Affinage

PSMD14

Ubiquitin C-terminal hydrolase PSMD14 · UniProt O00487

Length
310 aa
Mass
34.6 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PSMD14 (POH1/Rpn11) is a JAMM-motif zinc metalloprotease deubiquitinase that serves as the primary deubiquitinating enzyme of the 26S proteasome and additionally functions as a proteasome-independent deubiquitinase of specific substrates on chromatin and in the cytosol. Within the 19S regulatory particle, PSMD14 forms an obligate heterodimer with PSMD7 (Rpn8) and catalyzes en-bloc removal of polyubiquitin chains from committed substrates at the proteasomal entry pore, a reaction mechanochemically coupled to AAA+ ATPase-driven substrate translocation that activates an Insert-1 conformational switch from an autoinhibited state (PMID:12183636, PMID:24463465, PMID:28844860). Outside the proteasome, PSMD14 acts as a K63-linkage-preferring deubiquitinase in the DNA double-strand break response—opposing RNF8/RNF168-dependent ubiquitin signaling to promote the NHEJ-to-HR switch (PMID:22909820, PMID:24013561)—and functions as a histone H2AK119 deubiquitinase that cooperates with NSD2 to promote H3K36me2 and transcriptional activation at myelomagenesis-associated loci (PMID:37935198). PSMD14 also deubiquitinates and stabilizes numerous oncoproteins and signaling receptors including E2F1, SNAIL, ERα, GRB2, TGF-β receptors, ALK2, METTL3, and PKM2, linking its activity to EMT, metabolic reprogramming, and liver steatosis (PMID:26510456, PMID:29331416, PMID:38017133, PMID:39146936).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Establishing PSMD14 as an essential proteasomal subunit answered the question of whether this conserved MPN-domain protein was part of the 26S proteasome and required for viability, with human POH1 complementing yeast loss-of-function.

    Evidence Temperature-sensitive yeast mutants, cross-species complementation, cell cycle and mitochondrial phenotyping in S. cerevisiae and S. pombe

    PMID:9727008 PMID:9763452

    Open questions at the time
    • Enzymatic activity unknown at this point
    • Mechanism of essentiality (catalytic vs. structural) unresolved
  2. 2002 High

    Identification of Rpn11 as a JAMM-motif metalloprotease deubiquitinase resolved the long-standing question of how ubiquitin chains are removed during proteasomal degradation, showing that catalytic histidines are essential and that deubiquitination is coupled to substrate degradation.

    Evidence Active-site mutagenesis (rpn11AXA), in vitro deubiquitination/degradation assays with purified yeast proteasomes

    PMID:12183636 PMID:12370088

    Open questions at the time
    • Structural basis of catalysis unknown
    • Linkage specificity uncharacterized
    • Mechanism of coupling to degradation unclear
  3. 2003 High

    Demonstrating functional complementarity between Rpn11 and Ubp6 at the proteasome clarified that two distinct DUBs cooperate in proteasomal ubiquitin processing, and that the lid (containing Rpn11) is specifically required for degradation rather than just deubiquitination.

    Evidence Purification of mutant proteasomes, metal chelator sensitivity, synthetic lethality of rpn11/ubp6 double mutant

    PMID:14581483

    Open questions at the time
    • Whether Rpn11 acts en-bloc or processively unknown
    • Regulation of Rpn11 activity within the holoenzyme not addressed
  4. 2004 High

    Separation of Rpn11's catalytic (N-terminal MPN+) and C-terminal domains revealed a proteasome-independent function in mitochondrial morphology, establishing that PSMD14 has non-proteasomal roles.

    Evidence Domain-swap chimeras with Rpn8, intragene complementation, mitochondrial morphology microscopy in yeast

    PMID:15018611

    Open questions at the time
    • Molecular mechanism of mitochondrial function unknown
    • Relevance to mammalian cells not tested
  5. 2007 High

    Validation of the JAMM motif requirement in human cells confirmed that the catalytic metalloprotease activity characterized in yeast is conserved and essential in human PSMD14.

    Evidence RNAi complementation in HeLa cells with wild-type vs. JAMM-mutant Poh1

    PMID:17237285

    Open questions at the time
    • Human structural data lacking
    • Substrate specificity in human context undefined
  6. 2009 High

    Discovery of K63-linkage specificity for POH1 within the 19S particle revealed that proteasomal DUB activity is not limited to K48-linked chains and pointed to non-degradative ubiquitin signaling roles.

    Evidence Chromatographic fractionation from HeLa extracts, cleavage assays with all homotypic chain types, NEM/UbAl insensitivity

    PMID:19214193

    Open questions at the time
    • Whether K63 specificity applies to proteasome-incorporated Rpn11 or free enzyme
    • Conflict with later studies showing broader specificity when in proteasome context
  7. 2012 High

    Identification of POH1 as a K63-specific DUB at DNA double-strand break sites established a major proteasome-independent chromatin function: antagonizing RNF8/RNF168-dependent ubiquitin signaling to regulate the NHEJ-to-HR repair pathway choice.

    Evidence siRNA knockdown, K63-polyubiquitin and 53BP1 IRIF quantification, RAD51 foci assays, epistasis with RNF8/RNF168

    PMID:22909820 PMID:24013561

    Open questions at the time
    • How POH1 is recruited to DSB sites unknown
    • Whether this function requires the 19S particle or POH1 acts alone at DSBs
  8. 2014 High

    Crystal structures of the Rpn11–Rpn8 heterodimer and biochemical kinetics resolved how Rpn11 is kept autoinhibited (Insert-1 loop occludes active site) and activated ~100-fold upon proteasome incorporation, establishing the structural basis for gated deubiquitination.

    Evidence X-ray crystallography at 2.0 Å (Zn-free and Zn-bound), nanobody-assisted structures, kinetic analysis with defined ubiquitin chain substrates

    PMID:24463465 PMID:24516147 PMID:25389291

    Open questions at the time
    • No structure of Rpn11 in substrate-engaged proteasome at this point
    • Role of ATPase motor in activation inferred but not directly shown
  9. 2015 High

    Demonstration that POH1 deubiquitinates and stabilizes the transcription factor E2F1 in a conditional knockout mouse established PSMD14 as a substrate-specific DUB that regulates oncoprotein stability beyond its generic proteasomal role.

    Evidence Reciprocal Co-IP, in vivo ubiquitination assay, conditional Poh1 KO mouse hepatocytes, xenograft tumor model

    PMID:26510456

    Open questions at the time
    • Whether E2F1 deubiquitination occurs within or outside the proteasome
    • Linkage specificity on E2F1 not determined
  10. 2017 High

    The ubiquitin-bound crystal structure of Rpn11 and motor-mutant kinetics revealed that AAA+ ATPase-driven substrate translocation allosterically activates the Insert-1 β-hairpin switch, mechanochemically coupling deubiquitination to substrate commitment.

    Evidence Ubiquitin-bound Rpn11 crystal structure from S. cerevisiae, deubiquitination kinetics with ATPase motor mutants

    PMID:28844860

    Open questions at the time
    • Time-resolved conformational dynamics not captured
    • Whether the same mechanism operates on all ubiquitin linkage types
  11. 2017 High

    Development of Capzimin and thiolutin-class zinc-chelating inhibitors provided pharmacological tools confirming that Rpn11 active-site zinc is druggable and that its inhibition selectively blocks proteasomal degradation and kills bortezomib-resistant cancer cells.

    Evidence In vitro Rpn11 inhibition, JAMM family selectivity profiling, proteasome substrate stabilization, UPR induction

    PMID:28244987 PMID:28459440

    Open questions at the time
    • In vivo pharmacokinetics and therapeutic window not established
    • Off-target effects on other JAMM metalloproteases
  12. 2018 High

    Multiple studies expanded the substrate repertoire to include SNAIL (EMT), pro-IL-1β (inflammation via K63-deubiquitination in myeloid cells), and demonstrated POH1-dependent apoptosis regulation through p53/Bim stabilization, broadening PSMD14's roles to inflammation and cell death pathways.

    Evidence MS interaction screens, Co-IP, linkage-specific ubiquitination assays, myeloid-specific conditional KO mice, in vivo metastasis and inflammation models

    PMID:29331416 PMID:29573636 PMID:30315153

    Open questions at the time
    • Direct vs. indirect deubiquitination not always distinguished
    • Proteasome-dependent vs. -independent action unclear for several substrates
  13. 2019 High

    Identification of TGF-β receptors, CAV1, and ALK2 as PSMD14 substrates demonstrated that PSMD14 regulates receptor tyrosine kinase/BMP signaling by preventing lysosomal or proteasomal receptor degradation, acting on both K48 and K63 linkages depending on substrate.

    Evidence Co-IP, linkage-specific ubiquitination assays, conditional Poh1 KO hepatocytes, DUB siRNA library screen

    PMID:30745168 PMID:31685442

    Open questions at the time
    • How substrate selectivity outside the proteasome is achieved remains unknown
    • Structural basis of non-proteasomal PSMD14-substrate recognition absent
  14. 2023 High

    Discovery that PSMD14 functions as a chromatin-associated histone H2AK119 deubiquitinase cooperating with NSD2 to promote H3K36me2 and gene activation established a proteasome-independent epigenetic function with a RELA-driven positive feedback loop in myelomagenesis.

    Evidence ChIP-seq, chromatin-fraction Co-IP, histone ubiquitination and methylation assays, integrative genomic analysis

    PMID:37935198

    Open questions at the time
    • Whether PSMD14 acts alone or as part of an alternative complex on chromatin
    • How PSMD14 is recruited to specific genomic loci
  15. 2023 High

    Identification of ERα as a PSMD14 substrate with a reciprocal transcriptional feedback loop provided a mechanism for tamoxifen resistance and showed that PSMD14 inhibition can resensitize resistant breast cancer cells.

    Evidence DUB siRNA library screen, K48-specific ubiquitination assay, ChIP for ERα at PSMD14 promoter, tamoxifen-resistant model

    PMID:38017133

    Open questions at the time
    • Clinical validation of PSMD14 inhibition in endocrine-resistant breast cancer absent
    • Whether ERα deubiquitination is proteasome-dependent or -independent
  16. 2024 High

    A hepatocyte-specific RPN11 knockout revealed that PSMD14-mediated stabilization of METTL3 drives m6A modification, histone propionylation, and lipid metabolism gene activation, connecting PSMD14 to NAFLD/NASH pathogenesis.

    Evidence Conditional KO mouse, Co-IP, m6A sequencing, metabolomics, histone propionylation assays, Capzimin treatment

    PMID:39146936

    Open questions at the time
    • Whether METTL3 deubiquitination is direct or through proteasomal activity
    • Translational potential of Capzimin in metabolic liver disease untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A central unresolved question is how PSMD14 achieves substrate selectivity outside the proteasome—what determines whether it acts on a given substrate in a proteasome-dependent versus proteasome-independent manner, and whether alternative complexes or adaptors direct its non-proteasomal activities.
  • No structural data for PSMD14 in complex with non-proteasomal substrates or chromatin partners
  • Systematic identification of proteasome-independent vs. proteasome-dependent substrates lacking
  • Whether NSD2 interaction defines a stable non-proteasomal complex or transient association is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 5 GO:0042393 histone binding 1
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1430728 Metabolism 1 R-HSA-4839726 Chromatin organization 1
Partners
E2F1ESR1METTL3NSD2PSMD7SNAI1TGFBR1TGFBR2
Complex memberships
26S proteasome 19S regulatory particle (lid subcomplex)Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Rpn11 (PSMD14) is a metalloprotease deubiquitinase within the 26S proteasome lid subcomplex, whose JAMM motif (EX(n)HXHX(10)D) is essential for deubiquitination and substrate degradation. Mutation of the active-site histidines to alanine (rpn11AXA) was lethal, stabilized ubiquitin pathway substrates, and rpn11AXA mutant proteasomes assembled normally but failed to deubiquitinate or degrade ubiquitinated Sic1 in vitro, revealing coupling between substrate deubiquitination and degradation. Active-site mutagenesis, in vitro deubiquitination/degradation assay with purified proteasomes, yeast genetics Science High 12183636
2002 The MPN+ motif within the N-terminal domain of Rpn11 constitutes the putative catalytic site; single amino acid substitutions in MPN+ residues cause slow growth, temperature sensitivity, and defects in proteasome-dependent proteolysis, while a conserved Cys outside the MPN+ motif is not essential. Site-directed mutagenesis, growth phenotype assays, proteasome-dependent proteolysis assays in yeast BMC Biochemistry High 12370088
2003 Rpn11 and Ubp6 serve complementary roles in deubiquitination at the 26S proteasome: proteasomes purified from rpn11 catalytic mutants show slower deubiquitination and are less sensitive to metal chelators (consistent with Rpn11 metalloprotease function); the rpn11/ubp6 double mutant is synthetically lethal. Lidless proteasomes can deubiquitinate but cannot degrade ubiquitinated substrates, demonstrating the lid (Rpn11) is required for degradation. Purification of proteasomes from yeast mutants, in vitro deubiquitination assays, metal chelator sensitivity, genetic double mutant analysis Journal of Biological Chemistry High 14581483
2009 Poh1 (PSMD14), as part of the PA700/19S regulatory particle, exhibits K63-specific deubiquitinating activity; it cleaves K63-linked but not K48, K6, K11, K29, or alpha-linked polyubiquitin chains, and this activity is insensitive to N-ethylmaleimide and ubiquitin aldehyde (no active-site cysteine), consistent with its metalloprotease mechanism. Multi-step chromatographic co-fractionation from HeLa extracts, linkage-specific ubiquitin chain cleavage assays, inhibitor profiling The EMBO Journal High 19214193
2007 The intact JAMM zinc metalloproteinase motif of human Poh1 (PSMD14) is essential for cell viability and 26S proteasome function; RNAi rescue with wild-type but not histidine-to-alanine JAMM mutant Poh1 demonstrated catalytic activity is required. RNAi complementation in HeLa cells with wild-type vs. JAMM mutant Poh1, cell viability and proteasome activity assays Molecular Cancer Therapeutics High 17237285
2014 Crystal structure of the Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer at 2.0 Å revealed two distinct MPN-domain interaction interfaces; structural and mutational studies showed Rpn11 lacks a conserved surface for ubiquitin Ile44-patch binding, exhibits no linkage specificity, and functions as a promiscuous deubiquitinase acting on the isopeptide bond proximal to the substrate entry pore. X-ray crystallography (Zn2+-free and Zn2+-bound structures), in vitro deubiquitination assays, site-directed mutagenesis Nature Structural & Molecular Biology High 24463465
2014 Crystal structures of the Rpn8-Rpn11 (PSMD7-PSMD14) heterodimer showed that full Rpn11 activation requires incorporation into the 26S proteasome and is dependent on ATP hydrolysis; an insertion segment acts as a physical barrier across the substrate access channel and a conformationally unstable catalytic loop prevent premature activation. Contacts of Rpn11 with ATPase subunits stabilize the active conformation. X-ray crystallography (nanobody-assisted), in vitro deubiquitination activity assays, cryo-EM docking PNAS High 24516147
2017 An AAA+ motor-driven conformational switch in Rpn11 controls deubiquitination at the 26S proteasome: ubiquitin binding switches Rpn11's Insert-1 loop from an inactive closed state to an active β-hairpin, and mechanical substrate translocation by the ATPase motor strongly accelerates this switch, ensuring ubiquitin chains are removed only from committed substrates. Ubiquitin-bound crystal structure of Rpn11 from S. cerevisiae, biochemical deubiquitination kinetics, ATPase motor mutant analysis Molecular Cell High 28844860
2017 Capzimin, a quinoline-8-thiol derivative, is a potent and selective inhibitor of Rpn11/POH1 (PSMD14) that chelates the active-site zinc, stabilizes polyubiquitinated proteasome substrates, induces unfolded protein response, and blocks cancer cell proliferation including bortezomib-resistant cells. In vitro Rpn11 inhibition assays, selectivity profiling against JAMM family, cell-based proteasome substrate stabilization, UPR induction assays Nature Chemical Biology High 28244987
2017 Thiolutin, a dithiolopyrrolone antibiotic, inhibits Rpn11 (PSMD14) by acting as a zinc chelator in its reduced form, also inhibiting related JAMM metalloproteases (Csn5, AMSH, BRCC36). In vitro JAMM metalloprotease inhibition assays, zinc chelation characterization, comparison across JAMM family members Nature Chemical Biology High 28459440
2012 POH1/PSMD14, resident in the 19S proteasome regulatory particle, is required for processing K63-linked polyubiquitin formed at DNA double-strand break sites, acting in opposition to RNF8/RNF168. POH1 antagonizes 53BP1 accumulation at DSBs and promotes JMJD2A chromatin retention, and also acts independently in homologous recombination repair to promote RAD51 loading. siRNA knockdown, K63-polyubiquitin immunofluorescence at DSB foci, 53BP1 IRIF quantification, RAD51 foci assays, epistasis with RNF8/RNF168 The EMBO Journal High 22909820
2013 POH1 (PSMD14) depletion enlarges 53BP1, RAP80, and ubiquitin chain foci after DNA damage and prevents formation of an RPA-positive resection core. Co-depletion of POH1 and RAP80/BRCC36/ABRAXAS restores the 53BP1-devoid core, placing POH1 in a pathway that removes ubiquitin chains from the IRIF core to enable resection and the switch from NHEJ to homologous recombination. siRNA double depletions, IRIF immunofluorescence, RPA foci formation assays, epistasis analysis Nucleic Acids Research High 24013561
2015 POH1 (PSMD14) deubiquitylates and stabilizes E2F1 protein: POH1 binds E2F1, reduces its ubiquitination, and conditional knockout of Poh1 in primary mouse liver cells reduces E2F1 expression. POH1-mediated E2F1 stabilization upregulates Survivin and FOXM1 and promotes liver tumor growth. Co-immunoprecipitation, in vivo ubiquitination assay, conditional Poh1 knockout mouse, xenograft tumor model Nature Communications High 26510456
2018 PSMD14 deubiquitylates and stabilizes SNAIL: mass spectrometry identified PSMD14 as a SNAIL-interacting DUB, and PSMD14 knockdown blocks SNAIL-induced EMT, suppresses migration/invasion in vitro, and reduces metastasis in vivo in esophageal squamous cell carcinoma. Mass spectrometry interaction screen, Co-IP, in vivo ubiquitination assay, siRNA knockdown, in vivo metastasis model Cancer Letters High 29331416
2019 PSMD14 stabilizes GRB2 by deubiquitinating it, inhibiting its proteasomal degradation; pharmacological inhibition with O-phenanthroline suppresses GRB2 levels and HCC malignant behavior in vitro and in vivo. Co-IP, in vivo ubiquitination assay, PSMD14 knockdown/overexpression, xenograft model Cancer Letters Medium 31634528
2006 POH1 (PSMD14) deubiquitinates c-Jun: ectopic POH1 expression in HEK293 cells decreased c-Jun ubiquitination and accumulated c-Jun protein, increasing AP1-mediated gene expression and causing nuclear redistribution of c-Jun; these effects were reduced by mutation of Cys-120 in the MPN+ motif. Ectopic expression, ubiquitination assay, AP1 reporter assay, nuclear localization by immunofluorescence, site-directed mutagenesis Journal of Biological Chemistry Medium 16569633
2009 POH1/PSMD14 knockdown by siRNA in HeLa cells identifies POH1 as a critical regulator of ErbB2 apparent protein levels; POH1 depletion causes accumulation of higher molecular weight ubiquitinated ErbB2 species without major changes in cell surface ErbB2, suggesting POH1 deubiquitinates ErbB2 independent of coupling to degradation. siRNA library screen, immunoblotting, flow cytometry for surface ErbB2, proteasome inhibitor comparison PLoS One Medium 19436748
2009 PSMD14 knockdown by siRNA induces G0/G1 cell cycle arrest and cellular senescence in carcinoma cell lines, associated with downregulation of cyclin B1-CDK1-CDC25C and cyclin D1, upregulation of p21 and p27, and reduced Rb phosphorylation; these effects differ from 20S proteasome (PSMB5) subunit knockdown, indicating distinct biological functions of 19S vs. 20S components. siRNA knockdown, flow cytometry, senescence assays, Western blotting for cell cycle regulators Experimental Cell Research Medium 19732767
2018 POH1 (PSMD14) interacts with and deubiquitinates pro-IL-1β by reducing K63-linked polyubiquitin chains, decreasing its cleavage efficiency; myeloid-specific Poh1 deletion in mice aggravates LPS-induced systemic inflammation and alum-induced peritonitis. Co-IP, K63-specific ubiquitination assay, conditional myeloid-specific KO mouse, in vivo inflammatory models Nature Communications High 30315153
2019 POH1 (PSMD14) deubiquitinates TGF-β receptors (TGFBR1 and TGFBR2) and caveolin-1 (CAV1), preventing their lysosomal degradation, thereby hyperactivating TGF-β signaling. POH1-deficient mouse hepatocytes show severely downregulated TGF-β receptors. Co-IP, ubiquitination assay, conditional Poh1 KO mouse (Mx-Cre+, poh1f/f), Western blotting of TGF-β receptors, in vitro and in vivo metastasis assays EBioMedicine High 30745168
2019 PSMD14 deubiquitinates ALK2 (type I BMP receptor) by reversing K48-linked ubiquitination mediated by Smurf1, stabilizing ALK2 and initiating BMP6 signaling; this function is independent of PSMD14's intrinsic role in the 26S proteasome. DUB siRNA library screen, immunoprecipitation, K48-specific ubiquitination assay, Smurf1 E3 ligase identification, xenograft model EBioMedicine High 31685442
2014 Rpn11 (PSMD14) processes Lys11 and Lys63 linkages with comparable efficiencies but processes Lys48 linkages with efficiency inversely correlated with chain length; Rpn11 acts by random cleavage on Lys63-linked chains. Incorporation into proteasomes enhances Rpn11 enzymatic efficiency approximately 100-fold, partly by relieving autoinhibition by its C-terminus. In vitro deubiquitination assays with defined homogeneous and heterogeneous ubiquitin chain substrates, kinetic analysis of purified Rpn11 vs. holo-proteasome Journal of Biological Chemistry High 25389291
2004 The C-terminal domain of Rpn11 (PSMD14), distinct from the N-terminal catalytic MPN+/JAMM domain, is necessary and sufficient for maintaining mitochondrial tubular morphology and respiratory function in yeast; Rpn8 overexpression rescues cell cycle but not mitochondrial phenotypes of rpn11 mutants, separating the two functions. Rpn11-Rpn8 chimera analysis, site-directed mutagenesis, intragene complementation, microscopy of mitochondrial morphology, respiratory growth assays Biochemical Journal High 15018611
2018 Epidithiodiketopiperazines (ETPs) inhibit proteasome-mediated protein degradation by targeting Rpn11 (PSMD14); an improved ETP compound (SOP11) stabilizes a subset of proteasome substrates in cells, induces the unfolded protein response, and causes cell death. In vitro proteasome degradation assay (newly developed), Rpn11 inhibition characterization, JAMM family selectivity assay, cell-based substrate stabilization and UPR assays Cell Chemical Biology High 30146242
2010 POH1 (PSMD14) interacts with and enhances the transcriptional activation by Mitf in osteoclasts in a RANKL-dependent manner; the amino terminus of POH1 mediates binding to Mitf, and mutations in the JAMM motif of POH1 reduce Mitf activation of target promoters. Co-immunoprecipitation, reporter gene assays (5XGal4-TK and Acp5 promoters), JAMM motif mutagenesis, overexpression in osteoclasts Journal of Cellular Biochemistry Medium 20058232
2018 Rpn11 (PSMD14) from an ancestral archaeal ubiquitination system shows a catalytic mechanism involving a conformational switch in the Ins-1 site upon ubiquitin binding, revealed by comparison of CsRpn11 and CsRpn11-CsUb crystal structures; activity is affected by metal ion type and small molecule inhibitors. Crystal structures of apo and ubiquitin-bound archaeal Rpn11, in vitro deubiquitinase activity assays, inhibitor and metal ion characterization Nature Communications High 30002364
2021 PSMD14 decreases K63-linked ubiquitination on PKM2, reducing the ratio of tetramers to dimers/monomers and diminishing pyruvate kinase activity, while promoting nuclear translocation of PKM2 to contribute to aerobic glycolysis in ovarian cancer cells. Co-IP, K63-specific ubiquitination assay, pyruvate kinase activity assay, subcellular fractionation, PSMD14 KD/OE experiments Molecular Oncology Medium 34382324
2022 PSMD14 directly interacts with LRPPRC and deubiquitinates it, inhibiting autophagy through the LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway in ovarian cancer. Co-IP, ubiquitination assay, autophagy flux assays, PSMD14 KD with in vivo xenograft Biochimica et Biophysica Acta - Molecular Basis of Disease Medium 36328147
2023 PSMD14 acts as a histone H2AK119 deubiquitinase independently of the 19S proteasome regulatory particle: it interacts with NSD2 on chromatin, promotes H3K36 dimethylation, and activates transcription of myelomagenesis-associated target genes (e.g., RELA); RELA reciprocally transactivates PSMD14, forming a positive feedback loop. ChIP-seq, Co-IP (chromatin fraction), histone ubiquitination assays, H3K36me2 ChIP, integrative genomic/epigenomic analysis Molecular Cell High 37935198
2023 PSMD14 deubiquitinates ERα by inhibiting K48-linked polyubiquitination, stabilizing ERα protein and facilitating ERα transcriptome activity; ERα reciprocally binds to the PSMD14 promoter and activates its transcription, forming a positive feedback loop. PSMD14 inhibition destabilizes tamoxifen-resistant ERα (Y537S) and restores drug sensitivity. DUB siRNA library screen, Co-IP, K48-specific ubiquitination assay, ChIP assay, tamoxifen-resistant model Oncogene High 38017133
2024 RPN11 (PSMD14) deubiquitinates and stabilizes METTL3 to enhance m6A modification and expression of ACSS3, which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation, promoting NAFLD/NASH; hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis. Hepatocyte-specific KO mouse, Co-IP, ubiquitination assay, m6A sequencing, metabolomics, histone propionylation assay, pharmacological inhibition with Capzimin Cell Metabolism High 39146936
2018 POH1 knockdown induces cancer cell apoptosis through increased stability of p53 and Bim, attenuating their ubiquitination; p53 or Bim siRNA markedly attenuates POH1 depletion-induced apoptosis. siRNA knockdown, ubiquitination assay for p53 and Bim, apoptosis assays, genetic epistasis with p53/Bim siRNA, in vivo intratumoral siRNA injection Neoplasia Medium 29573636
2025 PSMD14 deubiquitinates PKM2 to maintain its protein stability, activates PINK1-mediated mitophagy through improved PINK1 phosphorylation at Thr257, reduces ROS production, and inhibits neuron PANoptosis after traumatic brain injury; neuronal PSMD14 upregulation is driven by histone lactylation (H3K18la). LC-MS proteomics, Co-IP, ubiquitination assay, PINK1 phosphorylation assay, mitophagy assays, CCI mouse model, histone lactylation analysis Autophagy Medium 40000916
1998 Pad1/Rpn11 (PSMD14 ortholog) in fission yeast is a subunit of the 26S proteasome; the pad1/mts5-1 mutant phenocopies other 26S proteasome mutants and Pad1 interacts genetically with proteasome subunits Mts3 and Mts4. Genetic screen for MBC-resistance and temperature sensitivity, proteasome subunit genetic interaction analysis Journal of Biological Chemistry Medium 9727008
1998 Rpn11/Mpr1 (PSMD14 ortholog) in S. cerevisiae is a proteasomal regulatory subunit essential for viability; its loss causes cell cycle arrest (large bud accumulation), nuclear division failure, overreplication of nuclear and mitochondrial DNA, and altered mitochondrial morphology; human POH1 complements the yeast mpr1-1 mutation. Temperature-sensitive mutant characterization, flow cytometry, GFP fusion localization, human POH1 complementation Molecular Biology of the Cell High 9763452

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science (New York, N.Y.) 847 12183636
2007 Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis and rheumatism 307 17968929
1994 Genetic structure of the Enterococcus faecalis plasmid pAD1-encoded cytolytic toxin system and its relationship to lantibiotic determinants. Journal of bacteriology 197 7961506
2009 K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. The EMBO journal 194 19214193
2002 MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function. BMC biochemistry 181 12370088
2012 The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response. The EMBO journal 136 22909820
1984 Genetic analysis of the pAD1 pheromone response in Streptococcus faecalis, using transposon Tn917 as an insertional mutagen. Journal of bacteriology 136 6327637
1990 Sequence analysis of Enterococcus faecalis aggregation substance encoded by the sex pheromone plasmid pAD1. Molecular microbiology 133 2120541
2014 Structure of the Rpn11-Rpn8 dimer reveals mechanisms of substrate deubiquitination during proteasomal degradation. Nature structural & molecular biology 131 24463465
2017 Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nature chemical biology 126 28244987
2009 PAD1 and FDC1 are essential for the decarboxylation of phenylacrylic acids in Saccharomyces cerevisiae. Journal of bioscience and bioengineering 125 20471595
2003 Complementary roles for Rpn11 and Ubp6 in deubiquitination and proteolysis by the proteasome. The Journal of biological chemistry 121 14581483
1990 Genetic analysis of the pAD1 hemolysin/bacteriocin determinant in Enterococcus faecalis: Tn917 insertional mutagenesis and cloning. Journal of bacteriology 116 2152897
2014 Crystal structure of the proteasomal deubiquitylation module Rpn8-Rpn11. Proceedings of the National Academy of Sciences of the United States of America 113 24516147
2017 Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases. Nature chemical biology 110 28459440
2015 POH1 deubiquitylates and stabilizes E2F1 to promote tumour formation. Nature communications 98 26510456
2013 Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic acids research 94 24013561
1987 Transfer functions of the Streptococcus faecalis plasmid pAD1: organization of plasmid DNA encoding response to sex pheromone. Journal of bacteriology 93 3038841
2019 ECT2/PSMD14/PTTG1 axis promotes the proliferation of glioma through stabilizing E2F1. Neuro-oncology 90 30590814
2019 Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2. Cancer letters 90 31634528
1994 PAD1 encodes phenylacrylic acid decarboxylase which confers resistance to cinnamic acid in Saccharomyces cerevisiae. Gene 87 8181743
2017 An AAA Motor-Driven Mechanical Switch in Rpn11 Controls Deubiquitination at the 26S Proteasome. Molecular cell 84 28844860
2017 Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance. Oncogene 83 28581522
1988 Regulation of the pAD1 sex pheromone response in Enterococcus faecalis: construction and characterization of lacZ transcriptional fusions in a key control region of the plasmid. Journal of bacteriology 79 2842316
1993 Identification, characterization, and nucleotide sequence of a region of Enterococcus faecalis pheromone-responsive plasmid pAD1 capable of autonomous replication. Journal of bacteriology 73 8384618
2018 Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma. Cancer letters 72 29331416
2017 PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling. Cancer letters 71 28844713
1993 Characterization of the traC determinant of the Enterococcus faecalis hemolysin-bacteriocin plasmid pAD1: binding of sex pheromone. Journal of bacteriology 69 8349566
1998 A mutation in a novel yeast proteasomal gene, RPN11/MPR1, produces a cell cycle arrest, overreplication of nuclear and mitochondrial DNA, and an altered mitochondrial morphology. Molecular biology of the cell 68 9763452
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1992 Transcriptional control of sex-pheromone-inducible genes on plasmid pAD1 of Enterococcus faecalis and sequence analysis of a third structural gene for (pPD1-encoded) aggregation substance. Molecular microbiology 68 1640831
2015 Isofunctional enzymes PAD1 and UbiX catalyze formation of a novel cofactor required by ferulic acid decarboxylase and 4-hydroxy-3-polyprenylbenzoic acid decarboxylase. ACS chemical biology 65 25647642
2000 The antisense RNA of the par locus of pAD1 regulates the expression of a 33-amino-acid toxic peptide by an unusual mechanism. Molecular microbiology 65 10931358
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2009 Identification and characterization of a family of toxin-antitoxin systems related to the Enterococcus faecalis plasmid pAD1 par addiction module. Microbiology (Reading, England) 62 19542006
2007 The JAMM motif of human deubiquitinase Poh1 is essential for cell viability. Molecular cancer therapeutics 60 17237285
2021 Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness. Theranostics 59 33456565
2021 Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2. Molecular oncology 58 34382324
2021 The PSMD14 inhibitor Thiolutin as a novel therapeutic approach for esophageal squamous cell carcinoma through facilitating SNAIL degradation. Theranostics 54 33897885
2009 Knockdown of human deubiquitinase PSMD14 induces cell cycle arrest and senescence. Experimental cell research 54 19732767
2002 Transfer origins in the conjugative Enterococcus faecalis plasmids pAD1 and pAM373: identification of the pAD1 nic site, a specific relaxase and a possible TraG-like protein. Molecular microbiology 52 12123451
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2019 The deubiquitinating enzyme PSMD14 facilitates tumor growth and chemoresistance through stabilizing the ALK2 receptor in the initiation of BMP6 signaling pathway. EBioMedicine 46 31685442
2015 Overexpression of PAD1 and FDC1 results in significant cinnamic acid decarboxylase activity in Saccharomyces cerevisiae. AMB Express 46 25852989
2007 Decarboxylation of sorbic acid by spoilage yeasts is associated with the PAD1 gene. Applied and environmental microbiology 46 17766451
2014 Single nucleotide polymorphisms of PAD1 and FDC1 show a positive relationship with ferulic acid decarboxylation ability among industrial yeasts used in alcoholic beverage production. Journal of bioscience and bioengineering 44 24507903
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2006 The 19 S proteasomal subunit POH1 contributes to the regulation of c-Jun ubiquitination, stability, and subcellular localization. The Journal of biological chemistry 41 16569633
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2004 Crystal structure of a dodecameric FMN-dependent UbiX-like decarboxylase (Pad1) from Escherichia coli O157: H7. Protein science : a publication of the Protein Society 40 15459342
2003 Enterococcus faecalis plasmid pAD1-encoded Fst toxin affects membrane permeability and alters cellular responses to lantibiotics. Journal of bacteriology 40 12644486
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2019 POH1 contributes to hyperactivation of TGF-β signaling and facilitates hepatocellular carcinoma metastasis through deubiquitinating TGF-β receptors and caveolin-1. EBioMedicine 38 30745168
2018 Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11. Cell chemical biology 38 30146242
2018 POH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity. Nature communications 37 30315153
2014 Disassembly of Lys11 and mixed linkage polyubiquitin conjugates provides insights into function of proteasomal deubiquitinases Rpn11 and Ubp6. The Journal of biological chemistry 37 25389291
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2020 Loss of function of the Pad-1 aminotransferase gene, which is involved in auxin homeostasis, induces parthenocarpy in Solanaceae plants. Proceedings of the National Academy of Sciences of the United States of America 30 32461365
2004 Replication of Enterococcus faecalis pheromone-responding plasmid pAD1: location of the minimal replicon and oriV site and RepA involvement in initiation of replication. Journal of bacteriology 30 15262938
2000 A pAD1-encoded small RNA molecule, mD, negatively regulates Enterococcus faecalis pheromone response by enhancing transcription termination. Journal of bacteriology 30 10648533
2023 The proteasome component PSMD14 drives myelomagenesis through a histone deubiquitinase activity. Molecular cell 29 37935198
2023 PSMD14 stabilizes estrogen signaling and facilitates breast cancer progression via deubiquitinating ERα. Oncogene 29 38017133
2010 The 19S proteasomal lid subunit POH1 enhances the transcriptional activation by Mitf in osteoclasts. Journal of cellular biochemistry 29 20058232
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2017 ALD5, PAD1, ATF1 and ATF2 facilitate the catabolism of coniferyl aldehyde, ferulic acid and p-coumaric acid in Saccharomyces cerevisiae. Scientific reports 27 28205618
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2022 PSMD14 Targeting Triggers Paraptosis in Breast Cancer Cells by Inducing Proteasome Inhibition and Ca2+ Imbalance. International journal of molecular sciences 22 35269789
2013 Catalytic domain of plasmid pAD1 relaxase TraX defines a group of relaxases related to restriction endonucleases. Proceedings of the National Academy of Sciences of the United States of America 22 23904483
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2025 Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury. Autophagy 21 40000916
2022 Novel insights into the non-canonical roles of PSMD14/POH1/Rpn11 in proteostasis and in the modulation of cancer progression. Cellular signalling 20 36241058
2019 Targeting POH1 inhibits prostate cancer cell growth and enhances the suppressive efficacy of androgen deprivation and docetaxel. The Prostate 20 31212367
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2022 Deubiquitinating enzyme PSMD14 facilitates gastric carcinogenesis through stabilizing PTBP1. Experimental cell research 17 35405117