Affinage

Showing PSMD11 — RPN6 is a alias.

PSMD11

26S proteasome non-ATPase regulatory subunit 11 · UniProt O00231

Length
422 aa
Mass
47.5 kDa
Annotated
2026-06-10
25 papers in source corpus 20 papers cited in narrative 20 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

PSMD11 (Rpn6/RPN-6) is a non-ATPase lid subunit of the 19S regulatory particle that is structurally essential for assembly of the 26S/30S proteasome and serves as a rate-limiting determinant of cellular proteasome capacity (PMID:15611133, PMID:22972301). In yeast, Rpn6 is required for lid integrity, scaffolding incorporation of Rpn3, Rpn7, Rpn12, and Sem1 into the lid sub-complex (PMID:15611133). Because its abundance limits proteasome assembly, PSMD11 functions as a node through which proteostasis is tuned: its transcription is driven by FOXO factors (DAF-16/FOXO4), and elevating PSMD11 alone is sufficient to increase 26S/30S assembly and activity, enhance clearance of damaged proteins, and extend lifespan (PMID:22922647, PMID:22972301). Acutely, proteasome activity is switched on by PKA phosphorylation of PSMD11 at Ser14, an event that is both necessary and sufficient to activate 26S proteasomes and promote degradation of ubiquitinated and aggregation-prone proteins (PMID:26669444). This Ser14 phosphorylation is engaged by cAMP-raising hormones and physiological states such as exercise and fasting, selectively accelerating turnover of short-lived misfolded and regulatory proteins across hepatocytes, muscle, heart, and kidney without affecting bulk proteolysis (PMID:30782827). Knock-in mouse studies establish the in vivo requirement: phospho-deficient S14A abolishes PKA-dependent activation while phosphomimetic S14D constitutively elevates activity and protects against cardiac proteotoxicity, and loss of pS14-Rpn6 worsens tau pathology and neurodegeneration (PMID:37641975, PMID:40196506). PSMD11 is essential for mammalian development—whole-body knockout is embryonic lethal—and its loss-of-function in humans causes a neurodevelopmental proteasomopathy in which impaired proteasome assembly triggers a PKR-driven type I interferon signature (PMID:33517884, PMID:38866022). Beyond the proteasome, PSMD11 is a component of the NRON ribonucleoprotein complex, where it controls stability and nuclear translocation of circadian clock proteins (PER2, CRY2, CRY1) (PMID:36961772).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 High

    Established the structural role of Rpn6 within the proteasome: it is required for lid integrity and 26S assembly rather than being a passive subunit.

    Evidence Temperature-sensitive rpn6 mutants and affinity purification of proteasome complexes in S. cerevisiae

    PMID:15611133

    Open questions at the time
    • Did not define how Rpn6 contacts the other lid subunits structurally
    • Did not address regulation of assembly in higher eukaryotes
  2. 2012 High

    Showed that PSMD11/Rpn6 abundance is a rate-limiting, FOXO-controlled determinant of proteasome capacity linked to organismal proteostasis and longevity.

    Evidence Ectopic expression and DAF-16/FOXO4 epistasis in C. elegans and human embryonic stem cells with proteasome activity and native gel assays

    PMID:22922647 PMID:22972301

    Open questions at the time
    • Did not identify acute post-translational control of activity
    • Mechanism by which a single subunit limits whole-complex assembly not fully resolved
  3. 2002 Medium

    Identified an early non-proteasomal physical partner and confirmed essentiality in development via the PCI domain interaction with COP9 signalosome subunit Alien/CSN2.

    Evidence Yeast two-hybrid and P-element/loss-of-function genetics in Drosophila

    PMID:12426099

    Open questions at the time
    • Interaction not confirmed by Co-IP
    • Functional consequence of the CSN2 interaction not established
  4. 2015 High

    Defined the acute switch for proteasome activation: PKA phosphorylation at Ser14 is necessary and sufficient to activate the 26S proteasome.

    Evidence In vitro PKA phosphorylation, S14D/S14A mutagenesis, purified proteasome activity assays and phosphatase reversal

    PMID:26669444

    Open questions at the time
    • Did not establish physiological triggers in vivo
    • Structural basis of how Ser14 phosphorylation enhances activity not resolved
  5. 2019 High

    Connected the Ser14 phosphoswitch to physiology, showing hormones and metabolic states drive selective degradation of short-lived proteins via PKA-PSMD11.

    Evidence Phosphorylation and activity assays across mouse tissues and human muscle, PKA-knockout cells, cAMP manipulation

    PMID:30782827

    Open questions at the time
    • Substrate selectivity mechanism not defined
    • Did not test long-term consequences in disease models
  6. 2023 Medium

    Provided in vivo genetic proof that pS14-Rpn6 is required for inducible proteasome activity and protects against cardiac and neurodegenerative proteotoxicity.

    Evidence S14A/S14D knock-in mice, GFPdgn UPS reporter, cardiac R120G-CryAB model and PS19 tauopathy crosses with histopathology and behavior

    PMID:37641975 PMID:40196506

    Open questions at the time
    • Tauopathy findings from a single-lab preprint
    • Tissue-specific contributions of the phosphoswitch not fully dissected
  7. 2021 Medium

    Demonstrated absolute requirement of PSMD11 for early mammalian development and cell survival.

    Evidence Conditional knockout mice, embryo genotyping, MEF apoptosis assays

    PMID:33517884

    Open questions at the time
    • Did not separate proteasomal from non-proteasomal contributions to lethality
    • Cell-type-specific roles not addressed
  8. 2024 Medium

    Linked human PSMD11 loss-of-function to a neurodevelopmental proteasomopathy driven by ISR/PKR-mediated type I interferon signaling.

    Evidence Human patient cells and Drosophila Rpn6 depletion with proteasome assembly assays, interferon signature and PKR pathway analysis

    PMID:38866022

    Open questions at the time
    • Causal chain from assembly defect to PKR activation not fully reconstituted
    • Single publication
  9. 2023 Medium

    Revealed a proteasome-independent role: PSMD11 within the NRON complex controls circadian clock protein stability and nuclear translocation.

    Evidence Size-exclusion fractionation, siRNA knockdown, nuclear/cytosolic Western blots and circadian reporter assays

    PMID:36961772

    Open questions at the time
    • Direct binding partners within NRON not mapped
    • Mechanism of translocation control unresolved
    • Single lab
  10. 2022 Medium

    Established PSMD11 as a druggable target whose ligand binding can modulate 26S assembly and downstream signaling such as Nrf2.

    Evidence Affinity-based target identification (DDO-7263), TXS-8 peptoid thermal shift binding and selectivity, Nrf2 reporter and cytotoxicity assays

    PMID:31877015 PMID:35253427

    Open questions at the time
    • Binding site on PSMD11 not structurally defined
    • Therapeutic window and in vivo efficacy not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether PSMD11's reported cancer-associated interactions (CDK4, PD-L1/USP14, PGM3, AMPK, USP4) reflect direct substrate-stabilizing functions distinct from its core proteasome role remains unresolved.
  • Most interactions rest on single Co-IP without reconstitution or reciprocal validation
  • No structural basis for proposed direct binding
  • Functional separation from proteasome assembly role not demonstrated

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 3 R-HSA-9909396 Circadian clock 1
Partners
AMPKCDK4CSN2PD-L1PGM3USP14USP4
Complex memberships
26S proteasome (19S regulatory particle lid)NRON ribonucleoprotein complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 RPN-6 (C. elegans ortholog of PSMD11) is a 19S proteasome subunit whose increased expression, driven by the FOXO transcription factor DAF-16, is sufficient to elevate somatic proteasome activity, promote clearance of damaged proteins, confer proteotoxic stress resistance, and extend lifespan in germline-deficient animals. Genetic gain-of-function (ectopic expression), epistasis with DAF-16, in vivo proteasome activity assays Nature High 22922647
2012 In human embryonic stem cells, PSMD11 protein levels are elevated relative to differentiated cells, correlating with increased 26S/30S proteasome assembly and activity; ectopic expression of PSMD11 alone is sufficient to increase proteasome assembly and activity. FOXO4 transcriptionally regulates PSMD11 expression to control proteasome activity. Ectopic overexpression, proteasome activity assays, native gel analysis of proteasome complexes, FOXO4 knockdown Nature High 22972301
2004 In S. cerevisiae, Rpn6p is essential for lid integrity and 26S proteasome assembly; temperature-sensitive rpn6 mutants are defective in assembling the 26S proteasome at restrictive temperature and fail to incorporate Rpn3p, Rpn7p, Rpn12p, and Sem1p into the lid, resulting in an incomplete lid sub-complex of only Rpn5p, Rpn8p, Rpn9p, and Rpn11p. Temperature-sensitive mutant analysis, affinity purification of proteasome complexes, in vitro degradation assays with polyubiquitinated substrate The Journal of biological chemistry High 15611133
2015 PKA phosphorylates the 19S subunit Rpn6/PSMD11 at Ser14; this phosphorylation is necessary and sufficient to activate 26S proteasomes, increase degradation of ubiquitinated proteins and peptides, and promote clearance of aggregation-prone proteins. A phosphomimetic S14D mutant activates proteasomes, whereas a non-phosphorylatable S14A mutant decreases activity. cAMP elevation also increases doubly-capped 30S proteasome abundance. PKA phosphorylation assays, site-directed mutagenesis (S14D/S14A), purified 26S proteasome activity assays in vitro and in cells, phosphatase reversal Proceedings of the National Academy of Sciences of the United States of America High 26669444
2019 Physiological hormones (glucagon, epinephrine, vasopressin) and physiological states (exercise, fasting) activate 26S proteasomes through PKA-mediated phosphorylation of Rpn6/PSMD11 at Ser14, selectively promoting degradation of short-lived misfolded and regulatory proteins in hepatocytes, skeletal muscle, heart, and kidney without affecting bulk or lysosomal proteolysis. This activation is PKA-dependent, as cells lacking PKA do not respond. Rpn6 phosphorylation assays in mouse tissues and human muscle samples, proteasome activity assays, PKA-knockout cells, pharmacological manipulation of cAMP Proceedings of the National Academy of Sciences of the United States of America High 30782827
2023 In vivo knock-in mouse studies establish that Ser14 phosphorylation of Rpn6/PSMD11 (pS14-Rpn6) is required for PKA-mediated activation of 26S proteasomes; S14A mice show no PKA-dependent proteasome activation, while S14D mice show constitutively elevated proteasome activity and reduced accumulation of ubiquitin conjugates and protein aggregates in a cardiac proteotoxicity model (R120G-CryAB), delaying cardiac malfunction. Knock-in mouse models (S14A, S14D), GFPdgn reporter mouse for UPS flux, proteasome activity assays, ubiquitin conjugate measurements, echocardiography Circulation research High 37641975
2023 Genetic blockade of pS14-Rpn6 (S14A knock-in) in tauopathy (PS19) mice exacerbates cognitive and motor decline, synaptic loss, microglial activation, cardiac hypertrophy, and accumulation of total and hyperphosphorylated tau and ubiquitin conjugates in both brain and heart, demonstrating that homeostatic pS14-Rpn6 is required for proteostasis in neurodegeneration. Knock-in mouse crossed with PS19 tauopathy model, behavioral testing, histopathology, Western blot for tau and ubiquitin conjugates, echocardiography bioRxivpreprint Medium 40196506
2002 Drosophila Rpn6 physically interacts with the COP9 signalosome subunit Alien/CSN2 via its PCI domain, as identified by yeast two-hybrid; Rpn6 is essential for Drosophila development, demonstrated by lethality of P-element insertion and induced loss-of-function alleles. Yeast two-hybrid screen, P-element insertion and genetic allele analysis, developmental phenotyping Gene Medium 12426099
2009 PSMD11 physically interacts with AMPK (AMP-activated protein kinase) and AMPK modifies the phosphorylation status of PSMD11, suggesting AMPK can regulate proteasome function through PSMD11. Yeast two-hybrid screening of human skeletal muscle cDNA library, follow-up co-immunoprecipitation, phosphorylation assays The international journal of biochemistry & cell biology Low 19616115
2012 The deubiquitylating enzyme USP4 interacts with the S9/Rpn6 (PSMD11) subunit of the proteasome via an internal ubiquitin-like (UBL) domain of USP4, potentially regulating proteasome structure/function or turnover of specific substrates. Co-immunoprecipitation, domain mapping Biochemical and biophysical research communications Low 23022198
2018 PSMD11 protein synthesis is rapidly induced by homoharringtonine (a translation inhibitor) through activation of the MEK1/ERK1/2 signaling pathway in pancreatic cancer cells, and this induction contributes to resistance to acute apoptosis. Western blot, MEK1/ERK1/2 pharmacological inhibition (sorafenib), cell viability assays, in vivo mouse model Journal of cellular biochemistry Low 29665121
2020 PSMD11 physically interacts with AMPKα1/2 in auditory cortex and PC12 cells; AMPKα2 (but not AMPKα1) selectively regulates PSMD11 function in a D-galactose aging model. PSMD11 knockdown or overexpression alters oxidative state and proteasome activity in these models. Co-immunoprecipitation, Western blot, immunofluorescence, flow cytometry for ROS Experimental cell research Low 32450067
2022 DDO-7263 (a 1,2,4-oxadiazole Nrf2 activator) binds directly to Rpn6/PSMD11, blocking assembly of the 26S proteasome and thereby preventing ubiquitinated Nrf2 degradation, leading to Nrf2 pathway activation. Affinity chromatography with biotin-labeled probe, mass spectrometry target identification, in vitro affinity experiments, Nrf2 pathway reporter assays Journal of medicinal chemistry Medium 35253427
2020 A small molecule peptoid (TXS-8) binds Rpn6/PSMD11 with low micromolar affinity and limited off-target binding, demonstrating that Rpn6 is a druggable target; cytotoxicity was selectively increased in hematological cancer cell lines. One-bead-one-compound library screen, thermal shift assay, binding selectivity profiling, cell viability assays ACS chemical biology Medium 31877015
2024 PSMD11 loss-of-function in humans and in Drosophila (Rpn6 depletion) results in impaired 26S proteasome assembly and acquisition of a type I interferon gene signature mediated by the integrated stress response kinase PKR, establishing that PSMD11 deficiency causes neurodevelopmental proteasomopathy through ISR/PKR-driven interferon signaling. Human patient sample analysis, Drosophila genetic depletion of Rpn6 with behavioral testing, proteasome assembly assays, interferon signature profiling, PKR pathway analysis American journal of human genetics Medium 38866022
2023 PSMD11 is a component of the NRON ribonucleoprotein complex and, distinct from its proteasome role, regulates the stability and nuclear translocation of circadian clock proteins: PSMD11 knockdown reduces PER2 and CRY2 protein abundance and blocks nuclear translocation of CRY1, thereby disrupting circadian oscillations. Size exclusion chromatography to fractionate NRON complex, PSMD11 siRNA knockdown, Western blot for clock proteins in cytosolic/nuclear fractions, circadian reporter assays PloS one Medium 36961772
2021 Homozygous whole-body PSMD11 deletion causes early embryonic lethality in mice (no viable knockouts at E7.5-8.5), while single-allele deletion causes growth retardation, demonstrating PSMD11 is essential for early mammalian development. PSMD11 depletion in MEFs induces massive apoptosis. Conditional knockout mouse generation (floxed allele + Cre), embryo genotyping, MEF derivation and apoptosis assays BMC developmental biology Medium 33517884
2024 PSMD11 physically interacts with CDK4 and reduces its ubiquitination, stabilizing CDK4 protein and promoting hepatocellular carcinoma cell proliferation; PSMD11 knockdown destabilizes CDK4 and arrests cells in G0/G1. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, PSMD11 knockdown with flow cytometry cell cycle analysis Cellular signalling Low 38944255
2025 PSMD11 recruits USP14 (a deubiquitylating enzyme) to PD-L1, stabilizing PD-L1 protein levels and promoting immune escape in NSCLC; PSMD11 knockdown reduces PD-L1 and enhances T cell-mediated killing. Co-IP and mass spectrometry confirmed PSMD11–PD-L1 and PSMD11–USP14 interactions. Co-immunoprecipitation, mass spectrometry, USP14 overexpression/PSMD11 knockdown, T cell co-culture cytotoxicity assay, xenograft mouse model Journal of thoracic disease Low 41158392
2026 PSMD11 physically interacts with PGM3 and competitively antagonizes Parkin-mediated ubiquitination of PGM3, thereby preventing its proteasomal degradation and stabilizing PGM3 to enhance glycolysis and oxidative phosphorylation in bladder cancer cells. Co-immunoprecipitation, ubiquitination assay, PSMD11 and Parkin overexpression/knockdown, metabolic flux assays Cell death & disease Low 41942430

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 345 22922647
2012 Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 333 22972301
2015 cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins. Proceedings of the National Academy of Sciences of the United States of America 202 26669444
2019 26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 98 30782827
2004 Functional analysis of Rpn6p, a lid component of the 26 S proteasome, using temperature-sensitive rpn6 mutants of the yeast Saccharomyces cerevisiae. The Journal of biological chemistry 61 15611133
2022 Circular RNA circ-MTHFD1L induces HR repair to promote gemcitabine resistance via the miR-615-3p/RPN6 axis in pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 41 35459186
2002 The proteasome regulatory particle subunit Rpn6 is required for Drosophila development and interacts physically with signalosome subunit Alien/CSN2. Gene 30 12426099
2020 Long-noncoding RNA Peg13 alleviates epilepsy progression in mice via the miR-490-3p/Psmd11 axis to inactivate the Wnt/β-catenin pathway. American journal of translational research 28 33437373
2020 PSMD11, PTPRM and PTPRB as novel biomarkers of pancreatic cancer progression. Biochimica et biophysica acta. General subjects 24 32663515
2018 Homoharringtonine could induce quick protein synthesis of PSMD11 through activating MEK1/ERK1/2 signaling pathway in pancreatic cancer cells. Journal of cellular biochemistry 24 29665121
2009 Two-hybrid analysis identifies PSMD11, a non-ATPase subunit of the proteasome, as a novel interaction partner of AMP-activated protein kinase. The international journal of biochemistry & cell biology 23 19616115
2019 MicroRNA-451 inhibits inflammation and proliferation of glomerular mesangial cells through down-regulating PSMD11 and NF-κB p65. Bioscience reports 19 31652441
2022 Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome. Journal of medicinal chemistry 13 35253427
2023 S14-Phosphorylated RPN6 Mediates Proteasome Activation by PKA and Alleviates Proteinopathy. Circulation research 12 37641975
2020 Discovery of a Small Molecule Probe of Rpn-6, an Essential Subunit of the 26S Proteasome. ACS chemical biology 12 31877015
2024 PSMD11 promotes the proliferation of hepatocellular carcinoma by regulating the ubiquitination degradation of CDK4. Cellular signalling 9 38944255
2020 The effect and mechanism of 19S proteasome PSMD11/Rpn6 subunit in D-Galactose induced mimetic aging models. Experimental cell research 9 32450067
2012 The ubiquitin specific protease-4 (USP4) interacts with the S9/Rpn6 subunit of the proteasome. Biochemical and biophysical research communications 9 23022198
2024 PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response. American journal of human genetics 7 38866022
2023 PSMD11 modulates circadian clock function through PER and CRY nuclear translocation. PloS one 4 36961772
2021 Generation and identification of a conditional knockout allele for the PSMD11 gene in mice. BMC developmental biology 4 33517884
2023 Ser14-RPN6 Phosphorylation Mediates the Activation of 26S Proteasomes by cAMP and Protects against Cardiac Proteotoxic Stress in Mice. bioRxiv : the preprint server for biology 1 37066344
2026 PSMD11 stabilizes PGM3 by antagonizing Parkin to promote bladder cancer progression through energy metabolism reprogramming. Cell death & disease 0 41942430
2025 Ser14-phosphorylated Rpn6 Limits Proteostasis Impairment and Pathology in Both Brain and Heart of Tauopathy Mice. bioRxiv : the preprint server for biology 0 40196506
2025 PSMD11 facilitates immune escape by recruiting USP14 to modulate the deubiquitinating degradation of PD-L1 in non-small cell lung cancer. Journal of thoracic disease 0 41158392

Missed literature

Know a paper Affinage missed for PSMD11? Flag it for the maintainers and the community.

No submissions yet.