monoubiquitin molecules revealed that the two UIMs of S5a have different ubiquitin-binding mechanisms and distinct specificities; S5a (196–306) binds both K63-linked and K48-linked polyubiquitin, preferring longer chains. X-ray crystallography, NMR, polyubiquitin chain binding assays Journal of molecular biology High 15826667
2003 Binding of proteasomal subunit S5a to hHR23a disrupts intramolecular interdomain contacts (UBL–UBA) causing hHR23a to transition from a closed to an open conformation, as determined by NMR spectroscopy including residual dipolar coupling and chemical shift perturbation analysis. NMR spectroscopy (structure determination, RDC, chemical shift perturbation) Proceedings of the National Academy of Sciences of the United States of America High 14557549
2003 NMR structure of the S5a UIM bound to the UBL domain of HR23B was determined; the UBL domain presents hydrophobic and polar contact sites that are conserved in ubiquitin; pH-dependent protonation of a histidine residue unique to ubiquitin interferes with ubiquitin access to UIM and UBA domains. NMR spectroscopy (structure determination) The Journal of biological chemistry High 14585839
2003 NMR chemical shift perturbation mapped binding surfaces of the hHR23B UBL domain and ubiquitin to the polyubiquitin-binding site 2 (PUbS2) of S5a; intramolecular UBL–UBA interaction was identified for the first time; UBA domains bind ubiquitin at the Lys-48 surface, providing a mechanistic basis for inhibition of polyubiquitin chain assembly. NMR spectroscopy (chemical shift perturbation), deletion mutagenesis The Journal of biological chemistry High 12832454
2010 Rpn10/S5a is monoubiquitinated in vivo by the E3 ligase Rsp5 (NEDD4 family); this modification inhibits the UIM of Rpn10, reducing its ability to interact with ubiquitinated substrates; the deubiquitinating enzyme Ubp2 reverses this modification; monoubiquitination is decreased under stress conditions, suggesting a regulatory mechanism for proteasomal substrate recruitment. In vivo ubiquitination assays, E3/DUB identification by genetics, UIM activity assays Molecular cell High 20542005
2012 FAT10 and NUB1L interact with hRpn10/S5a via its VWA (von Willebrand factor type A) domain—not the UIMs—to enable proteasomal degradation of FAT10-conjugated proteins; depletion of hRpn10 causes accumulation of FAT10 conjugates; the VWA domain of hRpn10 alone suffices to enable FAT10 degradation in yeast. Co-immunoprecipitation, domain deletion/reconstitution in yeast, siRNA knockdown, ubiquitin-independent degradation assays Nature communications High 22434192
2010 Crystal structure of full-length Schizosaccharomyces pombe Rpn10 was determined; the single UIM of SpRpn10 binds Lys48-linked diUb selectively over monoUb and Lys63-linked diUb in a 1:1 complex; the SpRpn10 UIM also binds SpRpn12 (a lid subunit) with affinity comparable to Lys48-diUb, suggesting Rpn12 can modulate Rpn10 ubiquitin-receptor activity. X-ray crystallography (VWA domain), NMR (full-length), ITC binding assays The Journal of biological chemistry High 20739285
2016 Crystal structure of ubiquitylated Rpn10 was determined; a novel ubiquitin-binding patch on Rpn10 directs K84 monoubiquitylation; superimposition on EM proteasome models indicates that Rpn10-conjugated ubiquitin clashes with Rpn9; ubiquitylation on immobilized proteasomes dissociates modified Rpn10 from the complex while unmodified Rpn10 remains associated; Rpn10-K84R is stably associated with Rpn9 in vivo, whereas ubiquitylated Rpn10 does not bind Rpn9 in vitro. Bacterial ubiquitylation system, X-ray crystallography, EM model superimposition, in vitro binding assays, in vivo mutagenesis Nature communications High 27698474
2007 NMR mapping of UIM binding to Lys48- and Lys63-linked diubiquitin showed that UIM binding involves a conformational transition in Lys48-linked diUb that opens the hydrophobic interdomain interface, allowing UIM to enter and contact the same hydrophobic patch as in monoUb complexes; up to two UIM molecules can bind diUb. NMR spectroscopy (chemical shift perturbation, binding surface mapping) Journal of molecular biology Medium 17368669
2009 S5a (free cytosolic form) promotes degradation of ubiquitinated substrates by preventing formation of nondegradable forked ubiquitin chains during ubiquitination by ring-finger/U-box E3s with UbcH5; mass spectrometry showed S5a and GST-UIM prevented Ub fork formation without affecting standard isopeptide linkages. In vitro ubiquitination/degradation assay, mass spectrometry chain analysis The EMBO journal High 19387488
2009 S5a is ubiquitinated by all classes of E3 ubiquitin ligases tested (RING, U-box, HECT) when assayed with UbcH5, but not by UbcH1 or UbcH13/Uev1a; ubiquitination depends on S5a's UIM domains binding to ubiquitin chains on the E3 or substrate, not on specific substrate-recognition degrons; UIM deletion abolishes S5a ubiquitination. In vitro ubiquitination assays with multiple E3/E2 combinations, UIM deletion mutagenesis The Journal of biological chemistry High 19240029
2002 Triple deletion of RAD23, DSK2, and RPN10 in yeast causes accumulation of large amounts of polyubiquitinated proteins, establishing cooperative roles; Dsk2, Rad23, and Rpn10 have different capacities to bind multiubiquitin chains; Ddi1 shows similar multiubiquitin chain-binding activity. Yeast genetics (triple deletion mutants), polyubiquitin chain-binding assays Biochemical and biophysical research communications Medium 12051757
2008 Extraproteasomal Rpn10 (free pool) restricts access of the polyubiquitin-shuttling protein Dsk2 to the proteasome; upon DSK2 induction, Lys48-linked conjugates accumulate and cytotoxicity results; extraproteasomal Rpn10 alleviates this stress by filtering Dsk2 interactions. Quantitative mass spectrometry of ubiquitin chain linkages, yeast genetics, DSK2 overexpression Molecular cell High 18995839
2015 Rpn10 monoubiquitination decreases both Rpn10–proteasome and Rpn10–Dsk2 associations, thereby facilitating formation of Dsk2-proteasomes; Rpn10 monoubiquitination switches the proteasome from 'Rpn10 high/Dsk2 low' to 'Rpn10 low/Dsk2 high' state. Yeast genetics, co-immunoprecipitation, in vivo ubiquitination assays The Biochemical journal Medium 26450923
2015 Liver-specific deletion of both Rpn10 and Rpn13 in mice causes severe liver injury with massive ubiquitin conjugate accumulation; single deletion of either causes only modest impairment; mHR23B and ubiquilin/Plic-1 and -4 fail to bind the proteasome when both Rpn10 and Rpn13 are absent, establishing Rpn10 and Rpn13 as the main proteasomal receptors for UBL-UBA shuttle proteins. Conditional knockout mice (liver-specific), biochemical fractionation, ubiquitin conjugate analysis PLoS genetics High 26222436
2000 Fission yeast Rpn10 (Pus1) is not required for viability but is synthetically lethal with mutations in proteasomal subunits mts3, pad1, and mts4; overexpression of Pus1 with an intact polyubiquitin-binding site rescues mts3-1, but a polyubiquitin-binding-deficient mutant cannot, demonstrating that the polyubiquitin-binding site of Rpn10 is essential when Rpn12/Mts3 activity is compromised. Genetic epistasis (synthetic lethality), polyubiquitin binding assays, in vitro protein binding The Journal of biological chemistry High 10809753
2003 Deletion of the S5a/Rpn10/p54-encoding gene in Drosophila causes larval-pupal lethality, multiple mitotic defects, accumulation of higher-molecular-weight ubiquitinated protein multimers, and accumulation of defective 26S proteasome particles; the deletion does not destabilize or disrupt assembly of the regulatory complex or catalytic core. Drosophila genetic deletion, immunofluorescence, proteasome assembly analysis, ubiquitin conjugate accumulation assays Journal of cell science High 12584246
2000 Mouse Rpn10 mRNAs occur in at least five alternatively spliced forms (Rpn10a–e) from a single gene; Rpn10a is ubiquitously expressed while Rpn10e is embryo/brain specific; both forms bind multiubiquitylated lysozyme with similar affinity in vitro, but exert markedly divergent effects on B-type cyclin destruction in Xenopus egg extracts, indicating functionally distinct 26S proteasome populations. RT-PCR/cDNA cloning, in vitro ubiquitin binding, Xenopus egg extract cyclin degradation assay The EMBO journal High 10921894
1997 S5a interacts specifically with the helix-loop-helix protein Id1 (and less strongly with MyoD and E12) in a ubiquitin-independent manner; S5a restores DNA binding by MyoD–Id1 and E12–Id1 heterodimers, enhances homodimer DNA binding, and reverses Id1-mediated repression of the muscle creatine kinase promoter; the interaction requires the N-terminal half of S5a and specific residues flanking the HLH domain of Id1. Yeast two-hybrid, co-immunoprecipitation, DNA-binding (gel shift) assays, reporter gene assays, deletion/mutagenesis mapping The Journal of biological chemistry Medium 9235903
2013 S5a/Rpn10 localizes to centrosomes in mammalian neurons and is essential for centrosomal proteasomal activity; loss of S5a impairs ubiquitin conjugate clearance at centrosomes and reduces dendrite arbor elaboration in rodent brain in vivo; Id1 disrupts S5a/Rpn10 interaction with the proteasomal lid to inhibit centrosomal proteasome activity. In vivo knockdown in rodent brain, centrosome fractionation, proteasome activity assays, co-immunoprecipitation Cell reports Medium 23831032
2013 Knockdown of S5a/PSMD4/Rpn10 inhibits p53 degradation and causes accumulation of ubiquitinated p53; UIMs of S5a are required for maintenance of low p53 levels (shown by dominant-negative UIM deletion and siRNA rescue); Mdm2 degradation is not affected by S5a knockdown, demonstrating selective proteasomal recognition of p53 via S5a-dependent and Mdm2 via S5a-independent pathways. siRNA knockdown, dominant-negative overexpression, pulse-chase/protein stability assays, siRNA rescue experiments Oncogene High 24121268
2013 Ube3a (E3 ubiquitin ligase, Drosophila orthologue of UBE3A) directly ubiquitinates Rpn10 in a neuronal cell system; only Rpn10 (not Uch-L5 or CG8209) is targeted for degradation upon ubiquitination by Ube3a; in vivo genetic interaction between Ube3a and C-terminal part of Rpn10 was confirmed, with co-overexpression leading to enhanced accumulation of ubiquitinated proteins. In vitro ubiquitination assay, Drosophila genetics, neuronal cell biochemistry Cellular and molecular life sciences : CMLS Medium 24292889
2016 MHC class I processing of the NY-ESO-1 cancer antigen is regulated by Rpn10 and Rpn13 proteasome ubiquitin receptors; non-lysine (non-canonical) ubiquitination on NY-ESO-1 governs its processing by standard and immunoproteasomes via Rpn10/Rpn13. siRNA knockdown, ubiquitination site mapping (mutagenesis), antigen presentation assay The Journal of biological chemistry Medium 26903513
2010 PSMD4/Rpn10 is exposed on the sperm acrosomal surface; anti-PSMD4 antibody and mutant ubiquitins (Ub+1, Ub5+1) block sperm–zona pellucida penetration but not sperm–ZP binding during porcine in vitro fertilization; PSMD4 co-precipitates with acrosin inhibitor (a ubiquitinated ZP-associated substrate), suggesting PSMD4 on the sperm acrosome recognizes ubiquitinated substrates on the ZP to enable penetration. Antibody inhibition in IVF, immunofluorescence localization, immunoprecipitation + proteomics, biotinylated proteasome inhibitor labeling Cell and tissue research Medium 20526895
2013 Human cytomegalovirus UL76 interacts with S5a via UL76's conserved region and the VWA domain of S5a; UL76 sequesters polyubiquitinated proteins and S5a to nuclear aggresomes; knockdown of endogenous S5a significantly reduces the number of cells with UL76 nuclear aggresomes, indicating S5a plays a key role in aggresome formation. Co-immunoprecipitation, siRNA knockdown, FRAP, immunofluorescence co-localization Journal of virology Medium 23966401
2007 Rpn10/S5a's UIM domain controls a broad fraction of ubiquitinated substrate turnover; quantitative proteomics in yeast showed 27% of UPS substrates accumulate as ubiquitin conjugates in rpn10Δ cells, while only ~5% accumulate in UIM-domain-only deletion cells, indicating that Rpn10 contributes to substrate turnover beyond just its UIM domain. Quantitative mass spectrometry (14N/15N metabolic labeling), yeast genetics (rpn10Δ, uimΔ) Molecular & cellular proteomics : MCP Medium 17644757
2001 GST-S5a fusion protein bound to a resin purifies polyubiquitinated proteins from mammalian tissue extracts; hHR23B was identified as the major S5a-binding protein from human placental extract via S5a affinity chromatography, interacting through its UBL domain rather than by ubiquitination. S5a-affinity chromatography, 2D gel electrophoresis, Edman degradation, Western blot Proteomics Medium 11677784
2012 Ubiquitylation of Drosophila p54/Rpn10 occurs at a conserved C-terminal cluster of lysines; extraproteasomal p54 is extensively multiubiquitylated while proteasome-assembled p54 shows only modest modification; ubiquitylation of p54 inhibits its interaction with the UBL domains of Dsk2 and Rad23; transgenic p54 lacking the conserved lysine cluster partially rescues the lethal phenotype but shifts lethality, indicating this modification has essential roles in vivo. In vivo ubiquitylation site mapping, transgenic rescue experiments, co-immunoprecipitation Biochemistry Medium 22364263
2012 Rpn12 binds Rpn10 in vitro and mutating specific residues at the Rpn12 interaction surface impairs Rpn10 incorporation into proteasomes in vivo; Rpn12 crystal structure identified and its PCI domain defined. X-ray crystallography (Rpn12), in vitro binding assays, in vivo proteasome incorporation assay with mutagenesis The Biochemical journal Medium 22906049
2009 The parkin ubiquitin-like domain (Ubld) preferentially binds UIM I of S5a using a surface centered on K48; S5a interaction involves residues distinct from those used to recruit Eps15, where both UIM sequences are engaged; NMR structure of parkin Ubld–S5a interaction was determined. NMR spectroscopy, mutagenesis (K48A substitution), binding assays The Journal of biological chemistry Medium 19875440
2019 Knockdown of Rpn10 in hepatocellular carcinoma (HCC) cells induces G1 cell cycle arrest and decreases proliferation; Rpn10 promotes PTEN degradation through the ubiquitin-proteasome system, thereby activating Akt signaling; overexpression of active Akt rescues proliferation defects caused by Rpn10 knockdown; HIF1α directly binds the Rpn10 promoter to increase its expression. siRNA knockdown, overexpression rescue, PTEN protein stability assay, chromatin immunoprecipitation (HIF1α–Rpn10 promoter binding) Cancer letters Medium 30673593
2016 Cytoplasmic Nrf2 persistently increases PSMD4 expression via the HIF1α/β-catenin axis; PSMD4 reciprocally enhances Nrf2 nuclear export by increasing CRM1 expression through p53 degradation, establishing a feedback loop between PSMD4 and Nrf2 localization. Cell models with Nrf2 localization variants, PSMD4 overexpression/knockdown, xenograft model with proteasome inhibitor Free radical biology & medicine Medium 27033953
2023 Inducible knockout or knockdown of Rpn10 in multiple myeloma cells decreases viability by triggering polyubiquitinated protein accumulation, cell cycle arrest, and apoptosis via caspase activation and unfolded protein response; proteomic analysis revealed Rpn10 inhibition increases autophagy, antigen presentation, and immune cell activation; a small-molecule inhibitor (SB699551) identified by AlphaScreen binds Rpn10 and recapitulates genetic Rpn10 loss. Inducible knockout/knockdown, proteomics, flow cytometry (cell cycle/apoptosis), xenograft models, AlphaScreen high-throughput binding assay Blood High 36630605
2017 Knockdown of PSMD4 in amplified breast cancer cells decreases PARP1 protein levels; loss of the PSMD4 amplicon confers resistance to the PARP inhibitor talazoparib; breast cancer cell lines with PSMD4 copy number gain are significantly more sensitive to talazoparib, suggesting PSMD4 controls PARP1 protein stability. siRNA knockdown, array-CGH, cell viability assays, protein level analysis Genes, chromosomes & cancer Medium 28316110
1997 Yeast Sun1p is a homologue of S5a and binds ubiquitin–lysozyme conjugates as does human S5a; Sun1p co-migrates with known proteasome components on glycerol gradients and can suppress a null nin1 mutation, identifying it as a functional component of the regulatory module of the yeast 26S proteasome. Genetic suppressor screen, ubiquitin-lysozyme conjugate binding assay, glycerol density gradient sedimentation Molecular biology of the cell Medium 9017604

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Pulsed Field Ablation for the Treatment of Atrial Fibrillation: PULSED AF Pivotal Trial. Circulation 486 36877118
2017 Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration. Circulation 443 28483832
2004 Rad23 and Rpn10 serve as alternative ubiquitin receptors for the proteasome. The Journal of biological chemistry 277 15117949
1999 Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. The EMBO journal 229 10508170
1999 Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26 S proteasome. The Journal of biological chemistry 224 10488153
2002 Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a. Biochemistry 200 11827521
1996 Identification of AF-6 and canoe as putative targets for Ras. The Journal of biological chemistry 184 8557659
2022 SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2. PLoS computational biology 169 35994486
2005 Structure of S5a bound to monoubiquitin provides a model for polyubiquitin recognition. Journal of molecular biology 160 15826667
2011 Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3. Blood 146 21628408
2003 DNA-repair protein hHR23a alters its protein structure upon binding proteasomal subunit S5a. Proceedings of the National Academy of Sciences of the United States of America 129 14557549
2010 Monoubiquitination of RPN10 regulates substrate recruitment to the proteasome. Molecular cell 121 20542005
1994 A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL. Oncogene 118 8134107
2002 Ubiquitin-like proteins and Rpn10 play cooperative roles in ubiquitin-dependent proteolysis. Biochemical and biophysical research communications 111 12051757
2010 AF-353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist. British journal of pharmacology 106 20590629
2004 Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain. Endocrine-related cancer 102 15163303
2003 Binding surface mapping of intra- and interdomain interactions among hHR23B, ubiquitin, and polyubiquitin binding site 2 of S5a. The Journal of biological chemistry 97 12832454
1997 Yeast counterparts of subunits S5a and p58 (S3) of the human 26S proteasome are encoded by two multicopy suppressors of nin1-1. Molecular biology of the cell 93 9017604
2000 TFIIH interacts with the retinoic acid receptor gamma and phosphorylates its AF-1-activating domain through cdk7. The Journal of biological chemistry 90 10748061
2007 Quantitative profiling of ubiquitylated proteins reveals proteasome substrates and the substrate repertoire influenced by the Rpn10 receptor pathway. Molecular & cellular proteomics : MCP 87 17644757
2003 AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1. The Journal of biological chemistry 82 12590145
2008 Extraproteasomal Rpn10 restricts access of the polyubiquitin-binding protein Dsk2 to proteasome. Molecular cell 80 18995839
2011 Estrogen receptor α AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proceedings of the National Academy of Sciences of the United States of America 77 21873215
2014 Exposure to Bisphenol AF disrupts sex hormone levels and vitellogenin expression in zebrafish. Environmental toxicology 76 25213402
2003 The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain. Molecular and cellular biology 76 12808105
2019 Bisphenol AF compromises blood-testis barrier integrity and sperm quality in mice. Chemosphere 74 31362132
2012 FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis. Nature communications 73 22434192
2015 Redundant Roles of Rpn10 and Rpn13 in Recognition of Ubiquitinated Proteins and Cellular Homeostasis. PLoS genetics 72 26222436
2013 Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10. Cellular and molecular life sciences : CMLS 71 24292889
2003 Structure of the ubiquitin-interacting motif of S5a bound to the ubiquitin-like domain of HR23B. The Journal of biological chemistry 71 14585839
2000 Analysis of a gene encoding Rpn10 of the fission yeast proteasome reveals that the polyubiquitin-binding site of this subunit is essential when Rpn12/Mts3 activity is compromised. The Journal of biological chemistry 71 10809753
2013 Afadin/AF-6 and canoe: roles in cell adhesion and beyond. Progress in molecular biology and translational science 68 23481206
2004 Rad23 and Rpn10: perennial wallflowers join the melee. Trends in biochemical sciences 65 15544949
2009 S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains. The EMBO journal 63 19387488
2014 Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer. Biochimica et biophysica acta 60 24373847
2008 Protein polarization is critical to stabilizing AF-2 and helix-2' domains in ligand binding to PPAR-gamma. Journal of the American Chemical Society 60 19007119
2010 Structure of Rpn10 and its interactions with polyubiquitin chains and the proteasome subunit Rpn12. The Journal of biological chemistry 58 20739285
2003 Deletion of proteasomal subunit S5a/Rpn10/p54 causes lethality, multiple mitotic defects and overexpression of proteasomal genes in Drosophila melanogaster. Journal of cell science 57 12584246
2003 Ligand-independent coactivation of ERalpha AF-1 by steroid receptor RNA activator (SRA) via MAPK activation. The Journal of steroid biochemistry and molecular biology 53 12943696
2016 The AF-1-deficient estrogen receptor ERα46 isoform is frequently expressed in human breast tumors. Breast cancer research : BCR 51 27927249
1999 In vivo interaction of AF-6 with activated Ras and ZO-1. Biochemical and biophysical research communications 51 10334923
2021 Extracellular matrix remodeling precedes atrial fibrillation: Results of the PREDICT-AF trial. Heart rhythm 48 34332113
2023 Integrated Care for Atrial Fibrillation Using the ABC Pathway in the Prospective APHRS-AF Registry. JACC. Asia 47 37614548
2018 Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite. Chemosphere 47 30408883
2018 Bisphenol AF exerts estrogenic activity in MCF-7 cells through activation of Erk and PI3K/Akt signals via GPER signaling pathway. Chemosphere 47 30590302
2001 Differential contributions of AF-1 and AF-2 activities to the developmental functions of RXR alpha. Development (Cambridge, England) 47 11493527
2001 Purification of poly-ubiquitinated proteins by S5a-affinity chromatography. Proteomics 45 11677784
2000 Developmentally regulated, alternative splicing of the Rpn10 gene generates multiple forms of 26S proteasomes. The EMBO journal 45 10921894
2009 The ubiquitin-interacting motif protein, S5a, is ubiquitinated by all types of ubiquitin ligases by a mechanism different from typical substrate recognition. The Journal of biological chemistry 42 19240029
2019 Nature's Combinatorial Biosynthesis Produces Vatiamides A-F. Angewandte Chemie (International ed. in English) 41 31071229
2019 LncRNA-LINC00472 contributes to the pathogenesis of atrial fibrillation (Af) by reducing expression of JP2 and RyR2 via miR-24. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 31562981
2008 Active nuclear receptors exhibit highly correlated AF-2 domain motions. PLoS computational biology 40 18617990
2003 The AF-1 and AF-2 domains of RAR gamma 2 and RXR alpha cooperate for triggering the transactivation and the degradation of RAR gamma 2/RXR alpha heterodimers. The Journal of biological chemistry 40 12824162
1998 Critical structural elements and multitarget protein interactions of the transcriptional activator AF-1 of hepatocyte nuclear factor 4. The Journal of biological chemistry 40 9792714
2009 An improved manufacturing process for Xyntha/ReFacto AF. Haemophilia : the official journal of the World Federation of Hemophilia 39 20041957
2022 Bisphenol AF blocks Leydig cell regeneration from stem cells in male rats. Environmental pollution (Barking, Essex : 1987) 38 35026324
2002 Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness. The Journal of biological chemistry 38 12149260
2012 Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Steroids 37 23200732
2021 Molecular and Spectroscopic Characterization of Green and Red Cyanine Fluorophores from the Alexa Fluor and AF Series*. Chemphyschem : a European journal of chemical physics and physical chemistry 35 34185946
2020 AF cell derived exosomes regulate endothelial cell migration and inflammation: Implications for vascularization in intervertebral disc degeneration. Life sciences 35 33217442
2016 Cytoplasmic localization of Nrf2 promotes colorectal cancer with more aggressive tumors via upregulation of PSMD4. Free radical biology & medicine 35 27033953
2016 Structure of ubiquitylated-Rpn10 provides insight into its autoregulation mechanism. Nature communications 35 27698474
2013 The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a. Oncogene 33 24121268
1997 Novel regulation of the helix-loop-helix protein Id1 by S5a, a subunit of the 26 S proteasome. The Journal of biological chemistry 32 9235903
2017 CLDN6 enhances chemoresistance to ADM via AF-6/ERKs pathway in TNBC cell line MDAMB231. Molecular and cellular biochemistry 31 29159771
2013 The ubiquitin receptor S5a/Rpn10 links centrosomal proteasomes with dendrite development in the mammalian brain. Cell reports 31 23831032
2012 Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor α is crucial to maintain male reproductive tract function. Proceedings of the National Academy of Sciences of the United States of America 31 23213263
2005 Mylar and Teflon-AF as cell culture substrates for studying endothelial cell adhesion. Biomaterials 31 15990164
2018 Oestrogen receptor α AF-1 and AF-2 domains have cell population-specific functions in the mammary epithelium. Nature communications 29 30413705
2007 Mapping the interactions between Lys48 and Lys63-linked di-ubiquitins and a ubiquitin-interacting motif of S5a. Journal of molecular biology 28 17368669
2006 Expression of JAM-A, AF-6, PAR-3 and PAR-6 during the assembly and remodeling of RPE tight junctions. Brain research 28 16859655
2024 Effects and mechanisms of endocrine disruptor bisphenol AF on male reproductive health: A mini review. Ecotoxicology and environmental safety 27 38583312
2022 Oxidative Stress and Apoptosis in Bisphenol AF-Induced Neurotoxicity in Zebrafish Embryos. Environmental toxicology and chemistry 27 35723417
2017 Proteasome ubiquitin receptor PSMD4 is an amplification target in breast cancer and may predict sensitivity to PARPi. Genes, chromosomes & cancer 27 28316110
2014 Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice. Behavioural brain research 27 25116251
2010 Interference with the 19S proteasomal regulatory complex subunit PSMD4 on the sperm surface inhibits sperm-zona pellucida penetration during porcine fertilization. Cell and tissue research 27 20526895
2023 Bisphenol B and bisphenol AF exposure enhances uterine diseases risks in mouse. Environment international 26 36881955
2022 4S-AF scheme and ABC pathway guided management improves outcomes in atrial fibrillation patients. European journal of clinical investigation 26 35080269
2007 Regulation of c-Src by binding to the PDZ domain of AF-6. The EMBO journal 26 17491594
1998 Complete genomic structure DNA polymorphisms, and alternative splicing of the human AF-6 gene. DNA research : an international journal for rapid publication of reports on genes and genomes 26 9679199
2024 Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies. The Journal of experimental medicine 25 39235529
2023 Exposure to bisphenol A alternatives bisphenol AF and fluorene-9-bisphenol induces gonadal injuries in male zebrafish. Ecotoxicology and environmental safety 25 36801538
2019 Rpn10 promotes tumor progression by regulating hypoxia-inducible factor 1 alpha through the PTEN/Akt signaling pathway in hepatocellular carcinoma. Cancer letters 24 30673593
2018 Hyaluronic acid-endostatin2-alft1 (HA-ES2-AF) nanoparticle-like conjugate for the target treatment of diseases. Journal of controlled release : official journal of the Controlled Release Society 24 30170067
2013 AF-MSCs fate can be regulated by culture conditions. Cell death & disease 24 23559005
2019 Bisphenol AF promotes inflammation in human white adipocytes. American journal of physiology. Cell physiology 23 31596606
2004 Partial A(1) adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF). Current topics in medicinal chemistry 23 15078215
2015 Rpn10 monoubiquitination orchestrates the association of the ubiquilin-type DSK2 receptor with the proteasome. The Biochemical journal 21 26450923
2009 Differential interaction of the E3 ligase parkin with the proteasomal subunit S5a and the endocytic protein Eps15. The Journal of biological chemistry 21 19875440
2019 Simple hematological predictors of AF recurrence in patients undergoing atrial fibrillation ablation. Journal of geriatric cardiology : JGC 20 31645852
2012 Ubiquitylation of Drosophila p54/Rpn10/S5a regulates its interaction with the UBA-UBL polyubiquitin receptors. Biochemistry 20 22364263
2021 Bisphenol analogs AF, S and F: Effects on functional characteristics of porcine granulosa cells. Reproductive toxicology (Elmsford, N.Y.) 19 34019995
2016 Major Histocompatibility Complex (MHC) Class I Processing of the NY-ESO-1 Antigen Is Regulated by Rpn10 and Rpn13 Proteins and Immunoproteasomes following Non-lysine Ubiquitination. The Journal of biological chemistry 19 26903513
2013 Human cytomegalovirus UL76 elicits novel aggresome formation via interaction with S5a of the ubiquitin proteasome system. Journal of virology 19 23966401
2012 Structural and functional characterization of Rpn12 identifies residues required for Rpn10 proteasome incorporation. The Biochemical journal 19 22906049
2005 Zn2+-induced reversible dissociation of subunit Rpn10/p54 of the Drosophila 26 S proteasome. The Biochemical journal 19 15946124
2023 Ubiquitin receptor PSMD4/Rpn10 is a novel therapeutic target in multiple myeloma. Blood 18 36630605
2019 PSMD4 regulates the malignancy of esophageal cancer cells by suppressing endoplasmic reticulum stress. The Kaohsiung journal of medical sciences 18 31162820
2018 N-terminal transactivation function, AF-1, of estrogen receptor alpha controls obesity through enhancement of energy expenditure. Molecular metabolism 18 30287090
2007 Solution structure and backbone dynamics of the AF-6 PDZ domain/Bcr peptide complex. Protein science : a publication of the Protein Society 18 17473018

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