{"gene":"PSMD1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"Human p112 (PSMD1) was cloned and identified as the largest regulatory subunit of the 26S proteasome; its yeast homologue Sen3p is required for ubiquitin-pathway proteolysis, N-end rule degradation, stress response, and nuclear protein transport, and human p112 cDNA functionally complements the yeast SEN3 disruptant, establishing it as a bona fide proteasomal subunit with roles in multiple proteasome-mediated processes.","method":"cDNA cloning, yeast complementation of SEN3 disruptant, phenotypic analysis of SEN3 disruption (proteolysis, N-end rule, stress response, nuclear transport defects)","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional complementation across species combined with multiple orthogonal phenotypic readouts in a single study; foundational characterization paper","pmids":["8816993"],"is_preprint":false},{"year":2014,"finding":"PSMD1 is SUMOylated by the SUMO E3 ligase PIASy at a critical lysine immediately adjacent to its Adrm1-binding domain; this SUMOylation regulates the association of Adrm1 (a ubiquitinated-substrate recruitment subunit) with PSMD1 and thereby controls proteasome composition. The SUMO deconjugating enzyme xSENP1 specifically interacts with PSMD1, and disruption of xSENP1 targeting delays mitotic exit.","method":"Co-IP, SUMOylation site mapping by mutagenesis, SUMO E3 (PIASy) identification, functional assays for Adrm1 binding, mitotic exit assay with xSENP1 disruption","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis mapping SUMOylation sites, reciprocal Co-IP, E3 identification, and functional consequence (Adrm1 binding, mitotic exit), multiple orthogonal methods in single study","pmids":["24910440"],"is_preprint":false},{"year":2018,"finding":"PSMD1 knockdown in breast cancer cells causes cell cycle arrest and accumulation of p53 protein by inhibiting p53 protein degradation, with concomitant upregulation of p53 target genes p21 and SFN, placing PSMD1 in the ubiquitin-proteasome pathway responsible for p53 turnover.","method":"siRNA-mediated knockdown, Western blot for p53 accumulation, cell cycle analysis, gene expression assays","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined molecular readout (p53 protein accumulation), single lab, single primary method","pmids":["28992264"],"is_preprint":false},{"year":2019,"finding":"Knockdown of PSMD1 and/or PSMD2 in HepG2 cells decreases formation of cellular lipid droplets and reduces cell proliferation; mechanistically, PSMD1 and PSMD2 regulate expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.","method":"siRNA knockdown, lipid droplet quantification, Western blot for signaling intermediates (p38, JNK, AKT), gene expression analysis","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — KD with defined cellular phenotype and pathway placement (p38-JNK/AKT), two orthogonal readouts, single lab","pmids":["31703613"],"is_preprint":false},{"year":2021,"finding":"PSMD1 and PSMD3 (19S regulatory complex subunits) promote NF-κB protein expression in CML cells; knockdown of PSMD1 reduces NF-κB activity (measured by luciferase reporter and immunoblot), decreases cell survival, and increases apoptosis in CML cells but not in normal progenitors.","method":"Nucleocytoplasmic fractionation, luciferase reporter assay, immunoblot, shRNA knockdown, flow cytometry for apoptosis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter, fractionation, immunoblot, KD phenotype), single lab","pmids":["33712704"],"is_preprint":false},{"year":2018,"finding":"PSMD1 and PSMD2, components of the 19S regulatory particle, directly interact with Dictyostelium ATG16 (autophagy protein); PSMD1 interacts with both the N-terminal and C-terminal half of ATG16, while PSMD2 interacts only with the C-terminal half. RFP-PSMD1 and RFP-PSMD2 localize to ATG16/ATG8a-positive autophagosomes and are delivered to lysosomes in an ATG16-dependent manner, revealing autophagic degradation as a regulatory mechanism for these proteasome subunits.","method":"Co-IP, deletion analysis of ATG16, co-localization by fluorescence microscopy, LysoTracker labeling, proteolytic cleavage assay, genetic knockouts (atg16−, atg9−)","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, deletion mapping, live-cell imaging with functional consequence (lysosomal delivery), multiple methods, single lab","pmids":["30269947"],"is_preprint":false},{"year":2022,"finding":"PSMD1 interacts with PTEN-induced kinase 1 (PINK1) by co-immunoprecipitation; PSMD1 inhibits ubiquitination of PINK1 and enhances PINK1 protein stability, thereby promoting lung adenocarcinoma cell viability and suppressing apoptosis. PSMD1 knockdown reduces PINK1 protein levels and suppresses tumor growth in vivo.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression vectors, xenograft mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft validation, single lab","pmids":["35192838"],"is_preprint":false},{"year":1988,"finding":"P112 (PSMD1) was identified as a 112 kDa protein preferentially expressed on the surface of lung endothelial cells; immunogold electron microscopy and in vivo radiolabeled antibody localization demonstrated specific enrichment in lung relative to other organs.","method":"Monoclonal antibody generation, immunohistochemistry, immunogold electron microscopy, in vivo radiolabeled antibody biodistribution, immunoaffinity chromatography purification, two-site quantitative assay","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein localization by immunogold EM and in vivo biodistribution, two orthogonal antibodies, single lab","pmids":["2460698"],"is_preprint":false}],"current_model":"PSMD1 (p112) is the largest non-ATPase subunit of the 19S regulatory particle of the 26S proteasome, where it serves as a docking site for the ubiquitinated-substrate receptor Adrm1; this interaction is dynamically regulated by PIASy-mediated SUMOylation of PSMD1 and reversed by xSENP1, linking SUMOylation to proteasome composition and mitotic progression. Through its proteasomal role, PSMD1 controls turnover of substrates including p53, regulates de novo lipid synthesis gene expression via p38-JNK and AKT signaling, stabilizes NF-κB and PINK1 to promote cancer cell survival, and is itself subject to autophagic degradation via direct interaction with ATG16."},"narrative":{"mechanistic_narrative":"PSMD1 (p112) is the largest non-ATPase subunit of the 19S regulatory particle of the 26S proteasome, established by cDNA cloning and functional complementation of the yeast SEN3 disruptant, where it supports ubiquitin-pathway proteolysis, N-end rule degradation, stress response, and nuclear protein transport [PMID:8816993]. Within the regulatory particle it provides a docking platform for the ubiquitinated-substrate recruitment subunit Adrm1, and this interaction is controlled by PIASy-mediated SUMOylation of PSMD1 at a lysine adjacent to the Adrm1-binding domain; the deconjugating enzyme xSENP1 reverses this modification, coupling proteasome composition to timely mitotic exit [PMID:24910440]. Through its proteasomal function PSMD1 governs turnover of regulatory substrates—its depletion stabilizes p53 and induces p21 and SFN with cell-cycle arrest [PMID:28992264]—and in cancer cells it stabilizes pro-survival factors, promoting NF-κB protein expression in CML cells [PMID:33712704] and suppressing PINK1 ubiquitination to enhance PINK1 stability and lung adenocarcinoma viability [PMID:35192838]. PSMD1 also regulates expression of de novo lipid synthesis genes through p38-JNK and AKT signaling, supporting lipid droplet formation and proliferation [PMID:31703613], and is itself subject to autophagic clearance via direct interaction with ATG16 and delivery to lysosomes [PMID:30269947].","teleology":[{"year":1988,"claim":"Before its proteasomal role was known, PSMD1 was first detected as a tissue-enriched cell-surface antigen, raising the question of what this 112 kDa lung endothelial protein was.","evidence":"monoclonal antibody, immunogold EM, and in vivo radiolabeled antibody biodistribution in lung endothelium","pmids":["2460698"],"confidence":"Medium","gaps":["molecular identity and function not established at this stage","surface localization not reconciled with later proteasomal assignment","no link to ubiquitin-proteasome system"]},{"year":1996,"claim":"Cloning and cross-species complementation established p112 as a bona fide largest regulatory subunit of the 26S proteasome with conserved roles in ubiquitin-dependent proteolysis.","evidence":"cDNA cloning and yeast SEN3-disruptant complementation with phenotypic analysis of proteolysis, N-end rule, stress, and nuclear transport defects","pmids":["8816993"],"confidence":"High","gaps":["substrate-specific contributions not dissected","structural position within 19S particle not resolved","regulation of subunit incorporation unknown"]},{"year":2014,"claim":"SUMOylation was shown to be a regulatory switch governing how PSMD1 recruits the substrate receptor Adrm1, linking a post-translational modification to proteasome composition and cell-cycle timing.","evidence":"Co-IP, SUMOylation site mapping by mutagenesis, PIASy E3 identification, Adrm1-binding and xSENP1 mitotic-exit assays","pmids":["24910440"],"confidence":"High","gaps":["fraction of proteasomes modified in vivo unquantified","consequences for global substrate degradation not measured","human SENP/PIAS specificity not addressed"]},{"year":2018,"claim":"PSMD1 was placed in the pathway controlling p53 stability, explaining how its loss imposes a cell-cycle checkpoint.","evidence":"siRNA knockdown in breast cancer cells with p53/p21/SFN immunoblot and cell-cycle analysis","pmids":["28992264"],"confidence":"Medium","gaps":["single primary method and single lab","direct role in p53 ubiquitin transfer versus general proteasome capacity not separated","no in vivo validation"]},{"year":2018,"claim":"Discovery of a direct PSMD1-ATG16 interaction revealed that proteasome subunits are themselves turned over by autophagy, identifying a cross-regulatory link between the two degradation systems.","evidence":"reciprocal Co-IP, ATG16 deletion mapping, autophagosome/lysosome co-localization imaging, and atg16-/atg9- knockouts in Dictyostelium","pmids":["30269947"],"confidence":"Medium","gaps":["demonstrated in Dictyostelium, not human cells","physiological trigger for autophagic clearance unknown","effect on assembled 26S proteasome levels not quantified"]},{"year":2019,"claim":"PSMD1 was connected to lipid metabolism, showing its proteasomal activity feeds into signaling that drives de novo lipid synthesis gene expression.","evidence":"siRNA knockdown in HepG2 with lipid droplet quantification, signaling immunoblots (p38/JNK/AKT), and gene expression analysis","pmids":["31703613"],"confidence":"Medium","gaps":["mechanism linking proteasome to p38-JNK/AKT not defined","direct versus indirect effect on lipogenic genes unresolved","single lab, single cell line"]},{"year":2021,"claim":"PSMD1 was shown to sustain NF-κB in leukemic cells with a selectivity for malignant over normal progenitors, nominating it as a context-dependent survival dependency.","evidence":"shRNA knockdown, luciferase reporter, nucleocytoplasmic fractionation, immunoblot, and apoptosis flow cytometry in CML cells","pmids":["33712704"],"confidence":"Medium","gaps":["molecular basis of NF-κB regulation not defined","selectivity for CML cells mechanistically unexplained","no in vivo confirmation in this study"]},{"year":2022,"claim":"PSMD1 was found to stabilize PINK1 by limiting its ubiquitination, providing a substrate-level mechanism for its pro-tumorigenic role in lung adenocarcinoma.","evidence":"Co-IP, ubiquitination assay, shRNA knockdown/overexpression, and xenograft mouse model","pmids":["35192838"],"confidence":"Medium","gaps":["how a proteasome subunit inhibits substrate ubiquitination not mechanistically resolved","directness of PSMD1-PINK1 interaction not validated reciprocally","generality across tumor types untested"]},{"year":null,"claim":"How PSMD1's SUMOylation-controlled Adrm1 docking, autophagic turnover, and apparent substrate-selective stabilization of factors like PINK1 and NF-κB are mechanistically integrated within the assembled 26S proteasome remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model connecting modification state to substrate selectivity","human-cell confirmation of autophagic clearance lacking","whether substrate-specific effects reflect direct binding or general proteasome capacity unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":["26S proteasome 19S regulatory particle"],"partners":["ADRM1","PIASY","SENP1","ATG16","PINK1","PSMD2","PSMD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99460","full_name":"26S proteasome non-ATPase regulatory subunit 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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","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q99460/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD1","classification":"Common 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PSMD1","url":"https://www.omim.org/entry/617842"},{"mim_id":"610650","title":"ADHESION-REGULATING MOLECULE 1; ADRM1","url":"https://www.omim.org/entry/610650"},{"mim_id":"606576","title":"TAF3 RNA POLYMERASE II, TATA BOX-BINDING PROTEIN-ASSOCIATED FACTOR, 140-KD; TAF3","url":"https://www.omim.org/entry/606576"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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establishing it as a bona fide proteasomal subunit with roles in multiple proteasome-mediated processes.\",\n      \"method\": \"cDNA cloning, yeast complementation of SEN3 disruptant, phenotypic analysis of SEN3 disruption (proteolysis, N-end rule, stress response, nuclear transport defects)\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional complementation across species combined with multiple orthogonal phenotypic readouts in a single study; foundational characterization paper\",\n      \"pmids\": [\"8816993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PSMD1 is SUMOylated by the SUMO E3 ligase PIASy at a critical lysine immediately adjacent to its Adrm1-binding domain; this SUMOylation regulates the association of Adrm1 (a ubiquitinated-substrate recruitment subunit) with PSMD1 and thereby controls proteasome composition. The SUMO deconjugating enzyme xSENP1 specifically interacts with PSMD1, and disruption of xSENP1 targeting delays mitotic exit.\",\n      \"method\": \"Co-IP, SUMOylation site mapping by mutagenesis, SUMO E3 (PIASy) identification, functional assays for Adrm1 binding, mitotic exit assay with xSENP1 disruption\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis mapping SUMOylation sites, reciprocal Co-IP, E3 identification, and functional consequence (Adrm1 binding, mitotic exit), multiple orthogonal methods in single study\",\n      \"pmids\": [\"24910440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 knockdown in breast cancer cells causes cell cycle arrest and accumulation of p53 protein by inhibiting p53 protein degradation, with concomitant upregulation of p53 target genes p21 and SFN, placing PSMD1 in the ubiquitin-proteasome pathway responsible for p53 turnover.\",\n      \"method\": \"siRNA-mediated knockdown, Western blot for p53 accumulation, cell cycle analysis, gene expression assays\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined molecular readout (p53 protein accumulation), single lab, single primary method\",\n      \"pmids\": [\"28992264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Knockdown of PSMD1 and/or PSMD2 in HepG2 cells decreases formation of cellular lipid droplets and reduces cell proliferation; mechanistically, PSMD1 and PSMD2 regulate expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.\",\n      \"method\": \"siRNA knockdown, lipid droplet quantification, Western blot for signaling intermediates (p38, JNK, AKT), gene expression analysis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — KD with defined cellular phenotype and pathway placement (p38-JNK/AKT), two orthogonal readouts, single lab\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSMD1 and PSMD3 (19S regulatory complex subunits) promote NF-κB protein expression in CML cells; knockdown of PSMD1 reduces NF-κB activity (measured by luciferase reporter and immunoblot), decreases cell survival, and increases apoptosis in CML cells but not in normal progenitors.\",\n      \"method\": \"Nucleocytoplasmic fractionation, luciferase reporter assay, immunoblot, shRNA knockdown, flow cytometry for apoptosis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter, fractionation, immunoblot, KD phenotype), single lab\",\n      \"pmids\": [\"33712704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 and PSMD2, components of the 19S regulatory particle, directly interact with Dictyostelium ATG16 (autophagy protein); PSMD1 interacts with both the N-terminal and C-terminal half of ATG16, while PSMD2 interacts only with the C-terminal half. RFP-PSMD1 and RFP-PSMD2 localize to ATG16/ATG8a-positive autophagosomes and are delivered to lysosomes in an ATG16-dependent manner, revealing autophagic degradation as a regulatory mechanism for these proteasome subunits.\",\n      \"method\": \"Co-IP, deletion analysis of ATG16, co-localization by fluorescence microscopy, LysoTracker labeling, proteolytic cleavage assay, genetic knockouts (atg16−, atg9−)\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, deletion mapping, live-cell imaging with functional consequence (lysosomal delivery), multiple methods, single lab\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PSMD1 interacts with PTEN-induced kinase 1 (PINK1) by co-immunoprecipitation; PSMD1 inhibits ubiquitination of PINK1 and enhances PINK1 protein stability, thereby promoting lung adenocarcinoma cell viability and suppressing apoptosis. PSMD1 knockdown reduces PINK1 protein levels and suppresses tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, overexpression vectors, xenograft mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"35192838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"P112 (PSMD1) was identified as a 112 kDa protein preferentially expressed on the surface of lung endothelial cells; immunogold electron microscopy and in vivo radiolabeled antibody localization demonstrated specific enrichment in lung relative to other organs.\",\n      \"method\": \"Monoclonal antibody generation, immunohistochemistry, immunogold electron microscopy, in vivo radiolabeled antibody biodistribution, immunoaffinity chromatography purification, two-site quantitative assay\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein localization by immunogold EM and in vivo biodistribution, two orthogonal antibodies, single lab\",\n      \"pmids\": [\"2460698\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD1 (p112) is the largest non-ATPase subunit of the 19S regulatory particle of the 26S proteasome, where it serves as a docking site for the ubiquitinated-substrate receptor Adrm1; this interaction is dynamically regulated by PIASy-mediated SUMOylation of PSMD1 and reversed by xSENP1, linking SUMOylation to proteasome composition and mitotic progression. Through its proteasomal role, PSMD1 controls turnover of substrates including p53, regulates de novo lipid synthesis gene expression via p38-JNK and AKT signaling, stabilizes NF-κB and PINK1 to promote cancer cell survival, and is itself subject to autophagic degradation via direct interaction with ATG16.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMD1 (p112) is the largest non-ATPase subunit of the 19S regulatory particle of the 26S proteasome, established by cDNA cloning and functional complementation of the yeast SEN3 disruptant, where it supports ubiquitin-pathway proteolysis, N-end rule degradation, stress response, and nuclear protein transport [#0]. Within the regulatory particle it provides a docking platform for the ubiquitinated-substrate recruitment subunit Adrm1, and this interaction is controlled by PIASy-mediated SUMOylation of PSMD1 at a lysine adjacent to the Adrm1-binding domain; the deconjugating enzyme xSENP1 reverses this modification, coupling proteasome composition to timely mitotic exit [#1]. Through its proteasomal function PSMD1 governs turnover of regulatory substrates—its depletion stabilizes p53 and induces p21 and SFN with cell-cycle arrest [#2]—and in cancer cells it stabilizes pro-survival factors, promoting NF-\\u03baB protein expression in CML cells [#4] and suppressing PINK1 ubiquitination to enhance PINK1 stability and lung adenocarcinoma viability [#6]. PSMD1 also regulates expression of de novo lipid synthesis genes through p38-JNK and AKT signaling, supporting lipid droplet formation and proliferation [#3], and is itself subject to autophagic clearance via direct interaction with ATG16 and delivery to lysosomes [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Before its proteasomal role was known, PSMD1 was first detected as a tissue-enriched cell-surface antigen, raising the question of what this 112 kDa lung endothelial protein was.\",\n      \"evidence\": \"monoclonal antibody, immunogold EM, and in vivo radiolabeled antibody biodistribution in lung endothelium\",\n      \"pmids\": [\"2460698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"molecular identity and function not established at this stage\",\n        \"surface localization not reconciled with later proteasomal assignment\",\n        \"no link to ubiquitin-proteasome system\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning and cross-species complementation established p112 as a bona fide largest regulatory subunit of the 26S proteasome with conserved roles in ubiquitin-dependent proteolysis.\",\n      \"evidence\": \"cDNA cloning and yeast SEN3-disruptant complementation with phenotypic analysis of proteolysis, N-end rule, stress, and nuclear transport defects\",\n      \"pmids\": [\"8816993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"substrate-specific contributions not dissected\",\n        \"structural position within 19S particle not resolved\",\n        \"regulation of subunit incorporation unknown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"SUMOylation was shown to be a regulatory switch governing how PSMD1 recruits the substrate receptor Adrm1, linking a post-translational modification to proteasome composition and cell-cycle timing.\",\n      \"evidence\": \"Co-IP, SUMOylation site mapping by mutagenesis, PIASy E3 identification, Adrm1-binding and xSENP1 mitotic-exit assays\",\n      \"pmids\": [\"24910440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"fraction of proteasomes modified in vivo unquantified\",\n        \"consequences for global substrate degradation not measured\",\n        \"human SENP/PIAS specificity not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PSMD1 was placed in the pathway controlling p53 stability, explaining how its loss imposes a cell-cycle checkpoint.\",\n      \"evidence\": \"siRNA knockdown in breast cancer cells with p53/p21/SFN immunoblot and cell-cycle analysis\",\n      \"pmids\": [\"28992264\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"single primary method and single lab\",\n        \"direct role in p53 ubiquitin transfer versus general proteasome capacity not separated\",\n        \"no in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of a direct PSMD1-ATG16 interaction revealed that proteasome subunits are themselves turned over by autophagy, identifying a cross-regulatory link between the two degradation systems.\",\n      \"evidence\": \"reciprocal Co-IP, ATG16 deletion mapping, autophagosome/lysosome co-localization imaging, and atg16-/atg9- knockouts in Dictyostelium\",\n      \"pmids\": [\"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"demonstrated in Dictyostelium, not human cells\",\n        \"physiological trigger for autophagic clearance unknown\",\n        \"effect on assembled 26S proteasome levels not quantified\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PSMD1 was connected to lipid metabolism, showing its proteasomal activity feeds into signaling that drives de novo lipid synthesis gene expression.\",\n      \"evidence\": \"siRNA knockdown in HepG2 with lipid droplet quantification, signaling immunoblots (p38/JNK/AKT), and gene expression analysis\",\n      \"pmids\": [\"31703613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"mechanism linking proteasome to p38-JNK/AKT not defined\",\n        \"direct versus indirect effect on lipogenic genes unresolved\",\n        \"single lab, single cell line\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PSMD1 was shown to sustain NF-\\u03baB in leukemic cells with a selectivity for malignant over normal progenitors, nominating it as a context-dependent survival dependency.\",\n      \"evidence\": \"shRNA knockdown, luciferase reporter, nucleocytoplasmic fractionation, immunoblot, and apoptosis flow cytometry in CML cells\",\n      \"pmids\": [\"33712704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"molecular basis of NF-\\u03baB regulation not defined\",\n        \"selectivity for CML cells mechanistically unexplained\",\n        \"no in vivo confirmation in this study\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"PSMD1 was found to stabilize PINK1 by limiting its ubiquitination, providing a substrate-level mechanism for its pro-tumorigenic role in lung adenocarcinoma.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, shRNA knockdown/overexpression, and xenograft mouse model\",\n      \"pmids\": [\"35192838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"how a proteasome subunit inhibits substrate ubiquitination not mechanistically resolved\",\n        \"directness of PSMD1-PINK1 interaction not validated reciprocally\",\n        \"generality across tumor types untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMD1's SUMOylation-controlled Adrm1 docking, autophagic turnover, and apparent substrate-selective stabilization of factors like PINK1 and NF-\\u03baB are mechanistically integrated within the assembled 26S proteasome remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no structural model connecting modification state to substrate selectivity\",\n        \"human-cell confirmation of autophagic clearance lacking\",\n        \"whether substrate-specific effects reflect direct binding or general proteasome capacity unclear\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"26S proteasome 19S regulatory particle\"\n    ],\n    \"partners\": [\n      \"ADRM1\",\n      \"PIASy\",\n      \"SENP1\",\n      \"ATG16\",\n      \"PINK1\",\n      \"PSMD2\",\n      \"PSMD3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}