{"gene":"PSMD14","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Active-site mutagenesis, in vitro deubiquitination/degradation assay with purified proteasomes, yeast genetics","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in vitro + mutagenesis + genetic lethality, foundational paper with 847 citations","pmids":["12183636"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Site-directed mutagenesis, growth phenotype assays, proteasome-dependent proteolysis assays in yeast","journal":"BMC Biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with multiple functional readouts, replicated concept across labs","pmids":["12370088"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Purification of proteasomes from yeast mutants, in vitro deubiquitination assays, metal chelator sensitivity, genetic double mutant analysis","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution with purified mutant proteasomes plus genetic epistasis","pmids":["14581483"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Multi-step chromatographic co-fractionation from HeLa extracts, linkage-specific ubiquitin chain cleavage assays, inhibitor profiling","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical fractionation with multiple linkage-specific substrates, strong","pmids":["19214193"],"is_preprint":false},{"year":2007,"finding":"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.","method":"RNAi complementation in HeLa cells with wild-type vs. JAMM mutant Poh1, cell viability and proteasome activity assays","journal":"Molecular Cancer Therapeutics","confidence":"High","confidence_rationale":"Tier 2 — active-site mutagenesis with cellular functional rescue, human cells","pmids":["17237285"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography (Zn2+-free and Zn2+-bound structures), in vitro deubiquitination assays, site-directed mutagenesis","journal":"Nature Structural & Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.0 Å combined with mutagenesis and biochemical validation","pmids":["24463465"],"is_preprint":false},{"year":2014,"finding":"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.","method":"X-ray crystallography (nanobody-assisted), in vitro deubiquitination activity assays, cryo-EM docking","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures combined with biochemical activity assays","pmids":["24516147"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Ubiquitin-bound crystal structure of Rpn11 from S. cerevisiae, biochemical deubiquitination kinetics, ATPase motor mutant analysis","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of ubiquitin-bound form plus mechanistic biochemical assays","pmids":["28844860"],"is_preprint":false},{"year":2017,"finding":"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.","method":"In vitro Rpn11 inhibition assays, selectivity profiling against JAMM family, cell-based proteasome substrate stabilization, UPR induction assays","journal":"Nature Chemical Biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct enzyme inhibition with selectivity profiling and mechanistic cellular readouts","pmids":["28244987"],"is_preprint":false},{"year":2017,"finding":"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).","method":"In vitro JAMM metalloprotease inhibition assays, zinc chelation characterization, comparison across JAMM family members","journal":"Nature Chemical Biology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzyme inhibition with mechanistic characterization","pmids":["28459440"],"is_preprint":false},{"year":2012,"finding":"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.","method":"siRNA knockdown, K63-polyubiquitin immunofluorescence at DSB foci, 53BP1 IRIF quantification, RAD51 foci assays, epistasis with RNF8/RNF168","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 — clean KD with multiple orthogonal damage-response readouts, replicated across endpoints","pmids":["22909820"],"is_preprint":false},{"year":2013,"finding":"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.","method":"siRNA double depletions, IRIF immunofluorescence, RPA foci formation assays, epistasis analysis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 — multiple siRNA epistasis combinations with quantitative IRIF phenotypes","pmids":["24013561"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, conditional Poh1 knockout mouse, xenograft tumor model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, in vivo ubiquitination, conditional KO with specific substrate readout","pmids":["26510456"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Mass spectrometry interaction screen, Co-IP, in vivo ubiquitination assay, siRNA knockdown, in vivo metastasis model","journal":"Cancer Letters","confidence":"High","confidence_rationale":"Tier 2 — MS identification of interaction + Co-IP + functional ubiquitination assay + in vivo phenotype","pmids":["29331416"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-IP, in vivo ubiquitination assay, PSMD14 knockdown/overexpression, xenograft model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay from single lab","pmids":["31634528"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Ectopic expression, ubiquitination assay, AP1 reporter assay, nuclear localization by immunofluorescence, site-directed mutagenesis","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP/ubiquitination with functional promoter readout, single lab","pmids":["16569633"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA library screen, immunoblotting, flow cytometry for surface ErbB2, proteasome inhibitor comparison","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA screen-based identification with follow-up ubiquitination analysis, single lab","pmids":["19436748"],"is_preprint":false},{"year":2009,"finding":"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.","method":"siRNA knockdown, flow cytometry, senescence assays, Western blotting for cell cycle regulators","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean KD with specific cell cycle phenotype readouts, comparison with 20S subunit","pmids":["19732767"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-IP, K63-specific ubiquitination assay, conditional myeloid-specific KO mouse, in vivo inflammatory models","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — linkage-specific ubiquitination assay, conditional KO with in vivo inflammatory phenotype","pmids":["30315153"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, and conditional KO mouse with substrate expression readout","pmids":["30745168"],"is_preprint":false},{"year":2019,"finding":"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.","method":"DUB siRNA library screen, immunoprecipitation, K48-specific ubiquitination assay, Smurf1 E3 ligase identification, xenograft model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — DUB library screen + Co-IP + linkage-specific ubiquitination + E3 ligase identification","pmids":["31685442"],"is_preprint":false},{"year":2014,"finding":"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.","method":"In vitro deubiquitination assays with defined homogeneous and heterogeneous ubiquitin chain substrates, kinetic analysis of purified Rpn11 vs. holo-proteasome","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro kinetics with defined chain substrates and purified components","pmids":["25389291"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Rpn11-Rpn8 chimera analysis, site-directed mutagenesis, intragene complementation, microscopy of mitochondrial morphology, respiratory growth assays","journal":"Biochemical Journal","confidence":"High","confidence_rationale":"Tier 2 — domain-swap chimeras + mutagenesis + multiple phenotypic readouts separating two functions","pmids":["15018611"],"is_preprint":false},{"year":2018,"finding":"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.","method":"In vitro proteasome degradation assay (newly developed), Rpn11 inhibition characterization, JAMM family selectivity assay, cell-based substrate stabilization and UPR assays","journal":"Cell Chemical Biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzyme assay + mechanistic cellular validation","pmids":["30146242"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Co-immunoprecipitation, reporter gene assays (5XGal4-TK and Acp5 promoters), JAMM motif mutagenesis, overexpression in osteoclasts","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional reporter assay, single lab, no direct deubiquitination of Mitf shown","pmids":["20058232"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Crystal structures of apo and ubiquitin-bound archaeal Rpn11, in vitro deubiquitinase activity assays, inhibitor and metal ion characterization","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 — structural determination + biochemical characterization of ancestral enzyme","pmids":["30002364"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-IP, K63-specific ubiquitination assay, pyruvate kinase activity assay, subcellular fractionation, PSMD14 KD/OE experiments","journal":"Molecular Oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — linkage-specific ubiquitination assay + enzymatic activity + fractionation, single lab","pmids":["34382324"],"is_preprint":false},{"year":2022,"finding":"PSMD14 directly interacts with LRPPRC and deubiquitinates it, inhibiting autophagy through the LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway in ovarian cancer.","method":"Co-IP, ubiquitination assay, autophagy flux assays, PSMD14 KD with in vivo xenograft","journal":"Biochimica et Biophysica Acta - Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with ubiquitination assay and pathway readouts, single lab","pmids":["36328147"],"is_preprint":false},{"year":2023,"finding":"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.","method":"ChIP-seq, Co-IP (chromatin fraction), histone ubiquitination assays, H3K36me2 ChIP, integrative genomic/epigenomic analysis","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP on chromatin + ChIP-seq + histone modification assays + transcriptional readout","pmids":["37935198"],"is_preprint":false},{"year":2023,"finding":"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.","method":"DUB siRNA library screen, Co-IP, K48-specific ubiquitination assay, ChIP assay, tamoxifen-resistant model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — library screen + Co-IP + linkage-specific ubiquitination + ChIP feedback validation","pmids":["38017133"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Hepatocyte-specific KO mouse, Co-IP, ubiquitination assay, m6A sequencing, metabolomics, histone propionylation assay, pharmacological inhibition with Capzimin","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 — conditional KO mouse + Co-IP + ubiquitination + mechanistic metabolic pathway dissection","pmids":["39146936"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown, ubiquitination assay for p53 and Bim, apoptosis assays, genetic epistasis with p53/Bim siRNA, in vivo intratumoral siRNA injection","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2-3 — ubiquitination assay + genetic epistasis, single lab","pmids":["29573636"],"is_preprint":false},{"year":2025,"finding":"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).","method":"LC-MS proteomics, Co-IP, ubiquitination assay, PINK1 phosphorylation assay, mitophagy assays, CCI mouse model, histone lactylation analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP + ubiquitination + mitophagy assays in a disease model, single lab","pmids":["40000916"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Genetic screen for MBC-resistance and temperature sensitivity, proteasome subunit genetic interaction analysis","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic analysis identifying proteasomal membership in fission yeast","pmids":["9727008"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Temperature-sensitive mutant characterization, flow cytometry, GFP fusion localization, human POH1 complementation","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 — cross-species complementation + multiple cellular phenotypes, foundational paper","pmids":["9763452"],"is_preprint":false}],"current_model":"PSMD14 (POH1/Rpn11) is an essential JAMM-motif zinc metalloprotease deubiquitinase residing in the lid subcomplex of the 19S proteasome regulatory particle, where it catalyzes en-bloc removal of polyubiquitin chains from substrate proteins at the proteasomal entry pore in a process mechanochemically coupled to ATP-dependent substrate translocation by the AAA+ motor; it additionally functions outside the proteasome as a histone H2AK119 deubiquitinase on chromatin, as a K63-specific DUB in the DNA double-strand break response, and as a stabilizer of numerous oncoproteins (E2F1, SNAIL, GRB2, ERα, TGF-β receptors, PKM2, METTL3) through substrate-specific deubiquitination."},"narrative":{"teleology":[{"year":1998,"claim":"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","pmids":["9763452","9727008"],"confidence":"High","gaps":["Enzymatic activity unknown at this point","Mechanism of essentiality (catalytic vs. structural) unresolved"]},{"year":2002,"claim":"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","pmids":["12183636","12370088"],"confidence":"High","gaps":["Structural basis of catalysis unknown","Linkage specificity uncharacterized","Mechanism of coupling to degradation unclear"]},{"year":2003,"claim":"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","pmids":["14581483"],"confidence":"High","gaps":["Whether Rpn11 acts en-bloc or processively unknown","Regulation of Rpn11 activity within the holoenzyme not addressed"]},{"year":2004,"claim":"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","pmids":["15018611"],"confidence":"High","gaps":["Molecular mechanism of mitochondrial function unknown","Relevance to mammalian cells not tested"]},{"year":2007,"claim":"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","pmids":["17237285"],"confidence":"High","gaps":["Human structural data lacking","Substrate specificity in human context undefined"]},{"year":2009,"claim":"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","pmids":["19214193"],"confidence":"High","gaps":["Whether K63 specificity applies to proteasome-incorporated Rpn11 or free enzyme","Conflict with later studies showing broader specificity when in proteasome context"]},{"year":2012,"claim":"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","pmids":["22909820","24013561"],"confidence":"High","gaps":["How POH1 is recruited to DSB sites unknown","Whether this function requires the 19S particle or POH1 acts alone at DSBs"]},{"year":2014,"claim":"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","pmids":["24463465","24516147","25389291"],"confidence":"High","gaps":["No structure of Rpn11 in substrate-engaged proteasome at this point","Role of ATPase motor in activation inferred but not directly shown"]},{"year":2015,"claim":"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","pmids":["26510456"],"confidence":"High","gaps":["Whether E2F1 deubiquitination occurs within or outside the proteasome","Linkage specificity on E2F1 not determined"]},{"year":2017,"claim":"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","pmids":["28844860"],"confidence":"High","gaps":["Time-resolved conformational dynamics not captured","Whether the same mechanism operates on all ubiquitin linkage types"]},{"year":2017,"claim":"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","pmids":["28244987","28459440"],"confidence":"High","gaps":["In vivo pharmacokinetics and therapeutic window not established","Off-target effects on other JAMM metalloproteases"]},{"year":2018,"claim":"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","pmids":["29331416","30315153","29573636"],"confidence":"High","gaps":["Direct vs. indirect deubiquitination not always distinguished","Proteasome-dependent vs. -independent action unclear for several substrates"]},{"year":2019,"claim":"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","pmids":["30745168","31685442"],"confidence":"High","gaps":["How substrate selectivity outside the proteasome is achieved remains unknown","Structural basis of non-proteasomal PSMD14-substrate recognition absent"]},{"year":2023,"claim":"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","pmids":["37935198"],"confidence":"High","gaps":["Whether PSMD14 acts alone or as part of an alternative complex on chromatin","How PSMD14 is recruited to specific genomic loci"]},{"year":2023,"claim":"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","pmids":["38017133"],"confidence":"High","gaps":["Clinical validation of PSMD14 inhibition in endocrine-resistant breast cancer absent","Whether ERα deubiquitination is proteasome-dependent or -independent"]},{"year":2024,"claim":"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","pmids":["39146936"],"confidence":"High","gaps":["Whether METTL3 deubiquitination is direct or through proteasomal activity","Translational potential of Capzimin in metabolic liver disease untested"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,5,7,8,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,5,8,9]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[28,10,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[28,10,11]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,4,7,8,21,23]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[28,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[19,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[30]}],"complexes":["26S proteasome 19S regulatory particle (lid subcomplex)","Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer"],"partners":["PSMD7","NSD2","E2F1","SNAI1","TGFBR1","TGFBR2","ESR1","METTL3"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"O00487","full_name":"Ubiquitin C-terminal hydrolase PSMD14","aliases":["26S proteasome non-ATPase regulatory subunit 14","26S proteasome regulatory subunit RPN11","26S proteasome-associated PAD1 homolog 1"],"length_aa":310,"mass_kda":34.6,"function":"Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:9374539, PubMed:1317798). The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex (PubMed:22909820). Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation (PubMed:22909820). Also involved in homologous recombination repair by promoting RAD51 loading (PubMed:22909820). Regulates macroautophagy by ensuring Golgi-to-ER retrograde transport through its deubiquitinating activity on K63-linked ubiquitin chains. This activity prevents the retention of essential autophagy proteins at the Golgi, enabling their trafficking to autophagosome formation sites and supporting Golgi-ER membrane recycling critical for effective autophagy (PubMed:32210007)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O00487/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD14","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMD12","stoichiometry":10.0},{"gene":"PSMC4","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PSMD14","total_profiled":1310},"omim":[{"mim_id":"607274","title":"UBIQUITIN-SPECIFIC PROTEASE 14; USP14","url":"https://www.omim.org/entry/607274"},{"mim_id":"607173","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 14; PSMD14","url":"https://www.omim.org/entry/607173"},{"mim_id":"300617","title":"BRCA1/BRCA2-CONTAINING COMPLEX, SUBUNIT 3; BRCC3","url":"https://www.omim.org/entry/300617"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSMD14"},"hgnc":{"alias_symbol":["POH1","pad1","Rpn11"],"prev_symbol":[]},"alphafold":{"accession":"O00487","domains":[{"cath_id":"3.40.140.10","chopping":"29-219","consensus_level":"high","plddt":84.7158,"start":29,"end":219},{"cath_id":"1.10.287","chopping":"224-308","consensus_level":"high","plddt":87.4381,"start":224,"end":308}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00487","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00487-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00487-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD14","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD14"},"sequence":{"accession":"O00487","fasta_url":"https://rest.uniprot.org/uniprotkb/O00487.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00487/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00487"}},"corpus_meta":[{"pmid":"12183636","id":"PMC_12183636","title":"Role 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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.\",\n      \"method\": \"Active-site mutagenesis, in vitro deubiquitination/degradation assay with purified proteasomes, yeast genetics\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in vitro + mutagenesis + genetic lethality, foundational paper with 847 citations\",\n      \"pmids\": [\"12183636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, growth phenotype assays, proteasome-dependent proteolysis assays in yeast\",\n      \"journal\": \"BMC Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with multiple functional readouts, replicated concept across labs\",\n      \"pmids\": [\"12370088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Purification of proteasomes from yeast mutants, in vitro deubiquitination assays, metal chelator sensitivity, genetic double mutant analysis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution with purified mutant proteasomes plus genetic epistasis\",\n      \"pmids\": [\"14581483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Multi-step chromatographic co-fractionation from HeLa extracts, linkage-specific ubiquitin chain cleavage assays, inhibitor profiling\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical fractionation with multiple linkage-specific substrates, strong\",\n      \"pmids\": [\"19214193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi complementation in HeLa cells with wild-type vs. JAMM mutant Poh1, cell viability and proteasome activity assays\",\n      \"journal\": \"Molecular Cancer Therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — active-site mutagenesis with cellular functional rescue, human cells\",\n      \"pmids\": [\"17237285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (Zn2+-free and Zn2+-bound structures), in vitro deubiquitination assays, site-directed mutagenesis\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.0 Å combined with mutagenesis and biochemical validation\",\n      \"pmids\": [\"24463465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (nanobody-assisted), in vitro deubiquitination activity assays, cryo-EM docking\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures combined with biochemical activity assays\",\n      \"pmids\": [\"24516147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Ubiquitin-bound crystal structure of Rpn11 from S. cerevisiae, biochemical deubiquitination kinetics, ATPase motor mutant analysis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of ubiquitin-bound form plus mechanistic biochemical assays\",\n      \"pmids\": [\"28844860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro Rpn11 inhibition assays, selectivity profiling against JAMM family, cell-based proteasome substrate stabilization, UPR induction assays\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct enzyme inhibition with selectivity profiling and mechanistic cellular readouts\",\n      \"pmids\": [\"28244987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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).\",\n      \"method\": \"In vitro JAMM metalloprotease inhibition assays, zinc chelation characterization, comparison across JAMM family members\",\n      \"journal\": \"Nature Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzyme inhibition with mechanistic characterization\",\n      \"pmids\": [\"28459440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, K63-polyubiquitin immunofluorescence at DSB foci, 53BP1 IRIF quantification, RAD51 foci assays, epistasis with RNF8/RNF168\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple orthogonal damage-response readouts, replicated across endpoints\",\n      \"pmids\": [\"22909820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA double depletions, IRIF immunofluorescence, RPA foci formation assays, epistasis analysis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple siRNA epistasis combinations with quantitative IRIF phenotypes\",\n      \"pmids\": [\"24013561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, conditional Poh1 knockout mouse, xenograft tumor model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vivo ubiquitination, conditional KO with specific substrate readout\",\n      \"pmids\": [\"26510456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry interaction screen, Co-IP, in vivo ubiquitination assay, siRNA knockdown, in vivo metastasis model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS identification of interaction + Co-IP + functional ubiquitination assay + in vivo phenotype\",\n      \"pmids\": [\"29331416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, in vivo ubiquitination assay, PSMD14 knockdown/overexpression, xenograft model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay from single lab\",\n      \"pmids\": [\"31634528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Ectopic expression, ubiquitination assay, AP1 reporter assay, nuclear localization by immunofluorescence, site-directed mutagenesis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/ubiquitination with functional promoter readout, single lab\",\n      \"pmids\": [\"16569633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA library screen, immunoblotting, flow cytometry for surface ErbB2, proteasome inhibitor comparison\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA screen-based identification with follow-up ubiquitination analysis, single lab\",\n      \"pmids\": [\"19436748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, flow cytometry, senescence assays, Western blotting for cell cycle regulators\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean KD with specific cell cycle phenotype readouts, comparison with 20S subunit\",\n      \"pmids\": [\"19732767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, K63-specific ubiquitination assay, conditional myeloid-specific KO mouse, in vivo inflammatory models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — linkage-specific ubiquitination assay, conditional KO with in vivo inflammatory phenotype\",\n      \"pmids\": [\"30315153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, and conditional KO mouse with substrate expression readout\",\n      \"pmids\": [\"30745168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"DUB siRNA library screen, immunoprecipitation, K48-specific ubiquitination assay, Smurf1 E3 ligase identification, xenograft model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — DUB library screen + Co-IP + linkage-specific ubiquitination + E3 ligase identification\",\n      \"pmids\": [\"31685442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro deubiquitination assays with defined homogeneous and heterogeneous ubiquitin chain substrates, kinetic analysis of purified Rpn11 vs. holo-proteasome\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro kinetics with defined chain substrates and purified components\",\n      \"pmids\": [\"25389291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Rpn11-Rpn8 chimera analysis, site-directed mutagenesis, intragene complementation, microscopy of mitochondrial morphology, respiratory growth assays\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-swap chimeras + mutagenesis + multiple phenotypic readouts separating two functions\",\n      \"pmids\": [\"15018611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro proteasome degradation assay (newly developed), Rpn11 inhibition characterization, JAMM family selectivity assay, cell-based substrate stabilization and UPR assays\",\n      \"journal\": \"Cell Chemical Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzyme assay + mechanistic cellular validation\",\n      \"pmids\": [\"30146242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays (5XGal4-TK and Acp5 promoters), JAMM motif mutagenesis, overexpression in osteoclasts\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional reporter assay, single lab, no direct deubiquitination of Mitf shown\",\n      \"pmids\": [\"20058232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structures of apo and ubiquitin-bound archaeal Rpn11, in vitro deubiquitinase activity assays, inhibitor and metal ion characterization\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination + biochemical characterization of ancestral enzyme\",\n      \"pmids\": [\"30002364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-IP, K63-specific ubiquitination assay, pyruvate kinase activity assay, subcellular fractionation, PSMD14 KD/OE experiments\",\n      \"journal\": \"Molecular Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — linkage-specific ubiquitination assay + enzymatic activity + fractionation, single lab\",\n      \"pmids\": [\"34382324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMD14 directly interacts with LRPPRC and deubiquitinates it, inhibiting autophagy through the LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway in ovarian cancer.\",\n      \"method\": \"Co-IP, ubiquitination assay, autophagy flux assays, PSMD14 KD with in vivo xenograft\",\n      \"journal\": \"Biochimica et Biophysica Acta - Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with ubiquitination assay and pathway readouts, single lab\",\n      \"pmids\": [\"36328147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, Co-IP (chromatin fraction), histone ubiquitination assays, H3K36me2 ChIP, integrative genomic/epigenomic analysis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP on chromatin + ChIP-seq + histone modification assays + transcriptional readout\",\n      \"pmids\": [\"37935198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"DUB siRNA library screen, Co-IP, K48-specific ubiquitination assay, ChIP assay, tamoxifen-resistant model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — library screen + Co-IP + linkage-specific ubiquitination + ChIP feedback validation\",\n      \"pmids\": [\"38017133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Hepatocyte-specific KO mouse, Co-IP, ubiquitination assay, m6A sequencing, metabolomics, histone propionylation assay, pharmacological inhibition with Capzimin\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO mouse + Co-IP + ubiquitination + mechanistic metabolic pathway dissection\",\n      \"pmids\": [\"39146936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay for p53 and Bim, apoptosis assays, genetic epistasis with p53/Bim siRNA, in vivo intratumoral siRNA injection\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ubiquitination assay + genetic epistasis, single lab\",\n      \"pmids\": [\"29573636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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).\",\n      \"method\": \"LC-MS proteomics, Co-IP, ubiquitination assay, PINK1 phosphorylation assay, mitophagy assays, CCI mouse model, histone lactylation analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP + ubiquitination + mitophagy assays in a disease model, single lab\",\n      \"pmids\": [\"40000916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic screen for MBC-resistance and temperature sensitivity, proteasome subunit genetic interaction analysis\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic analysis identifying proteasomal membership in fission yeast\",\n      \"pmids\": [\"9727008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Temperature-sensitive mutant characterization, flow cytometry, GFP fusion localization, human POH1 complementation\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cross-species complementation + multiple cellular phenotypes, foundational paper\",\n      \"pmids\": [\"9763452\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD14 (POH1/Rpn11) is an essential JAMM-motif zinc metalloprotease deubiquitinase residing in the lid subcomplex of the 19S proteasome regulatory particle, where it catalyzes en-bloc removal of polyubiquitin chains from substrate proteins at the proteasomal entry pore in a process mechanochemically coupled to ATP-dependent substrate translocation by the AAA+ motor; it additionally functions outside the proteasome as a histone H2AK119 deubiquitinase on chromatin, as a K63-specific DUB in the DNA double-strand break response, and as a stabilizer of numerous oncoproteins (E2F1, SNAIL, GRB2, ERα, TGF-β receptors, PKM2, METTL3) through substrate-specific deubiquitination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"Temperature-sensitive yeast mutants, cross-species complementation, cell cycle and mitochondrial phenotyping in S. cerevisiae and S. pombe\",\n      \"pmids\": [\"9763452\", \"9727008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic activity unknown at this point\", \"Mechanism of essentiality (catalytic vs. structural) unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Active-site mutagenesis (rpn11AXA), in vitro deubiquitination/degradation assays with purified yeast proteasomes\",\n      \"pmids\": [\"12183636\", \"12370088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of catalysis unknown\", \"Linkage specificity uncharacterized\", \"Mechanism of coupling to degradation unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Purification of mutant proteasomes, metal chelator sensitivity, synthetic lethality of rpn11/ubp6 double mutant\",\n      \"pmids\": [\"14581483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rpn11 acts en-bloc or processively unknown\", \"Regulation of Rpn11 activity within the holoenzyme not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain-swap chimeras with Rpn8, intragene complementation, mitochondrial morphology microscopy in yeast\",\n      \"pmids\": [\"15018611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of mitochondrial function unknown\", \"Relevance to mammalian cells not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi complementation in HeLa cells with wild-type vs. JAMM-mutant Poh1\",\n      \"pmids\": [\"17237285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human structural data lacking\", \"Substrate specificity in human context undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Chromatographic fractionation from HeLa extracts, cleavage assays with all homotypic chain types, NEM/UbAl insensitivity\",\n      \"pmids\": [\"19214193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K63 specificity applies to proteasome-incorporated Rpn11 or free enzyme\", \"Conflict with later studies showing broader specificity when in proteasome context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"siRNA knockdown, K63-polyubiquitin and 53BP1 IRIF quantification, RAD51 foci assays, epistasis with RNF8/RNF168\",\n      \"pmids\": [\"22909820\", \"24013561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How POH1 is recruited to DSB sites unknown\", \"Whether this function requires the 19S particle or POH1 acts alone at DSBs\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography at 2.0 Å (Zn-free and Zn-bound), nanobody-assisted structures, kinetic analysis with defined ubiquitin chain substrates\",\n      \"pmids\": [\"24463465\", \"24516147\", \"25389291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of Rpn11 in substrate-engaged proteasome at this point\", \"Role of ATPase motor in activation inferred but not directly shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo ubiquitination assay, conditional Poh1 KO mouse hepatocytes, xenograft tumor model\",\n      \"pmids\": [\"26510456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E2F1 deubiquitination occurs within or outside the proteasome\", \"Linkage specificity on E2F1 not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Ubiquitin-bound Rpn11 crystal structure from S. cerevisiae, deubiquitination kinetics with ATPase motor mutants\",\n      \"pmids\": [\"28844860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Time-resolved conformational dynamics not captured\", \"Whether the same mechanism operates on all ubiquitin linkage types\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro Rpn11 inhibition, JAMM family selectivity profiling, proteasome substrate stabilization, UPR induction\",\n      \"pmids\": [\"28244987\", \"28459440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo pharmacokinetics and therapeutic window not established\", \"Off-target effects on other JAMM metalloproteases\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"MS interaction screens, Co-IP, linkage-specific ubiquitination assays, myeloid-specific conditional KO mice, in vivo metastasis and inflammation models\",\n      \"pmids\": [\"29331416\", \"30315153\", \"29573636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect deubiquitination not always distinguished\", \"Proteasome-dependent vs. -independent action unclear for several substrates\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination assays, conditional Poh1 KO hepatocytes, DUB siRNA library screen\",\n      \"pmids\": [\"30745168\", \"31685442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate selectivity outside the proteasome is achieved remains unknown\", \"Structural basis of non-proteasomal PSMD14-substrate recognition absent\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP-seq, chromatin-fraction Co-IP, histone ubiquitination and methylation assays, integrative genomic analysis\",\n      \"pmids\": [\"37935198\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSMD14 acts alone or as part of an alternative complex on chromatin\", \"How PSMD14 is recruited to specific genomic loci\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"DUB siRNA library screen, K48-specific ubiquitination assay, ChIP for ERα at PSMD14 promoter, tamoxifen-resistant model\",\n      \"pmids\": [\"38017133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical validation of PSMD14 inhibition in endocrine-resistant breast cancer absent\", \"Whether ERα deubiquitination is proteasome-dependent or -independent\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional KO mouse, Co-IP, m6A sequencing, metabolomics, histone propionylation assays, Capzimin treatment\",\n      \"pmids\": [\"39146936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether METTL3 deubiquitination is direct or through proteasomal activity\", \"Translational potential of Capzimin in metabolic liver disease untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 7, 8, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 5, 8, 9]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [28, 10, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [28, 10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 4, 7, 8, 21, 23]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [28, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [19, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"complexes\": [\n      \"26S proteasome 19S regulatory particle (lid subcomplex)\",\n      \"Rpn11-Rpn8 (PSMD14-PSMD7) heterodimer\"\n    ],\n    \"partners\": [\n      \"PSMD7\",\n      \"NSD2\",\n      \"E2F1\",\n      \"SNAI1\",\n      \"TGFBR1\",\n      \"TGFBR2\",\n      \"ESR1\",\n      \"METTL3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}