Affinage

PSMD13

26S proteasome non-ATPase regulatory subunit 13 · UniProt Q9UNM6

Round 2 corrected
Length
376 aa
Mass
42.9 kDa
Annotated
2026-04-28
41 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMD13 is a non-ATPase subunit of the 19S regulatory particle lid of the 26S proteasome, essential for efficient proteasome assembly and ubiquitin-dependent protein degradation. Its C-terminal PCI domain mediates interaction with the neighboring lid subunit Rpn5, while its N-terminal domain recruits the ubiquitin receptor Rpn10 into the 26S proteasome, as revealed by high-resolution NMR structure determination of the yeast ortholog Rpn9 (PMID:25631053, PMID:10490597). Loss of PSMD13/Rpn9 causes temperature-sensitive growth, accumulation of multiubiquitinated proteins, and defective proteasome assembly (PMID:10490597, PMID:9714768). Beyond its core proteasomal role, PSMD13 suppresses NF-κB signaling by inhibiting K63-linked ubiquitination of TAK1 (PMID:37257570), supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation downstream of IL-4 (PMID:37653079), and associates with Dicer to modulate miR-29a levels during neuronal differentiation (PMID:41734180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1998 Medium

    Identification of PSMD13 (p40.5) as a non-ATPase subunit of the 19S regulatory complex established its place within the 26S proteasome and showed, via yeast NAS7 disruption, that it is required for proteasome function under stress.

    Evidence cDNA cloning of human p40.5, yeast NAS7 gene disruption with temperature-sensitive growth phenotype

    PMID:9714768

    Open questions at the time
    • Biochemical role within the 19S lid not yet defined
    • No structural information on how PSMD13 integrates into the lid complex
    • Mechanism of temperature sensitivity not resolved
  2. 1999 High

    Deletion of the yeast ortholog Rpn9 demonstrated that PSMD13 is required for efficient 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, answering how loss of this subunit leads to ubiquitin-conjugate accumulation.

    Evidence Glycerol density gradient centrifugation, native PAGE, and genetic deletion in yeast showing incomplete proteasome complexes and loss of Rpn10 incorporation

    PMID:10490597

    Open questions at the time
    • Structural basis for Rpn10 recruitment unknown
    • Whether assembly role is conserved in mammalian cells not tested
  3. 2015 High

    The high-resolution NMR structure of yeast Rpn9 resolved the architectural basis for PSMD13 function: the N-terminal domain recruits Rpn10 and the C-terminal PCI domain contacts Rpn5 via a conserved hydrophobic/ionic winged-helix interface, establishing the structural logic of PCI-PCI interactions throughout the lid.

    Evidence NMR solution structure with functionally validated interaction surfaces for Rpn10 and Rpn5

    PMID:25631053

    Open questions at the time
    • No mammalian structure available
    • Dynamics of the semiflexible hinge between domains not functionally tested
    • How Rpn10 recruitment is coordinated with other assembly chaperones remains unclear
  4. 2023 Medium

    Three independent studies extended PSMD13 function beyond core proteasome biology: it suppresses NF-κB by inhibiting K63-linked ubiquitination of TAK1 in innate immunity, it sustains HSC repopulating capacity and megakaryocytic differentiation downstream of IL-4, and its genetic interaction with the BAP1 ortholog in C. elegans links it to ubiquitin homeostasis and organismal fitness.

    Evidence K63-ubiquitination assays on TAK1 in fish (PMID:37257570); shRNA knockdown with in vivo transplantation in mouse HSCs (PMID:37653079); CRISPR/RNAi synthetic lethal screen in C. elegans (PMID:36980270)

    PMID:36980270 PMID:37257570 PMID:37653079

    Open questions at the time
    • NF-κB regulatory function demonstrated only in teleost; mammalian validation lacking
    • Whether IL-4–Psmd13 axis acts through altered proteasome activity or a moonlighting function is unresolved
    • Synthetic lethality with BAP1 has not been confirmed in mammalian systems
  5. 2026 Medium

    Discovery that PSMD13 physically associates with Dicer and co-occupies the miR-29a locus in neural precursor cells revealed a potential non-proteasomal role in miRNA biogenesis during neuronal differentiation.

    Evidence Co-immunoprecipitation, ChIP-seq, RNAi knockdown, and MG132 treatment in mouse neural precursor cells

    PMID:41734180

    Open questions at the time
    • Dicer interaction not reconstituted with purified proteins; indirect bridging cannot be excluded
    • Whether the effect on miR-29a is proteasome-dependent or reflects a direct regulatory function is not delineated
    • Findings from a single study in one cell type

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether the non-proteasomal roles of PSMD13 (NF-κB suppression, miRNA biogenesis, HSC differentiation) reflect moonlighting functions independent of proteolytic activity or altered proteasome substrate selectivity, and no mammalian structural data or disease-causative mutations have been reported.
  • No separation-of-function mutants distinguishing proteasomal versus non-proteasomal roles
  • No mammalian crystal or cryo-EM structure of PSMD13 in the context of the human 26S proteasome lid
  • No Mendelian disease or GWAS locus directly attributed to PSMD13 coding variants

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-168256 Immune System 1
Partners
DICERRPN10RPN5TAK1
Complex memberships
26S proteasome 19S regulatory particle lid

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Human p40.5 (PSMD13) was identified by cDNA cloning as a non-ATPase subunit of PA700 (19S regulatory complex) of the 26S proteasome, consisting of 376 amino acids (calculated MW ~42.9 kDa, pI 5.46). Its yeast ortholog Nas7p was identified; disruption of NAS7 caused temperature-sensitive growth (inability to proliferate at 37°C), indicating a role in proteasome function under stress, while NAS6 disruption had no effect on viability. Similarly, human p28 (PSMD9) was found to contain five ankyrin repeats, suggesting protein-interaction roles. cDNA cloning, sequence homology analysis, yeast gene disruption with phenotypic analysis Gene Medium 9714768
1999 Yeast Rpn9 (ortholog of human PSMD13) is required for efficient 26S proteasome assembly. Deletion of RPN9 caused temperature-sensitive growth and accumulation of multiubiquitinated proteins at restrictive temperature. Glycerol density gradient centrifugation showed reduced 26S proteasome levels and shifted to lighter fractions, with accumulation of incomplete proteasome complexes. Rpn9 was found necessary for incorporating the ubiquitin receptor Rpn10 into the 26S proteasome. Yeast two-hybrid screening, glycerol density gradient centrifugation, native PAGE, genetic deletion with phenotypic analysis Molecular and cellular biology High 10490597
2006 PSMD13 and SIRT3 share a bidirectional promoter within a 788-bp intergenic region (head-to-head configuration). Transfection experiments in HeLa cells using deletion mutants of the PSMD13-SIRT3 intergenic region demonstrated a complex pathway of co-regulation acting in both transcriptional directions. Transfection of deletion mutant reporter constructs in HeLa cells, linkage disequilibrium analysis Genomics Medium 17059877
2015 The NMR solution structure of yeast Rpn9 (PSMD13 ortholog) was determined at high resolution, revealing an all-helical N-terminal domain and a C-terminal PCI domain linked via a semiflexible hinge. The N-terminal domain mediates interaction with the ubiquitin receptor Rpn10, while the PCI domain mediates interaction with neighboring PCI subunit Rpn5. The Rpn9-Rpn5 interface involves a hydrophobic center surrounded by ionic pairs within the winged-helix module, a pattern conserved across all PCI-PCI interactions in the lid complex. High-resolution NMR structure determination with functional interaction mapping The Journal of biological chemistry High 25631053
2023 PSMD13 inhibits the NF-κB pathway in fish (miiuy croaker) by targeting TAK1. PSMD13 expression was upregulated by Vibrio harveyi stimulation. Mechanistically, PSMD13 significantly inhibited K63-linked ubiquitination of TAK1, thereby suppressing TAK1 expression and downstream NF-κB signaling. Gene expression analysis, overexpression/knockdown assays, ubiquitination assays measuring K63-linked ubiquitin chains on TAK1 Fish & shellfish immunology Medium 37257570
2023 Psmd13 expression is required for megakaryocytic-erythroid development of hematopoietic stem cells (HSCs). IL-4 stimulation in vitro downregulates Psmd13. shRNA-mediated knockdown of Psmd13 in HSCs severely compromised repopulating capacity and megakaryocytic differentiation in vivo and increased apoptosis, placing Psmd13 downstream of IL-4 signaling in the HSC stress-resistance and megakaryocytic differentiation pathway. Single-cell transcriptome analysis, shRNA knockdown in HSCs, in vivo transplantation assays, functional differentiation assays Scientific reports Medium 37653079
2023 In C. elegans, rpn-9 (ortholog of human PSMD13) shows synthetic genetic interaction with ubh-4 (BAP1 ortholog). Combined inactivation of rpn-9 and ubh-4 affected body size, lifespan, and germ cell development, identifying PSMD13 as a synthetic lethal partner of BAP1. ubh-4 inactivation also sensitized animals to the proteasome inhibitor Bortezomib. CRISPR-Cas mutagenesis, RNAi screen, genetic epistasis in C. elegans, drug sensitivity assay Cells Medium 36980270
2026 Psmd13 interacts with Dicer in mouse neural precursor cells (mNPCs), as shown by co-immunoprecipitation, and this interaction modulates miR-29a levels in a differentiation-dependent manner. ChIP-seq revealed co-occupancy of Psmd13 and Dicer at genomic loci including the miR-29a locus. RNAi-mediated Psmd13 knockdown enhanced neuronal differentiation and altered miR-29a expression. Proteasome inhibition with MG132 reduced both Psmd13 and Dicer levels, downregulated miR-29a, and impaired neuronal differentiation, suggesting Psmd13 acts as an upstream modulator of miRNA biogenesis. QTL mapping in Collaborative Cross mice, RNAi knockdown, co-immunoprecipitation, ChIP-seq, MG132 pharmacological inhibition PloS one Medium 41734180

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2003 Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 1236 12808466
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
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
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nature medicine 798 14528300
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
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2003 HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nature medicine 679 14528301
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Molecular cell 607 14527406
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2003 Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science (New York, N.Y.) 570 12750511
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2005 Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 443 16239144
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1998 cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome. Gene 80 9714768
2006 Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13. Genomics 70 17059877
1999 Rpn9 is required for efficient assembly of the yeast 26S proteasome. Molecular and cellular biology 62 10490597
2006 Down-regulation of the 26S proteasome subunit RPN9 inhibits viral systemic transport and alters plant vascular development. Plant physiology 48 16905670
2015 Solution structure of yeast Rpn9: insights into proteasome lid assembly. The Journal of biological chemistry 12 25631053
2023 Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk. Journal of gynecologic oncology 6 36731897
2023 PSMD13 inhibits NF-κB pathway by targeting TAK1 for K63-linked ubiquitination in miiuy croaker (Miichthys miiuy). Fish & shellfish immunology 6 37257570
2023 BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13. Cells 4 36980270
2023 Interlukin-4 weakens resistance to stress injury and megakaryocytic differentiation of hematopoietic stem cells by inhibiting Psmd13 expression. Scientific reports 4 37653079
2026 Psmd13, a proteasome regulatory subunit identified in miR-29a regulation during neuronal differentiation. PloS one 1 41734180
2013 ¹H, ¹³C and ¹⁵N resonance assignments of Rpn9, a regulatory subunit of 26S proteasome from Saccharomyces cerevisiae. Biomolecular NMR assignments 1 23832675