PSMD13

PSMD13 (p40.5; yeast ortholog Nas7p/Rpn9) is a non-ATPase subunit of the PA700/19S regulatory particle of the 26S proteasome (PMID:9714768). Structurally it comprises an all-helical N-terminal domain joined by a semiflexible hinge to a C-terminal PCI domain; the N-terminal domain binds the ubiquitin receptor Rpn10, while the PCI domain engages the neighboring PCI subunit Rpn5 through a hydrophobic interface flanked by ionic pairs on its winged-helix module (PMID:25631053). Through these contacts PSMD13 is required for efficient 26S proteasome assembly and specifically for incorporation of Rpn10 into the regulatory particle, with its loss producing incomplete proteasome complexes (PMID:10490597); the yeast ortholog is dispensable for viability but needed for growth under elevated-temperature stress (PMID:9714768). Beyond its core assembly role, PSMD13 supports hematopoietic stem cell repopulating capacity and megakaryocytic differentiation, functions that are downregulated by IL-4 signaling (PMID:37653079), and it genetically intersects the BAP1 deubiquitinase pathway, showing synthetic lethality with the C. elegans BAP1 ortholog ubh-4 (PMID:36980270).

1. 1998 Medium

   Established PSMD13 as a bona fide subunit of the human proteasome and gave it a first functional context, answering whether p40.5 was proteasome-associated and whether it mattered.

   Evidence cDNA cloning and sequence homology with yeast gene disruption of the ortholog Nas7p/Rpn9

   PMID:9714768

   Open questions at the time

   • No structural or interaction detail for the human subunit
   • Stress-sensitivity phenotype defined only in yeast
   • Molecular function within the particle not yet defined
2. 1999 High

   Defined a concrete molecular role for the subunit by showing it is needed for 26S proteasome assembly and for incorporating the ubiquitin receptor Rpn10, explaining why its loss impairs proteasome function.

   Evidence Glycerol gradient fractionation, native PAGE, two-hybrid with Rpn10, and Δrpn9 deletion in yeast

   PMID:10490597

   Open questions at the time

   • Did not resolve the structural basis of Rpn10 recruitment
   • Mammalian assembly role inferred from yeast only
3. 2015 High

   Provided the atomic basis for the subunit's two interaction surfaces, mapping the N-terminal domain to Rpn10 and the PCI domain to the neighboring Rpn5 subunit.

   Evidence NMR solution structure of yeast Rpn9 with NMR-based interaction mapping

   PMID:25631053

   Open questions at the time

   • Structure determined for yeast ortholog, not the human protein
   • Interfaces not validated by mutation in the assembled proteasome
   • Does not address regulation of these contacts in vivo
4. 2023 Medium

   Connected the subunit to organismal phenotypes and a deubiquitinase pathway, showing synthetic lethality with the BAP1 ortholog ubh-4.

   Evidence CRISPR mutagenesis, RNAi screen, and genetic epistasis in C. elegans

   PMID:36980270

   Open questions at the time

   • Molecular basis of the genetic interaction with BAP1 unknown
   • Whether the interaction reflects proteasome function specifically is unresolved
5. 2023 Medium

   Linked PSMD13 to a specific physiological output by showing it is required for HSC repopulation and megakaryocytic differentiation and is suppressed by IL-4.

   Evidence shRNA knockdown in mouse HSCs, in vivo transplantation, single-cell transcriptomics, IL-4 stimulation

   PMID:37653079

   Open questions at the time

   • Mechanism linking IL-4 to Psmd13 transcription not defined
   • Whether phenotypes stem from proteasome assembly defects is untested
6. 2023 Low

   Proposed a non-proteasomal regulatory role in which PSMD13 dampens NF-κB signaling by reducing K63-linked ubiquitination of TAK1.

   Evidence Overexpression/knockdown, ubiquitination assays, and NF-κB reporter assays in miiuy croaker

   PMID:37257570

   Open questions at the time

   • Single set of overexpression assays without mutagenesis or reconstitution
   • Direct action on TAK1 ubiquitination not demonstrated mechanistically
   • Non-mammalian model, not independently confirmed
7. 2026 Low

   Associated PSMD13 with Dicer and miR-29a regulation during neuronal differentiation, hinting at a role coupling proteasome subunit levels to microRNA output.

   Evidence Co-IP, ChIP-seq co-occupancy, RNAi knockdown, and MG132 proteasome inhibition in mouse neural precursors

   PMID:41734180

   Open questions at the time

   • Co-IP shows association but not direct binding
   • ChIP-seq co-occupancy is correlative and RNAi phenotype not rescued
   • Mechanistic link between Psmd13-Dicer and miR-29a remains indirect

• It remains unresolved whether the reported non-proteasomal activities of PSMD13 (NF-κB/TAK1 modulation, Dicer/miR-29a regulation, HSC and BAP1-pathway phenotypes) are separable from its core role in 19S lid assembly or are downstream consequences of altered proteasome function.
• No experiment separates assembly-dependent from assembly-independent roles
• Human protein structure and interfaces not directly determined
• No reconstitution of proposed moonlighting activities