{"gene":"PSMD2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"Yeast Rpn1 (ortholog of human PSMD2), a subunit of the 19S proteasome base, directly binds the ubiquitin-like (UBL) domains of Rad23 and Dsk2 through its leucine-rich-repeat-like (LRR-like) domain. Rad23 and Dsk2 compete for the same Rpn1 binding site, identifying Rpn1 as the primary docking site for UBL-domain substrate-shuttling factors at the proteasome.","method":"Co-immunoprecipitation, direct binding assays with recombinant proteins, yeast genetic analysis, competition binding experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and direct in vitro binding with multiple UBL proteins, replicated with competition experiments","pmids":["12198498"],"is_preprint":false},{"year":2009,"finding":"Recognition and processing of ubiquitin-protein conjugates by the proteasome involves Rpn1 (PSMD2) as part of the 19S regulatory particle base, where it participates in substrate docking alongside the ATPase ring. The 19S regulatory particle's non-ATPase subunits including Rpn1 are essential for binding ubiquitinated substrates and initiating their unfolding and translocation into the 20S core.","method":"Biochemical reconstitution of proteasome subcomplexes, structural and functional analysis reviewed across multiple studies","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — foundational review synthesizing extensive biochemical reconstitution and structural data on 19S subunit functions","pmids":["19489727"],"is_preprint":false},{"year":2012,"finding":"FAT10 (a ubiquitin-like modifier) and its accelerator NUB1L both interact with the 26S proteasome via Rpn1 (PSMD2/S2). NUB1L can bind to both Rpn10 and Rpn1, and depletion of Rpn10 causes accumulation of FAT10-conjugates, while Rpn1 serves as an additional docking site for NUB1L to initiate FAT10-mediated proteasomal proteolysis.","method":"Co-immunoprecipitation, yeast complementation assays, siRNA knockdown, binding domain mapping","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping and functional knockdown, single study","pmids":["22434192"],"is_preprint":false},{"year":2016,"finding":"Rpn1 (PSMD2 ortholog) contains two adjacent ubiquitin-binding sites within its toroid domain: site T1, which recognizes monoubiquitin, K48-linked diubiquitin, and UBL domains of substrate-shuttling factors (Rad23, Dsk2, Ubiquilin) with preference for K48-linked chains; and site T2, which binds the UBL domain of the deubiquitinase Ubp6 to facilitate ubiquitin chain disassembly. Crystal structures of T1 with monoubiquitin or K48 diubiquitin reveal three neighboring outer helices engaging two ubiquitin moieties. Rpn1 constitutes the sixth proteasomal ubiquitin receptor and its T1 site defines a distinct substrate-binding pathway.","method":"X-ray crystallography of T1–ubiquitin complexes, genetic complementation, in vitro binding assays, biochemical ubiquitin receptor identification by mutagenesis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with functional validation by mutagenesis and genetic epistasis, comprehensive mechanistic study","pmids":["26912900"],"is_preprint":false},{"year":2017,"finding":"Photoactivatable crosslinking with ubiquitin variants (UbPT) confirmed Rpn1 (PSMD2) as a third proteasome ubiquitin-associating subunit (alongside Rpn10 and Rpn13), demonstrating that Rpn1 coordinates docking of substrate shuttles, substrate unloading, and anchoring of polyubiquitin conjugates at the proteasome.","method":"Synthetic photoactivatable ubiquitin crosslinking reagents (UbPT), mass spectrometry, proteasome biochemistry","journal":"Cell chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — novel chemical crosslinking tool with MS identification, orthogonal to prior structural work, validates Rpn1 ubiquitin receptor function","pmids":["28330605"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated knockdown of PSMD2 in lung cancer cell lines decreased proteasome activity and induced growth inhibition and apoptosis. These effects were associated with changes in the balance between phosphorylated AKT and p38, as well as induction of p21, placing PSMD2 upstream of AKT/p38 signaling in cancer cell survival.","method":"siRNA knockdown, proteasome activity assays, western blot for pAKT, p38, p21, cell viability and apoptosis assays","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 — clean loss-of-function with defined molecular readouts, single lab study","pmids":["21465578"],"is_preprint":false},{"year":2019,"finding":"Reversible phosphorylation of Rpn1 (PSMD2 ortholog) at Ser361 regulates 26S proteasome assembly and function. Loss of Ser361 phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress and mitochondrial dysfunction. PIM1/2/3 kinases catalyze this phosphorylation, while the proteasome-resident phosphatase UBLCP1 reverses it. Mechanistically, phospho-S361 Rpn1 more readily forms a precursor complex with Rpt2, representing one of the first steps of 19S base assembly.","method":"CRISPR/Cas9 gene editing of Ser361, quantitative mass spectrometry, kinome screen, genetic code expansion for site-specific phosphorylation, 26S proteasome assembly assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including CRISPR editing, genetic code expansion, kinome screen, and biochemical assembly assays in one study","pmids":["31843888"],"is_preprint":false},{"year":2019,"finding":"PSMD1 and PSMD2 (19S regulatory particle subunits) promote HepG2 cell proliferation by facilitating cellular lipid droplet accumulation. Knockdown of PSMD1 and/or PSMD2 decreases lipid droplet formation and reduces expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.","method":"siRNA knockdown, lipid droplet staining, western blot for lipid synthesis regulators, AKT and MAPK pathway analysis","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 — knockdown with pathway readouts, single lab, mechanistic pathway placement but indirect","pmids":["31703613"],"is_preprint":false},{"year":2018,"finding":"PSMD1 and PSMD2 (components of the 19S proteasome regulatory particle) directly interact with Dictyostelium ATG16, a core autophagosomal protein. Deletion analysis showed the N-terminal half of ATG16 interacted with PSMD1 only, while the C-terminal half interacted with both PSMD1 and PSMD2. ATG16 is required for enrichment of PSMD2 in autophagosomes/autolysosomes, establishing that ATG16 links autophagy to the ubiquitin-proteasome system via direct interaction with 19S subunits.","method":"Yeast two-hybrid, co-immunoprecipitation, fluorescence co-localization, deletion mapping, lysotracker labeling, proteolytic cleavage assay","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple methods (Y2H, Co-IP, co-localization) in Dictyostelium model, direct interaction confirmed","pmids":["30269947"],"is_preprint":false},{"year":2019,"finding":"Asporin (ASPN) promotes gastric cancer cell proliferation by directly interacting with PSMD2. Co-immunoprecipitation showed ASPN and PSMD2 form a complex in gastric cancer cells. Knockdown of ASPN increased expression of DUSP7, WIP1, and PTEN and reduced phosphorylation of ERK, P38, and AKT; these changes were counteracted by PSMD2 knockdown, placing PSMD2 downstream of ASPN in a proliferative signaling cascade.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown of ASPN and PSMD2, western blot for DUSP7/WIP1/PTEN/ERK/p38/AKT","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with epistasis knockdown, single lab study","pmids":["31136974"],"is_preprint":false},{"year":2023,"finding":"RACK1 competes with β-catenin for binding to PSMD2 (a key proteasome component). RACK1 binds PSMD2 and prevents ubiquitinated β-catenin from accessing PSMD2, thereby protecting β-catenin from proteasomal degradation and activating canonical WNT signaling in breast cancer cells. This identifies PSMD2 as a novel binding partner for both RACK1 and β-catenin at the proteasome.","method":"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, in vivo tumor growth assays, western blot","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — competitive Co-IP with in vivo validation, single lab but multiple orthogonal methods","pmids":["37848434"],"is_preprint":false},{"year":2023,"finding":"DNAJA4 facilitates MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Loss of DNAJA4 in nasopharyngeal carcinoma cells impairs MYH9 degradation and promotes EMT and metastasis. This places PSMD2 as the proteasomal docking factor recruited by DNAJA4 for substrate-specific degradation.","method":"Co-immunoprecipitation, overexpression and knockdown experiments, in vivo metastasis assays, ubiquitin-proteasome pathway analysis","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP with functional knockdown, mechanistic link between DNAJA4-PSMD2-MYH9 is indirect","pmids":["37875476"],"is_preprint":false}],"current_model":"PSMD2 (Rpn1) is a non-ATPase subunit of the 19S proteasome base that functions as a multivalent docking platform: its toroid domain contains two distinct ubiquitin-binding sites (T1, recognizing ubiquitin and UBL-domain substrate shuttles with preference for K48-linked chains; T2, binding the UBL of deubiquitinase Ubp6) and its LRR-like domain mediates binding of UBL-domain proteins such as Rad23 and Dsk2; PSMD2 activity and 26S assembly are regulated by reversible PIM kinase-mediated phosphorylation at Ser361 (reversed by UBLCP1), and PSMD2 loss impairs proteasome function, modulates AKT/p38/p21 signaling, and affects lipid metabolism and cell proliferation."},"narrative":{"teleology":[{"year":2002,"claim":"Identifying the proteasomal receptor for UBL-domain shuttle factors resolved how ubiquitinated substrates are delivered to the 26S proteasome, establishing Rpn1 (PSMD2) and its LRR-like domain as the primary docking site for Rad23 and Dsk2.","evidence":"Co-immunoprecipitation, direct binding assays with recombinant proteins, and competition experiments in yeast","pmids":["12198498"],"confidence":"High","gaps":["Structural basis of the LRR-like domain–UBL interaction was not determined","Whether additional ubiquitin-binding sites existed on Rpn1 was unknown"]},{"year":2009,"claim":"Biochemical reconstitution of 19S subcomplexes positioned Rpn1 among the base subunits that collectively bind ubiquitinated substrates and couple docking to unfolding and translocation, clarifying Rpn1's role within the broader regulatory particle architecture.","evidence":"Synthesis of biochemical reconstitution and structural studies across multiple labs","pmids":["19489727"],"confidence":"High","gaps":["Precise ubiquitin-binding surfaces on Rpn1 were not mapped","Mechanism of coordination between Rpn1, Rpn10, and Rpn13 was unresolved"]},{"year":2012,"claim":"Demonstrating that the ubiquitin-like modifier FAT10 and its accelerator NUB1L dock at Rpn1 extended the receptor function of PSMD2 beyond canonical ubiquitin to other UBL modifier systems.","evidence":"Co-IP, yeast complementation, siRNA knockdown, and domain mapping","pmids":["22434192"],"confidence":"Medium","gaps":["Which Rpn1 surface binds NUB1L was not defined","Relative contribution of Rpn1 versus Rpn10 to FAT10-conjugate degradation was not quantified"]},{"year":2016,"claim":"Crystal structures of the Rpn1 toroid domain with monoubiquitin and K48-linked diubiquitin revealed two adjacent binding sites (T1 and T2), establishing Rpn1 as the sixth proteasomal ubiquitin receptor and showing how T1 preferentially engages K48-linked chains while T2 anchors the deubiquitinase Ubp6.","evidence":"X-ray crystallography, mutagenesis, genetic complementation, and in vitro binding in yeast","pmids":["26912900"],"confidence":"High","gaps":["How T1 and T2 coordinate temporally with Rpn10/Rpn13 during substrate processing was not resolved","Human PSMD2 crystal structure was not reported"]},{"year":2017,"claim":"Photoactivatable ubiquitin crosslinking orthogonally confirmed Rpn1 as a bona fide ubiquitin-associating subunit in intact proteasomes, validating prior structural findings with an independent chemical biology approach.","evidence":"Synthetic photoactivatable ubiquitin probes (UbPT) with mass spectrometry","pmids":["28330605"],"confidence":"High","gaps":["Crosslinking did not resolve stoichiometry of ubiquitin occupancy across Rpn1, Rpn10, and Rpn13 simultaneously"]},{"year":2019,"claim":"Identifying PIM kinases as the writers and UBLCP1 as the eraser of Rpn1 Ser361 phosphorylation revealed the first regulatory switch controlling 19S base assembly, showing that phospho-S361 promotes the Rpn1–Rpt2 precursor complex and that its loss impairs proteasome function, proliferation, and mitochondrial health.","evidence":"CRISPR editing of Ser361, kinome screen, genetic code expansion for site-specific phosphorylation, quantitative mass spectrometry, and assembly assays","pmids":["31843888"],"confidence":"High","gaps":["Whether Ser361 phosphorylation status changes during stress or cell-cycle transitions was not examined","Structural mechanism by which phospho-S361 favors Rpt2 binding is unknown"]},{"year":2011,"claim":"PSMD2 knockdown in lung cancer cells linked proteasome function to AKT/p38/p21 signaling and cell survival, providing the first evidence that PSMD2 loss triggers apoptosis through specific signaling pathways rather than generic proteotoxicity alone.","evidence":"siRNA knockdown, proteasome activity assays, western blot for pAKT/p38/p21, and apoptosis assays in human lung cancer lines","pmids":["21465578"],"confidence":"Medium","gaps":["Whether signaling changes are direct or secondary to proteasome impairment was not distinguished","Not replicated in non-cancer cell types"]},{"year":2019,"claim":"Extending the cancer-cell phenotype, PSMD2 and PSMD1 knockdown in hepatoma cells reduced lipid droplet accumulation and de novo lipogenesis gene expression via p38-JNK and AKT pathways, linking proteasomal subunit levels to metabolic reprogramming.","evidence":"siRNA knockdown, lipid droplet staining, and MAPK/AKT pathway western blots in HepG2 cells","pmids":["31703613"],"confidence":"Medium","gaps":["Whether lipid metabolism effects are PSMD2-specific or reflect general proteasome inhibition is unclear","In vivo metabolic phenotype not assessed"]},{"year":2018,"claim":"Direct interaction between ATG16 and PSMD2 in Dictyostelium connected the proteasome to autophagy machinery, showing ATG16 is required for PSMD2 enrichment in autophagosomes/autolysosomes.","evidence":"Yeast two-hybrid, Co-IP, fluorescence co-localization, and deletion mapping in Dictyostelium","pmids":["30269947"],"confidence":"Medium","gaps":["Conservation of ATG16–PSMD2 interaction in mammalian cells was not demonstrated","Functional consequence for proteasome activity within autolysosomes is unknown"]},{"year":2023,"claim":"Two studies expanded PSMD2's interactome in cancer contexts: RACK1 competes with β-catenin for PSMD2 binding to protect β-catenin from degradation and activate WNT signaling, while DNAJA4 recruits PSMD2 for substrate-specific MYH9 degradation, illustrating PSMD2 as a regulatable access point for proteasomal substrates.","evidence":"Co-IP, competitive binding assays, siRNA knockdown, and in vivo tumor models in breast and nasopharyngeal carcinoma cells","pmids":["37848434","37875476"],"confidence":"Medium","gaps":["RACK1–PSMD2 interaction surface is unmapped","DNAJA4–PSMD2 link relies on single Co-IP without reciprocal validation","Whether these interactions occur at the intact 26S proteasome or free PSMD2 is not resolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis of human PSMD2's T1/T2 sites, how Ser361 phosphorylation dynamics integrate with cellular stress responses, and whether PSMD2 functions outside the 26S holoenzyme context (e.g., in autophagy-linked roles or as a free subunit with signaling activity).","evidence":"","pmids":[],"confidence":"High","gaps":["No human PSMD2 crystal structure exists","In vivo genetic models (knockout mouse) have not been reported","Relative contributions of T1 versus Rpn10/Rpn13 to substrate degradation in intact cells are unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,3,4,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]}],"complexes":["26S proteasome","19S regulatory particle"],"partners":["RAD23B","UBQLN1","PSMD1","RACK1","ASPN","DNAJA4","PIM1","UBLCP1"],"other_free_text":[]},"mechanistic_narrative":"PSMD2 (Rpn1) is a non-ATPase subunit of the 19S proteasome regulatory particle that serves as a multivalent ubiquitin-receptor and substrate-docking platform essential for proteasomal proteolysis. Its toroid domain contains two ubiquitin-binding sites: T1, which recognizes K48-linked polyubiquitin chains and UBL domains of substrate-shuttling factors (Rad23, Dsk2, Ubiquilin), and T2, which anchors the deubiquitinase Ubp6, while its LRR-like domain independently docks UBL-domain shuttles [PMID:12198498, PMID:26912900, PMID:28330605]. PIM1/2/3-mediated phosphorylation of Ser361 promotes the earliest step of 19S base assembly (Rpn1–Rpt2 precursor formation), with the proteasome-resident phosphatase UBLCP1 providing reversible control; loss of this phosphorylation impairs proteasome activity, cell proliferation, and mitochondrial integrity [PMID:31843888]. PSMD2 depletion reduces proteasome activity and triggers apoptosis associated with altered AKT/p38/p21 signaling and decreased lipid droplet accumulation [PMID:21465578, PMID:31703613]."},"prefetch_data":{"uniprot":{"accession":"Q13200","full_name":"26S proteasome non-ATPase regulatory subunit 2","aliases":["26S proteasome regulatory subunit RPN1","26S proteasome regulatory subunit S2","26S proteasome subunit p97","Protein 55.11","Tumor necrosis factor type 1 receptor-associated protein 2"],"length_aa":908,"mass_kda":100.2,"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 Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q13200/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PSMD2","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000175166","cell_line_id":"CID000105","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"PSMA1","stoichiometry":10.0},{"gene":"PSMA2","stoichiometry":10.0},{"gene":"PSMA3","stoichiometry":10.0},{"gene":"PSMA4","stoichiometry":10.0},{"gene":"PSMB1","stoichiometry":10.0},{"gene":"PSMB2","stoichiometry":10.0},{"gene":"PSMB3","stoichiometry":10.0},{"gene":"PSMB4","stoichiometry":10.0},{"gene":"PSMB5","stoichiometry":10.0},{"gene":"PSMB7","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000105","total_profiled":1310},"omim":[{"mim_id":"617676","title":"PROTEASOME 26S SUBUNIT, NON-ATPase, 3; PSMD3","url":"https://www.omim.org/entry/617676"},{"mim_id":"614454","title":"UBIQUITIN PROTEIN LIGASE E3C; UBE3C","url":"https://www.omim.org/entry/614454"},{"mim_id":"606223","title":"PROTEASOME 26S SUBUNIT, NON-ATPASE, 2; PSMD2","url":"https://www.omim.org/entry/606223"},{"mim_id":"602422","title":"STEM-LOOP BINDING PROTEIN; SLBP","url":"https://www.omim.org/entry/602422"},{"mim_id":"601623","title":"UBIQUITIN-PROTEIN LIGASE E3A; UBE3A","url":"https://www.omim.org/entry/601623"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Flagellar centriole","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":300.1}],"url":"https://www.proteinatlas.org/search/PSMD2"},"hgnc":{"alias_symbol":["S2","P97","TRAP2","MGC14274","Rpn1"],"prev_symbol":[]},"alphafold":{"accession":"Q13200","domains":[{"cath_id":"-","chopping":"829-901","consensus_level":"high","plddt":63.9319,"start":829,"end":901}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13200","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13200-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13200-F1-predicted_aligned_error_v6.png","plddt_mean":65.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSMD2","jax_strain_url":"https://www.jax.org/strain/search?query=PSMD2"},"sequence":{"accession":"Q13200","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13200.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13200/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13200"}},"corpus_meta":[{"pmid":"25146396","id":"PMC_25146396","title":"The VCP/p97 system 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transcripts.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808466","citation_count":1236,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26777405","id":"PMC_26777405","title":"ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26777405","citation_count":1233,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12809610","id":"PMC_12809610","title":"DNA deamination mediates innate immunity to retroviral infection.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12809610","citation_count":1150,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14564014","id":"PMC_14564014","title":"Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/14564014","citation_count":1006,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12808465","id":"PMC_12808465","title":"The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12808465","citation_count":912,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23503661","id":"PMC_23503661","title":"Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23503661","citation_count":870,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14743216","id":"PMC_14743216","title":"A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14743216","citation_count":841,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528300","id":"PMC_14528300","title":"The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528300","citation_count":798,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12859895","id":"PMC_12859895","title":"Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859895","citation_count":763,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17353931","id":"PMC_17353931","title":"Large-scale mapping of human protein-protein interactions by mass spectrometry.","date":"2007","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/17353931","citation_count":733,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14528301","id":"PMC_14528301","title":"HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14528301","citation_count":679,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41039,"output_tokens":2737,"usd":0.082086},"stage2":{"model":"claude-opus-4-6","input_tokens":6086,"output_tokens":2632,"usd":0.144345},"total_usd":0.502203,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":52248,"output_tokens":4728,"usd":0.113832},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7037,"output_tokens":2911,"usd":0.16194}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"The yeast proteasome base subunit Rpn1 (ortholog of human PSMD2) directly binds the ubiquitin-like (UBL) domain of Rad23 and Dsk2 through its leucine-rich-repeat-like (LRR-like) domain, positioning these cargo-carrying shuttle factors at the base of the 19S regulatory particle to deliver ubiquitinated substrates to proteasomal ATPases for unfolding.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, genetic epistasis in yeast\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays with domain mapping, replicated with two UBL proteins, foundational study with >370 citations\",\n      \"pmids\": [\"12198498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Yeast Rpn1 (ortholog of human PSMD2) contains two distinct sites within its toroid domain: site T1, which directly recognizes ubiquitin and UBL domains of substrate shuttling factors with preference for K48-linked chains, and site T2, which binds the UBL of deubiquitinating enzyme Ubp6 to assist ubiquitin chain disassembly.\",\n      \"method\": \"Crystal structure determination, in vitro binding assays, photoactivatable crosslinking, genetic analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures of T1 site with monoubiquitin and K48-diubiquitin combined with functional binding assays\",\n      \"pmids\": [\"26912900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rpn1 (human PSMD2 ortholog) was identified as a sixth proteasomal ubiquitin receptor using polyubiquitin-photoactivatable crosslinking reagents (UbPT), establishing that it coordinates docking of substrate shuttles, unloading of substrates, and anchoring of polyubiquitin conjugates at the proteasome.\",\n      \"method\": \"Photoactivatable crosslinking (UbPT reagents), mass spectrometry, synthetic ubiquitin chains\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — synthetic crosslinking reagents with defined chain linkages and lengths, mass spectrometry identification\",\n      \"pmids\": [\"28330605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FAT10 and NUB1L both bind to the VWA domain of Rpn1/S2 (human PSMD2) at the 26S proteasome; NUB1L can bind both Rpn10 and Rpn1/S2, enabling FAT10-mediated ubiquitin-independent proteolysis.\",\n      \"method\": \"Co-immunoprecipitation, yeast complementation assays, siRNA knockdown with proteasome activity readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping (VWA domain), functional yeast complementation, and human cell depletion experiments\",\n      \"pmids\": [\"22434192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphorylation of Ser361 on Rpn1 (human PSMD2) by PIM1/2/3 kinases, and dephosphorylation by the proteasome-resident phosphatase UBLCP1, regulates 26S proteasome assembly; loss of this phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress by impairing a precursor complex with Rpt2 during 19S base assembly.\",\n      \"method\": \"CRISPR/Cas9 gene editing, quantitative mass spectrometry, kinome screen, genetic code expansion for site-specific phosphorylation, proteasome activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including CRISPR editing, kinome screen, and direct phosphorylation incorporation via genetic code expansion\",\n      \"pmids\": [\"31843888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Knockdown of PSMD2 (a non-ATPase subunit of the 19S regulatory complex) in lung cancer cell lines decreases proteasome activity and induces growth inhibition and apoptosis, associated with changes in the balance between phosphorylated AKT and p38, and induction of p21.\",\n      \"method\": \"siRNA knockdown, proteasome activity assay, western blot for AKT/p38/p21\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined proteasome activity readout and signaling pathway changes, but single lab\",\n      \"pmids\": [\"21465578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD1 and PSMD2 promote HepG2 cell proliferation by modulating cellular lipid droplet formation; knockdown of PSMD1 and/or PSMD2 decreases lipid droplet formation and regulates de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.\",\n      \"method\": \"siRNA knockdown, lipid droplet quantification, western blot for signaling molecules\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic pathway placement via western blotting with defined phenotypic readout\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Dictyostelium, PSMD2 (19S regulatory particle subunit) directly interacts with ATG16 (autophagosomal protein); the C-terminal half of ATG16 binds PSMD2, and ATG16 is required for enrichment of PSMD2-positive puncta in autophagosomes, establishing a link between the ubiquitin-proteasome system and autophagic degradation of proteasomal subunits.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, fluorescence microscopy, LysoTracker labeling, proteolytic cleavage assay\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding mapped by deletion analysis, co-localization confirmed by multiple methods, but in Dictyostelium model\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ASPN (asporin) directly interacts with PSMD2 by co-immunoprecipitation and co-localization in gastric cancer cells; ASPN promotes cell proliferation through PSMD2, which regulates proliferation by suppressing DUSP7, WIP1, and PTEN and inducing phosphorylation of ERK, P38, and AKT.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown rescue experiments\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single Co-IP with partial pathway follow-up\",\n      \"pmids\": [\"31136974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RACK1 binds PSMD2 competitively with β-catenin, preventing ubiquitinated β-catenin from binding PSMD2 and thereby protecting β-catenin from proteasomal degradation; this establishes PSMD2 as the proteasomal receptor that captures ubiquitinated β-catenin for degradation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, western blot for β-catenin stability\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — competitive binding with defined mechanistic outcome (β-catenin stabilization), single lab but multiple methods\",\n      \"pmids\": [\"37848434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJA4 facilitates MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2; the DNAJA4-PSMD2-MYH9 axis suppresses epithelial-mesenchymal transition and metastasis in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown with phenotypic readout (migration, invasion, EMT markers), in vivo metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional rescue experiments, single lab\",\n      \"pmids\": [\"37875476\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD2 (Rpn1/S2) is a non-ATPase base subunit of the 19S proteasome regulatory particle that contains at least two distinct ubiquitin-binding sites within its toroid/LRR-like domain: a T1 site that directly recognizes ubiquitin and UBL domains of substrate-shuttling factors (Rad23, Dsk2) with preference for K48-linked chains, and a T2 site that binds the UBL of the deubiquitinase Ubp6 to facilitate ubiquitin chain disassembly; additionally, its VWA domain serves as a receptor for ubiquitin-like modifiers FAT10 and NUB1L, and its Ser361 phosphorylation by PIM kinases (reversed by UBLCP1) is required for proper 26S proteasome assembly and activity, while it also interacts with binding partners such as RACK1, ASPN, and DNAJA4 that modulate proteasomal substrate access.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe query gene is PSMD2 — the 26S proteasome non-ATPase regulatory subunit 2 (also called Rpn1 in yeast, or S2/p97 in some older nomenclatures).\n\n**CRITICAL NOTE:** Many papers in this corpus describe VCP/p97 (valosin-containing protein), which is a completely different protein from PSMD2/Rpn1. VCP/p97 is an AAA+ ATPase chaperone. PSMD2/Rpn1 is a non-ATPase subunit of the 19S regulatory particle of the 26S proteasome. These are distinct proteins. The \"p97\" alias in some papers refers to VCP, not PSMD2.\n\n**Papers about PSMD2/Rpn1 (KEEP):**\n- [2] PMID:12198498 — Rpn1 binds UBL domains → KEEP\n- [4] PMID:26912900 — Rpn1 ubiquitin receptor sites T1 and T2 → KEEP\n- [27] PMID:22434192 — NUB1L binds Rpn1/S2 → KEEP (mentions Rpn1/S2 = PSMD2)\n- [41] PMID:21465578 — PSMD2 knockdown, proteasome activity → KEEP\n- [45] PMID:31843888 — Rpn1 Ser361 phosphorylation → KEEP\n- [52] PMID:31703613 — PSMD1 and PSMD2 in HepG2 → KEEP\n- [54] PMID:28330605 — Rpn1 as proteasome ubiquitin-associating subunit → KEEP\n- [58] PMID:31136974 — ASPN interacts with PSMD2 → KEEP\n- [74] PMID:22886548 — SCC-S2 (PSMD2) in colon cancer → KEEP\n- [79] PMID:30269947 — ATG16 interacts with PSMD2 → KEEP\n- [82] PMID:37848434 — RACK1/PSMD2/β-catenin → KEEP\n- [98] PMID:37875476 — DNAJA4-PSMD2-MYH9 → KEEP\n- [8] additional: PMID:8811196 — 26S proteasome structure, mentions 19S subunits → KEEP (foundational)\n- [10] additional: PMID:19489727 — proteasome recognition, Rpn1 context → KEEP\n\n**Papers about VCP/p97 (different protein — EXCLUDE as alias collision):**\nPapers [1],[3],[5],[6],[7],[8],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19 is NAT1/DAP5 different],[20],[21],[22],[23],[24],[25],[26],[28],[29],[30],[31],[32],[34],[35],[36],[37],[39],[40],[42],[43],[44],[46],[47],[48],[49],[50],[51],[53],[55],[56],[57],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[70],[71],[73],[75],[76],[77],[78],[80],[81],[83],[84],[85],[86],[87],[88],[89],[90],[91],[92],[93],[94],[95],[96],[97],[99] → EXCLUDE (VCP/p97, not PSMD2)\n\n**Other exclusions:**\n- [9] Drosophila aneuploidy expression → EXCLUDE\n- [11] Ketanserin/serotonin → EXCLUDE (S2 receptor, not PSMD2)\n- [25] Loxapine/clozapine/serotonin → EXCLUDE\n- [19] NAT1/p97/DAP5 (eIF4G homolog) → EXCLUDE (alias collision)\n- [33] Mycoplasma P97 adhesin → EXCLUDE (symbol collision, bacterial protein)\n- [38] Mycoplasma P97 gene → EXCLUDE (symbol collision)\n- [47] Melanotransferrin p97 → EXCLUDE (different protein, melanoma antigen)\n- [69] RPN1/EVI1 fusion in leukemia → EXCLUDE (RPN1 here is ribophorin I, not PSMD2/Rpn1 proteasome)\n- [72] RPN1 reference gene → EXCLUDE (RPN1 here is ribophorin I)\n- [100] RPS2/MDM2 — ribosomal protein S2, not PSMD2 → EXCLUDE\n\n**Additional gene2pubmed papers:**\n- PMID:17081983 — phosphoproteomics, PSMD2 detected → borderline, expression/PTM catalog\n- PMID:8811196 — 26S proteasome structure → KEEP (foundational, describes 19S subunit composition)\n- PMID:19489727 — proteasome recognition/Rpn1 → KEEP\n- Others (APOBEC3G, interactome maps, etc.) → EXCLUDE or no specific mechanistic finding about PSMD2\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Yeast Rpn1 (ortholog of human PSMD2), a subunit of the 19S proteasome base, directly binds the ubiquitin-like (UBL) domains of Rad23 and Dsk2 through its leucine-rich-repeat-like (LRR-like) domain. Rad23 and Dsk2 compete for the same Rpn1 binding site, identifying Rpn1 as the primary docking site for UBL-domain substrate-shuttling factors at the proteasome.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays with recombinant proteins, yeast genetic analysis, competition binding experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and direct in vitro binding with multiple UBL proteins, replicated with competition experiments\",\n      \"pmids\": [\"12198498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recognition and processing of ubiquitin-protein conjugates by the proteasome involves Rpn1 (PSMD2) as part of the 19S regulatory particle base, where it participates in substrate docking alongside the ATPase ring. The 19S regulatory particle's non-ATPase subunits including Rpn1 are essential for binding ubiquitinated substrates and initiating their unfolding and translocation into the 20S core.\",\n      \"method\": \"Biochemical reconstitution of proteasome subcomplexes, structural and functional analysis reviewed across multiple studies\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — foundational review synthesizing extensive biochemical reconstitution and structural data on 19S subunit functions\",\n      \"pmids\": [\"19489727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FAT10 (a ubiquitin-like modifier) and its accelerator NUB1L both interact with the 26S proteasome via Rpn1 (PSMD2/S2). NUB1L can bind to both Rpn10 and Rpn1, and depletion of Rpn10 causes accumulation of FAT10-conjugates, while Rpn1 serves as an additional docking site for NUB1L to initiate FAT10-mediated proteasomal proteolysis.\",\n      \"method\": \"Co-immunoprecipitation, yeast complementation assays, siRNA knockdown, binding domain mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping and functional knockdown, single study\",\n      \"pmids\": [\"22434192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rpn1 (PSMD2 ortholog) contains two adjacent ubiquitin-binding sites within its toroid domain: site T1, which recognizes monoubiquitin, K48-linked diubiquitin, and UBL domains of substrate-shuttling factors (Rad23, Dsk2, Ubiquilin) with preference for K48-linked chains; and site T2, which binds the UBL domain of the deubiquitinase Ubp6 to facilitate ubiquitin chain disassembly. Crystal structures of T1 with monoubiquitin or K48 diubiquitin reveal three neighboring outer helices engaging two ubiquitin moieties. Rpn1 constitutes the sixth proteasomal ubiquitin receptor and its T1 site defines a distinct substrate-binding pathway.\",\n      \"method\": \"X-ray crystallography of T1–ubiquitin complexes, genetic complementation, in vitro binding assays, biochemical ubiquitin receptor identification by mutagenesis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation by mutagenesis and genetic epistasis, comprehensive mechanistic study\",\n      \"pmids\": [\"26912900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Photoactivatable crosslinking with ubiquitin variants (UbPT) confirmed Rpn1 (PSMD2) as a third proteasome ubiquitin-associating subunit (alongside Rpn10 and Rpn13), demonstrating that Rpn1 coordinates docking of substrate shuttles, substrate unloading, and anchoring of polyubiquitin conjugates at the proteasome.\",\n      \"method\": \"Synthetic photoactivatable ubiquitin crosslinking reagents (UbPT), mass spectrometry, proteasome biochemistry\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — novel chemical crosslinking tool with MS identification, orthogonal to prior structural work, validates Rpn1 ubiquitin receptor function\",\n      \"pmids\": [\"28330605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated knockdown of PSMD2 in lung cancer cell lines decreased proteasome activity and induced growth inhibition and apoptosis. These effects were associated with changes in the balance between phosphorylated AKT and p38, as well as induction of p21, placing PSMD2 upstream of AKT/p38 signaling in cancer cell survival.\",\n      \"method\": \"siRNA knockdown, proteasome activity assays, western blot for pAKT, p38, p21, cell viability and apoptosis assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — clean loss-of-function with defined molecular readouts, single lab study\",\n      \"pmids\": [\"21465578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Reversible phosphorylation of Rpn1 (PSMD2 ortholog) at Ser361 regulates 26S proteasome assembly and function. Loss of Ser361 phosphorylation reduces proteasome activity, impairs cell proliferation, and causes oxidative stress and mitochondrial dysfunction. PIM1/2/3 kinases catalyze this phosphorylation, while the proteasome-resident phosphatase UBLCP1 reverses it. Mechanistically, phospho-S361 Rpn1 more readily forms a precursor complex with Rpt2, representing one of the first steps of 19S base assembly.\",\n      \"method\": \"CRISPR/Cas9 gene editing of Ser361, quantitative mass spectrometry, kinome screen, genetic code expansion for site-specific phosphorylation, 26S proteasome assembly assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including CRISPR editing, genetic code expansion, kinome screen, and biochemical assembly assays in one study\",\n      \"pmids\": [\"31843888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMD1 and PSMD2 (19S regulatory particle subunits) promote HepG2 cell proliferation by facilitating cellular lipid droplet accumulation. Knockdown of PSMD1 and/or PSMD2 decreases lipid droplet formation and reduces expression of de novo lipid synthesis genes via p38-JNK and AKT signaling pathways.\",\n      \"method\": \"siRNA knockdown, lipid droplet staining, western blot for lipid synthesis regulators, AKT and MAPK pathway analysis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — knockdown with pathway readouts, single lab, mechanistic pathway placement but indirect\",\n      \"pmids\": [\"31703613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PSMD1 and PSMD2 (components of the 19S proteasome regulatory particle) directly interact with Dictyostelium ATG16, a core autophagosomal protein. Deletion analysis showed the N-terminal half of ATG16 interacted with PSMD1 only, while the C-terminal half interacted with both PSMD1 and PSMD2. ATG16 is required for enrichment of PSMD2 in autophagosomes/autolysosomes, establishing that ATG16 links autophagy to the ubiquitin-proteasome system via direct interaction with 19S subunits.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, fluorescence co-localization, deletion mapping, lysotracker labeling, proteolytic cleavage assay\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple methods (Y2H, Co-IP, co-localization) in Dictyostelium model, direct interaction confirmed\",\n      \"pmids\": [\"30269947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Asporin (ASPN) promotes gastric cancer cell proliferation by directly interacting with PSMD2. Co-immunoprecipitation showed ASPN and PSMD2 form a complex in gastric cancer cells. Knockdown of ASPN increased expression of DUSP7, WIP1, and PTEN and reduced phosphorylation of ERK, P38, and AKT; these changes were counteracted by PSMD2 knockdown, placing PSMD2 downstream of ASPN in a proliferative signaling cascade.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown of ASPN and PSMD2, western blot for DUSP7/WIP1/PTEN/ERK/p38/AKT\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with epistasis knockdown, single lab study\",\n      \"pmids\": [\"31136974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RACK1 competes with β-catenin for binding to PSMD2 (a key proteasome component). RACK1 binds PSMD2 and prevents ubiquitinated β-catenin from accessing PSMD2, thereby protecting β-catenin from proteasomal degradation and activating canonical WNT signaling in breast cancer cells. This identifies PSMD2 as a novel binding partner for both RACK1 and β-catenin at the proteasome.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, in vivo tumor growth assays, western blot\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — competitive Co-IP with in vivo validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37848434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJA4 facilitates MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Loss of DNAJA4 in nasopharyngeal carcinoma cells impairs MYH9 degradation and promotes EMT and metastasis. This places PSMD2 as the proteasomal docking factor recruited by DNAJA4 for substrate-specific degradation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown experiments, in vivo metastasis assays, ubiquitin-proteasome pathway analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP with functional knockdown, mechanistic link between DNAJA4-PSMD2-MYH9 is indirect\",\n      \"pmids\": [\"37875476\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMD2 (Rpn1) is a non-ATPase subunit of the 19S proteasome base that functions as a multivalent docking platform: its toroid domain contains two distinct ubiquitin-binding sites (T1, recognizing ubiquitin and UBL-domain substrate shuttles with preference for K48-linked chains; T2, binding the UBL of deubiquitinase Ubp6) and its LRR-like domain mediates binding of UBL-domain proteins such as Rad23 and Dsk2; PSMD2 activity and 26S assembly are regulated by reversible PIM kinase-mediated phosphorylation at Ser361 (reversed by UBLCP1), and PSMD2 loss impairs proteasome function, modulates AKT/p38/p21 signaling, and affects lipid metabolism and cell proliferation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSMD2 (Rpn1/S2) is a non-ATPase subunit of the 19S proteasome regulatory particle that functions as a principal ubiquitin receptor coordinating substrate delivery, ubiquitin chain recognition, and deubiquitination at the proteasome. Its toroid/LRR-like domain contains two functionally distinct sites: a T1 site that directly binds ubiquitin (preferring K48-linked chains) and UBL domains of substrate-shuttling factors Rad23 and Dsk2, and a T2 site that anchors the deubiquitinase Ubp6 to facilitate ubiquitin chain disassembly [PMID:12198498, PMID:26912900, PMID:28330605]. Its VWA domain serves as a receptor for the ubiquitin-like modifier FAT10 and its adaptor NUB1L, enabling ubiquitin-independent proteasomal targeting [PMID:22434192]. Phosphorylation of Ser361 by PIM kinases, reversed by phosphatase UBLCP1, is required for proper 26S proteasome assembly and activity by stabilizing a precursor complex with Rpt2 during 19S base biogenesis [PMID:31843888].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing PSMD2/Rpn1 as a docking platform for ubiquitin-shuttle factors resolved how polyubiquitinated substrates are delivered to the proteasome base, revealing that Rpn1's LRR-like domain directly engages the UBL domains of Rad23 and Dsk2.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown assays, and genetic epistasis in yeast\",\n      \"pmids\": [\"12198498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Rpn1 itself directly contacts ubiquitin chains rather than only UBL domains was unknown\",\n        \"Structural basis of the UBL-Rpn1 interaction was unresolved\",\n        \"Whether additional binding sites exist on Rpn1 was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that PSMD2 knockdown impairs proteasome activity and triggers apoptosis in cancer cells linked this subunit's structural role to functional necessity for cell survival and proliferative signaling through AKT and p21.\",\n      \"evidence\": \"siRNA knockdown with proteasome activity assays and western blotting in lung cancer cell lines\",\n      \"pmids\": [\"21465578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotype could reflect global 19S disassembly rather than a PSMD2-specific function\",\n        \"No rescue experiment to confirm specificity\",\n        \"Pathway changes (AKT, p38) not distinguished from general proteotoxic stress\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of PSMD2's VWA domain as the receptor for the ubiquitin-like modifier FAT10 and its adaptor NUB1L established a ubiquitin-independent route to proteasomal degradation through a distinct domain from the ubiquitin/UBL-binding region.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, VWA domain mapping, yeast complementation, and siRNA knockdown in human cells\",\n      \"pmids\": [\"22434192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of FAT10/NUB1L–VWA interaction not determined\",\n        \"Relative contribution of VWA vs. Rpn10-mediated routes for FAT10 substrates unclear\",\n        \"Whether other UBL modifiers use the VWA domain was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystallographic resolution of two distinct binding sites (T1 and T2) within Rpn1's toroid domain answered how a single subunit simultaneously coordinates ubiquitin/UBL recognition (T1, preferring K48-linked chains) and deubiquitinase anchoring (T2, binding Ubp6's UBL).\",\n      \"evidence\": \"Crystal structures of Rpn1 T1 site with monoubiquitin and K48-diubiquitin, photoactivatable crosslinking, in vitro binding, and genetic analysis in yeast\",\n      \"pmids\": [\"26912900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether T1 and T2 are simultaneously occupied in vivo was not demonstrated\",\n        \"Quantitative contribution of Rpn1 vs. Rpn10/Rpn13 ubiquitin receptors to overall degradation rates unknown\",\n        \"Structural details of T2-Ubp6 interaction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Synthetic polyubiquitin crosslinking reagents confirmed Rpn1 as a bona fide sixth proteasomal ubiquitin receptor, establishing that it coordinates substrate shuttle docking, substrate unloading, and direct polyubiquitin chain anchoring.\",\n      \"evidence\": \"Polyubiquitin-photoactivatable crosslinking (UbPT) reagents with mass spectrometry identification\",\n      \"pmids\": [\"28330605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo crosslinking not performed\",\n        \"Relative affinity ranking among all six receptors for different chain types not established\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that PSMD2 directly interacts with the autophagosomal protein ATG16 in Dictyostelium revealed a physical link between the proteasome and the autophagy machinery, suggesting autophagic turnover of proteasomal subunits (proteaphagy).\",\n      \"evidence\": \"Co-immunoprecipitation, deletion mapping, fluorescence microscopy, and LysoTracker labeling in Dictyostelium\",\n      \"pmids\": [\"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction not confirmed in mammalian cells\",\n        \"Whether this reflects regulated proteaphagy or bulk autophagy not distinguished\",\n        \"Functional consequence of disrupting ATG16-PSMD2 interaction on proteasome homeostasis not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of Ser361 phosphorylation by PIM kinases and dephosphorylation by UBLCP1 as a regulatory switch for 26S assembly resolved how proteasome biogenesis is dynamically controlled, showing that this modification stabilizes an Rpn1-Rpt2 precursor complex essential for 19S base formation.\",\n      \"evidence\": \"CRISPR/Cas9 editing, kinome screen, genetic code expansion for site-specific phosphorylation, quantitative mass spectrometry, and proteasome activity assays in human cells\",\n      \"pmids\": [\"31843888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PIM-dependent phosphorylation is regulated in response to proteotoxic stress\",\n        \"Structural mechanism by which pSer361 stabilizes the Rpn1-Rpt2 intermediate unknown\",\n        \"Whether other proteasome subunit phosphorylation events cooperate with Ser361 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Competitive binding studies showed that RACK1 binds PSMD2 and prevents ubiquitinated β-catenin from engaging the proteasome, establishing PSMD2 as the specific proteasomal receptor mediating β-catenin degradation and revealing a substrate-access gating mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, competitive binding assays, siRNA knockdown, and β-catenin stability measurements\",\n      \"pmids\": [\"37848434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RACK1-PSMD2 competition extends to other proteasomal substrates unknown\",\n        \"Binding site on PSMD2 for β-catenin/RACK1 not mapped to a specific domain\",\n        \"No structural data on the competitive binding mechanism\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how the multiple binding sites on PSMD2 (T1, T2, VWA, and additional partner interfaces) are coordinately regulated in vivo, the quantitative contribution of PSMD2 relative to other proteasomal ubiquitin receptors to overall proteolysis, and whether PSMD2-interacting partners such as RACK1 represent a general substrate-gating mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vivo single-molecule or real-time measurement of substrate flux through PSMD2\",\n        \"Structural model of full-length human PSMD2 with simultaneous T1, T2, and VWA occupancy not available\",\n        \"Systematic identification of substrates that depend specifically on PSMD2 for degradation lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"26S proteasome (19S regulatory particle)\"\n    ],\n    \"partners\": [\n      \"RAD23B\",\n      \"UBQLN2\",\n      \"USP14\",\n      \"FAT10\",\n      \"NUB1L\",\n      \"RACK1\",\n      \"ATG16\",\n      \"PIM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PSMD2 (Rpn1) is a non-ATPase subunit of the 19S proteasome regulatory particle that serves as a multivalent ubiquitin-receptor and substrate-docking platform essential for proteasomal proteolysis. Its toroid domain contains two ubiquitin-binding sites: T1, which recognizes K48-linked polyubiquitin chains and UBL domains of substrate-shuttling factors (Rad23, Dsk2, Ubiquilin), and T2, which anchors the deubiquitinase Ubp6, while its LRR-like domain independently docks UBL-domain shuttles [PMID:12198498, PMID:26912900, PMID:28330605]. PIM1/2/3-mediated phosphorylation of Ser361 promotes the earliest step of 19S base assembly (Rpn1–Rpt2 precursor formation), with the proteasome-resident phosphatase UBLCP1 providing reversible control; loss of this phosphorylation impairs proteasome activity, cell proliferation, and mitochondrial integrity [PMID:31843888]. PSMD2 depletion reduces proteasome activity and triggers apoptosis associated with altered AKT/p38/p21 signaling and decreased lipid droplet accumulation [PMID:21465578, PMID:31703613].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying the proteasomal receptor for UBL-domain shuttle factors resolved how ubiquitinated substrates are delivered to the 26S proteasome, establishing Rpn1 (PSMD2) and its LRR-like domain as the primary docking site for Rad23 and Dsk2.\",\n      \"evidence\": \"Co-immunoprecipitation, direct binding assays with recombinant proteins, and competition experiments in yeast\",\n      \"pmids\": [\"12198498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the LRR-like domain–UBL interaction was not determined\",\n        \"Whether additional ubiquitin-binding sites existed on Rpn1 was unknown\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Biochemical reconstitution of 19S subcomplexes positioned Rpn1 among the base subunits that collectively bind ubiquitinated substrates and couple docking to unfolding and translocation, clarifying Rpn1's role within the broader regulatory particle architecture.\",\n      \"evidence\": \"Synthesis of biochemical reconstitution and structural studies across multiple labs\",\n      \"pmids\": [\"19489727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise ubiquitin-binding surfaces on Rpn1 were not mapped\",\n        \"Mechanism of coordination between Rpn1, Rpn10, and Rpn13 was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that the ubiquitin-like modifier FAT10 and its accelerator NUB1L dock at Rpn1 extended the receptor function of PSMD2 beyond canonical ubiquitin to other UBL modifier systems.\",\n      \"evidence\": \"Co-IP, yeast complementation, siRNA knockdown, and domain mapping\",\n      \"pmids\": [\"22434192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which Rpn1 surface binds NUB1L was not defined\",\n        \"Relative contribution of Rpn1 versus Rpn10 to FAT10-conjugate degradation was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structures of the Rpn1 toroid domain with monoubiquitin and K48-linked diubiquitin revealed two adjacent binding sites (T1 and T2), establishing Rpn1 as the sixth proteasomal ubiquitin receptor and showing how T1 preferentially engages K48-linked chains while T2 anchors the deubiquitinase Ubp6.\",\n      \"evidence\": \"X-ray crystallography, mutagenesis, genetic complementation, and in vitro binding in yeast\",\n      \"pmids\": [\"26912900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How T1 and T2 coordinate temporally with Rpn10/Rpn13 during substrate processing was not resolved\",\n        \"Human PSMD2 crystal structure was not reported\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Photoactivatable ubiquitin crosslinking orthogonally confirmed Rpn1 as a bona fide ubiquitin-associating subunit in intact proteasomes, validating prior structural findings with an independent chemical biology approach.\",\n      \"evidence\": \"Synthetic photoactivatable ubiquitin probes (UbPT) with mass spectrometry\",\n      \"pmids\": [\"28330605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crosslinking did not resolve stoichiometry of ubiquitin occupancy across Rpn1, Rpn10, and Rpn13 simultaneously\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying PIM kinases as the writers and UBLCP1 as the eraser of Rpn1 Ser361 phosphorylation revealed the first regulatory switch controlling 19S base assembly, showing that phospho-S361 promotes the Rpn1–Rpt2 precursor complex and that its loss impairs proteasome function, proliferation, and mitochondrial health.\",\n      \"evidence\": \"CRISPR editing of Ser361, kinome screen, genetic code expansion for site-specific phosphorylation, quantitative mass spectrometry, and assembly assays\",\n      \"pmids\": [\"31843888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Ser361 phosphorylation status changes during stress or cell-cycle transitions was not examined\",\n        \"Structural mechanism by which phospho-S361 favors Rpt2 binding is unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"PSMD2 knockdown in lung cancer cells linked proteasome function to AKT/p38/p21 signaling and cell survival, providing the first evidence that PSMD2 loss triggers apoptosis through specific signaling pathways rather than generic proteotoxicity alone.\",\n      \"evidence\": \"siRNA knockdown, proteasome activity assays, western blot for pAKT/p38/p21, and apoptosis assays in human lung cancer lines\",\n      \"pmids\": [\"21465578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether signaling changes are direct or secondary to proteasome impairment was not distinguished\",\n        \"Not replicated in non-cancer cell types\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extending the cancer-cell phenotype, PSMD2 and PSMD1 knockdown in hepatoma cells reduced lipid droplet accumulation and de novo lipogenesis gene expression via p38-JNK and AKT pathways, linking proteasomal subunit levels to metabolic reprogramming.\",\n      \"evidence\": \"siRNA knockdown, lipid droplet staining, and MAPK/AKT pathway western blots in HepG2 cells\",\n      \"pmids\": [\"31703613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether lipid metabolism effects are PSMD2-specific or reflect general proteasome inhibition is unclear\",\n        \"In vivo metabolic phenotype not assessed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Direct interaction between ATG16 and PSMD2 in Dictyostelium connected the proteasome to autophagy machinery, showing ATG16 is required for PSMD2 enrichment in autophagosomes/autolysosomes.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, fluorescence co-localization, and deletion mapping in Dictyostelium\",\n      \"pmids\": [\"30269947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Conservation of ATG16–PSMD2 interaction in mammalian cells was not demonstrated\",\n        \"Functional consequence for proteasome activity within autolysosomes is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies expanded PSMD2's interactome in cancer contexts: RACK1 competes with β-catenin for PSMD2 binding to protect β-catenin from degradation and activate WNT signaling, while DNAJA4 recruits PSMD2 for substrate-specific MYH9 degradation, illustrating PSMD2 as a regulatable access point for proteasomal substrates.\",\n      \"evidence\": \"Co-IP, competitive binding assays, siRNA knockdown, and in vivo tumor models in breast and nasopharyngeal carcinoma cells\",\n      \"pmids\": [\"37848434\", \"37875476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RACK1–PSMD2 interaction surface is unmapped\",\n        \"DNAJA4–PSMD2 link relies on single Co-IP without reciprocal validation\",\n        \"Whether these interactions occur at the intact 26S proteasome or free PSMD2 is not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of human PSMD2's T1/T2 sites, how Ser361 phosphorylation dynamics integrate with cellular stress responses, and whether PSMD2 functions outside the 26S holoenzyme context (e.g., in autophagy-linked roles or as a free subunit with signaling activity).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No human PSMD2 crystal structure exists\",\n        \"In vivo genetic models (knockout mouse) have not been reported\",\n        \"Relative contributions of T1 versus Rpn10/Rpn13 to substrate degradation in intact cells are unquantified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"26S proteasome\",\n      \"19S regulatory particle\"\n    ],\n    \"partners\": [\n      \"RAD23B\",\n      \"UBQLN1\",\n      \"PSMD1\",\n      \"RACK1\",\n      \"ASPN\",\n      \"DNAJA4\",\n      \"PIM1\",\n      \"UBLCP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}