{"gene":"PSMC5","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1996,"finding":"Yeast Sug1 (ortholog of human PSMC5) is a subunit of the 26S proteasome, not of the RNA polymerase II holoenzyme; it co-purifies with the proteasome by conventional and nickel-chelate affinity chromatography, and sug1 mutations reduce ubiquitin-dependent proteolysis.","method":"Biochemical co-purification (conventional and affinity chromatography), functional proteolysis assays in yeast mutants","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution-level biochemical purification, replicated across multiple chromatography methods, consistent with parallel mammalian data","pmids":["8628401"],"is_preprint":false},{"year":1996,"finding":"Mammalian Sug1 (FZA-B/mSug1, ortholog of PSMC5) is present in the nuclear 26S proteasome and interacts with c-Fos through its leucine zipper motif; depletion of FZA-B by antibody removes peptidase activity, proteasomal proteins, and c-Fos from 26S proteasome preparations.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, subcellular fractionation, antibody-depletion of proteasome activity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro binding, fractionation, and functional depletion in a single study","pmids":["8710853"],"is_preprint":false},{"year":1997,"finding":"SUG1 (PSMC5) possesses intrinsic 3′→5′ DNA helicase activity that is dependent on an intact ATP-binding domain; sedimentation heterogeneity suggests it is associated with distinct protein complexes.","method":"In vitro helicase assay with recombinant protein, ATPase domain mutagenesis, sedimentation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic reconstitution with mutagenesis in a single study","pmids":["9054406"],"is_preprint":false},{"year":1997,"finding":"Recombinant rat SUG1 (PSMC5) has Mg²⁺-dependent ATPase activity (Km ~35 µM for ATP); this activity is specifically stimulated by poly(U) and poly(C) RNA and by cellular poly(A)⁺ mRNA, but not by poly(A), poly(G), or any DNA tested, suggesting SUG1 can interact specifically with mRNA.","method":"In vitro ATPase activity assay with purified recombinant protein, UV cross-linking with [α-³²P]ATP, RNA-stimulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with purified recombinant protein and multiple RNA substrates tested","pmids":["9287326"],"is_preprint":false},{"year":1997,"finding":"SUG1 (PSMC5) directly interacts with XPB, a subunit of the DNA repair/transcription factor TFIIH; a portion of SUG1 co-purifies with the TFIIH holocomplex under non-overexpression conditions, and overexpression of SUG1 induces transcription arrest and chromatin collapse in normal fibroblasts.","method":"Yeast two-hybrid, baculovirus co-expression, co-purification, immunopurification, nickel-chelate affinity chromatography; in vivo overexpression phenotype","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding methods (yeast 2-hybrid, co-expression, co-purification) plus in vivo functional phenotype, single lab","pmids":["9173976"],"is_preprint":false},{"year":1998,"finding":"PSMC5/mSUG1 interacts with the AF-2 domain of the vitamin D receptor (VDR) in a 1,25-(OH)₂D₃-dependent manner; overexpression of wild-type mSUG1 generates a novel ~50 kDa VDR proteolytic fragment that is blocked by proteasome inhibitors or non-hydrolyzable ATP analogue, whereas the K196H ATPase mutant that does not interact with VDR fails to produce this fragment or inhibit VDR-driven transcription.","method":"Co-immunoprecipitation, transient overexpression, proteasome inhibitor treatment, ATPase mutant (K196H), reporter gene assay, cycloheximide chase","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis (K196H) combined with proteasome inhibition and functional reporter assay, multiple orthogonal approaches","pmids":["9831079"],"is_preprint":false},{"year":1998,"finding":"PSMC5 (TRIP-1) associates with and is phosphorylated by the TGF-β type II receptor kinase; overexpression of TRIP-1 represses TGF-β-induced transcription from the PAI-1 promoter and inhibits Smad-driven and constitutively active TβRI-driven PAI-1 expression; two distinct non-WD40 regions are required for inhibitory activity.","method":"Transient transfection, luciferase reporter assay, deletion mutagenesis, co-expression with Smads and constitutively active receptors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with deletion mutants across multiple TGF-β pathway components, single lab","pmids":["9813058"],"is_preprint":false},{"year":2000,"finding":"Human Sug1/PSMC5 interacts with the transcription factor Sp1 through the C-terminal ATPase-containing region of hSug1; full-length hSug1 stimulates proteasome-dependent degradation of Sp1 in vitro and in vivo, whereas an ATPase mutant of hSug1 still binds Sp1 but acts as a dominant negative, blocking Sp1 degradation; ATP hydrolysis by hSug1 is required for this process.","method":"In vitro binding, co-immunoprecipitation, in vitro reconstituted degradation assay, in vivo overexpression in NRK cells, ATPase mutant and truncation dominant-negative analysis","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of degradation plus ATPase mutagenesis plus in vivo overexpression, multiple orthogonal methods in one study","pmids":["10816420"],"is_preprint":false},{"year":2002,"finding":"SUG-1 (PSMC5) is recruited to the AF-2 domain of RAR-γ2 and this interaction is required for RA-induced proteasome-mediated degradation of RAR-γ2; blocking either the p38MAPK pathway (which phosphorylates AF-1 of RAR-γ2) or 26S proteasome function impairs RA-induced transactivation by RAR-γ2, demonstrating that ligand-induced receptor turnover is coupled to transcriptional activation.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, p38MAPK inhibitor treatment, transcription reporter assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP combined with pharmacological inhibition and functional transcription assays, single lab","pmids":["12110588"],"is_preprint":false},{"year":2008,"finding":"The 19S proteasome ATPase Sug1 (PSMC5) associates with the MHC class II transactivator CIITA and with the MHC class II proximal promoter; reduction of Sug1 decreases HLA-DR promoter activity and MHC class II transcription, and dramatically reduces CIITA association with the MHC II promoter even under conditions of proteasome inhibition.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assay, proteasome inhibition","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus functional knockdown, single lab, multiple orthogonal methods","pmids":["18215421"],"is_preprint":false},{"year":2008,"finding":"Sug1 (PSMC5) binds acetylated histone H3 and the histone acetyltransferase CBP; absence of Sug1 decreases histone H3 acetylation (preferentially H3K18) at the MHC II proximal promoter and reduces CBP recruitment to that promoter, indicating Sug1 regulates chromatin acetylation to initiate MHC II transcription.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, histone acetylation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP demonstrating direct binding to acetylated histone H3 and CBP, single lab","pmids":["18662994"],"is_preprint":false},{"year":2009,"finding":"SUG-1 (PSMC5) directly interacts with the coactivator SRC-3 and is recruited to promoters of retinoic acid target genes; SUG-1 mediates proteasomal degradation of SRC-3, and excess SUG-1 blocks RA-induced activation of RARα target genes by interfering with SRC-3 recruitment to the AF-2 domain of RARα.","method":"Co-immunoprecipitation, ChIP, overexpression/dominant-negative analysis, transcription reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional reporter assays, single lab","pmids":["19144644"],"is_preprint":false},{"year":2010,"finding":"Sug1 (PSMC5) interacts with NLRC4/Ipaf (binding residues 91–253), enabling ubiquitination of Ipaf; co-expression of Sug1 with Ipaf leads to formation of cytoplasmic aggregates, caspase-8 activation, and caspase-8-dependent cell death; RNAi or dominant-negative Sug1 blocks Ipaf-induced and TNF-α/doxorubicin-induced cell death.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, ubiquitination assay, caspase-8 activation assay, RNAi knockdown, cell death assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast 2-hybrid, Co-IP, ubiquitination, caspase assays, RNAi), single lab","pmids":["20085538"],"is_preprint":false},{"year":2015,"finding":"PSMC5 (AAA+ ATPase) binds to the scaffold protein Shoc2 and triggers translocation of Shoc2 to endosomes; at endosomes, PSMC5 displaces the E3 ligase HUWE1 from the Shoc2-RAF-1 complex, attenuating ubiquitylation of Shoc2 and RAF-1; a RASopathy mutation in Shoc2 that alters its subcellular distribution disrupts accessibility to PSMC5 and consequently alters Shoc2 ubiquitylation.","method":"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, ubiquitylation assay, RASopathy mutant analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, live imaging, and ubiquitylation assay with mechanistic mutagenesis, single lab","pmids":["26519477"],"is_preprint":false},{"year":2015,"finding":"PSMC5 interacts with ΔFosB in the nucleus accumbens; chronic cocaine increases nuclear (but not cytoplasmic) PSMC5 levels in the NAc; overexpression of PSMC5 in the NAc promotes locomotor responses to cocaine; endogenous PSMC5 and ΔFosB form complexes with chromatin regulatory proteins associated with gene activation.","method":"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, subcellular fractionation, viral overexpression in vivo, behavioral locomotor assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP, subcellular fractionation, and in vivo behavioral readout, single lab","pmids":["25962134"],"is_preprint":false},{"year":2015,"finding":"PSMC5 depletion in H460 lung cancer cells decreases proteasome activity, enhances AKT activation and MDM2 transcription, promotes degradation of p53 and p21, and converts radiosensitive cells to a radioresistant phenotype; inhibition of AKT or knockdown of MDM2 restores p21 levels in PSMC5-knockdown cells.","method":"siRNA knockdown, AKT inhibitor (triciribine), MDM2 siRNA, western blotting, clonogenic survival assay after irradiation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis by double knockdown (PSMC5 + MDM2) with pharmacological inhibitor orthogonal validation, single lab","pmids":["26592665"],"is_preprint":false},{"year":2016,"finding":"The autoinflammatory NLRC4 mutant H443P shows stronger interaction with SUG1 (PSMC5) and with ubiquitinated cellular proteins than wild-type NLRC4, and constitutively activates caspase-8 and induces FADD-dependent apoptosis without requiring Ser533 phosphorylation; the phosphomimetic NLRC4 S533D mutant does not require SUG1 activity for cell death induction.","method":"Co-immunoprecipitation with NLRC4 mutants, caspase-8 activation assay, cell death assay, FADD dependency analysis, ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative Co-IP of mutant vs. wild-type, caspase assays, multiple mutants tested, single lab","pmids":["27974463"],"is_preprint":false},{"year":2020,"finding":"Sug1 (PSMC5) binds to CIITA in mesenchymal stem cells (MSCs); hypoxia upregulates Sug1, which promotes acetylation and K63-ubiquitination of CIITA, leading to CIITA nuclear translocation and MHC-II upregulation; Sug1 knockdown inactivates MHC-II expression and preserves immunoprivilege under hypoxia in vitro and in vivo.","method":"Co-immunoprecipitation, ubiquitination and acetylation assays, siRNA knockdown, nuclear fractionation, in vivo rat model of myocardial infarction with Sug1-knockdown MSC transplantation","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PTM assays, nuclear fractionation, and in vivo validation, single lab","pmids":["32770803"],"is_preprint":false},{"year":2024,"finding":"PSMC5 P320R mutation (found in individuals with neurodevelopmental disorders) weakens the association between the 19S regulatory particle and the 20S core particle of the proteasome, impairing overall proteasome function and activating apoptosis; PSMC5 haploinsufficiency also impairs proteasome function.","method":"Patient-derived cells, proteasome activity assays, co-immunoprecipitation of 19S-20S interface, western blotting for apoptosis markers","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct proteasome activity assay and 19S-20S association Co-IP with disease mutant, single lab","pmids":["38776958"],"is_preprint":false},{"year":2023,"finding":"PSMC5 interacts with TLR4 (via residues Glu284, Met139, Leu127, Phe283 of PSMC5); PSMC5 knockdown reduces TLR4 expression and attenuates LPS-induced NF-κB activation (IκB-α and p65 phosphorylation) in microglia; PSMC5 site mutations reduce TLR4-mediated MyD88-dependent NF-κB activation and pro-inflammatory cytokine release.","method":"siRNA/shRNA knockdown, molecular dynamics simulation, site-directed mutagenesis, co-immunoprecipitation (implied by interaction characterization), NF-κB pathway western blotting, cytokine measurement, TLR4-/- mouse model","journal":"Journal of neuroinflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction supported primarily by computational docking and knockdown phenotype; direct binding biochemistry not clearly demonstrated in abstract","pmids":["38001534"],"is_preprint":false},{"year":2025,"finding":"Loss of PSMC5/RPT6 function (via 26 distinct patient variants) impairs proteasome activity leading to protein aggregation, disruption of mitochondrial homeostasis, dysregulation of lipid metabolism and immune signaling, compromised synaptic balance, neuritogenesis, and neural progenitor stemness; pharmacological inhibition of integrated stress response kinases PKR and GCN2 ameliorates immune dysregulation in patient-derived cells.","method":"Patient-derived cell models, multi-omics (transcriptomics, proteomics), Drosophila genetic knockdown, proteasome activity assays, neuronal morphology assays, pharmacological kinase inhibition","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with biochemical validation and cross-species genetic evidence, though mechanistic depth per individual finding is moderate","pmids":["41298377"],"is_preprint":false},{"year":2006,"finding":"A dominant-negative truncated TRIP1/S8/hSug1 (PSMC5) decreases cellular proteasome activity, increases mitotic index, and enhances apoptosis in response to spindle poisons (Taxol, vinblastine) or proteasome inhibitors; siRNA knockdown of TRIP1/hSug1 similarly reduces proteasome activity and increases cell death after spindle poison treatment, coinciding with decreased BubR1 expression.","method":"Expression cloning, stable transfection of dominant-negative truncation, siRNA knockdown, proteasome activity assay, mitotic index measurement, apoptosis assay","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative and siRNA genetic approaches with proteasome activity measurement and defined cellular phenotype, single lab","pmids":["16432160"],"is_preprint":false},{"year":2012,"finding":"Sug1 (PSMC5) also regulates transcription of MHC class I and the atypical MHC II molecules HLA-DM and HLA-DO; reduction of Sug1 expression decreases recruitment of CBP and CIITA to MHC class I and HLA-DM/DO promoters and reduces histone H3 acetylation at these promoters.","method":"siRNA knockdown, ChIP, transcription assays","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with siRNA knockdown showing promoter occupancy changes, single lab, extends prior MHC II findings","pmids":["22771340"],"is_preprint":false},{"year":2011,"finding":"TRIP-1 (PSMC5) knockdown in A549 lung epithelial cells promotes TGF-β1-induced epithelial-mesenchymal transition; mechanistically, TRIP-1 depletion leads to increased TGF-β type II receptor levels, enhanced Smad3 phosphorylation, and induction of the transcription factor SLUG.","method":"shRNA knockdown, western blotting, morphology and migration assays, Smad3 phosphorylation measurement, EMT marker analysis","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA loss-of-function with defined pathway (TGFβRII/Smad3/SLUG) and multiple phenotypic readouts, single lab","pmids":["21378021"],"is_preprint":false},{"year":2014,"finding":"TRIP-1 (PSMC5) knockdown in primary human lung fibroblasts induces α-SMA expression and myofibroblast features; this effect is mediated through AKT phosphorylation (not through Smad3), as AKT inhibition prevents α-SMA induction in TRIP-1 knockdown cells and constitutively active AKT drives collagen contraction.","method":"siRNA knockdown, plasmid overexpression, AKT inhibitor, constitutively active AKT construct, α-SMA western blotting, collagen contraction assay, apoptosis assay, Smad3 knockdown","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via AKT inhibitor and constitutively active AKT orthogonally validated, loss-of-function phenotype, single lab","pmids":["24528651"],"is_preprint":false},{"year":1998,"finding":"Phosducin-like protein (PhLP) interacts with mouse SUG1 (PSMC5); inhibition of proteasome function with lactacystin leads to accumulation of high-molecular-weight ubiquitin-immunoreactive protein precipitated by PhLP antiserum, suggesting PhLP/SUG1 interaction may target PhLP for proteasomal degradation.","method":"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, proteasome inhibitor (lactacystin) treatment","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/Co-IP with pharmacological inhibitor but no direct degradation reconstitution, single lab","pmids":["9551090"],"is_preprint":false},{"year":2007,"finding":"Mouse SUG1 (PSMC5) interacts with mouse Prp19 (a ubiquitin ligase involved in pre-mRNA splicing/DNA repair); the N-terminus (U-box domain) of mPrp19 binds the C-terminus of mSUG1; co-expression of mPrp19 increases cellular proteasome activity; GFP-mPrp19 co-localizes with mSUG1 in cytoplasmic speckle-like structures in the presence of proteasome inhibitor MG132.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, GFP co-localization, proteasome activity assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple binding assays confirmed but functional link based on overexpression and single proteasome activity measurement, single lab","pmids":["17349974"],"is_preprint":false},{"year":2006,"finding":"Sug1 (PSMC5) interacts with the C-terminal tail of the unconventional myosin MYO18B; Sug1 knockdown or proteasome inhibitor treatment increases MYO18B protein levels, and MYO18B is polyubiquitinated in vivo, indicating MYO18B is a substrate targeted for proteasomal degradation via Sug1.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, ubiquitination assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple binding assays with siRNA and ubiquitination, but single lab and limited mechanistic depth","pmids":["16499872"],"is_preprint":false},{"year":1999,"finding":"Adenovirus E1A 12S and 13S proteins bind directly to mammalian SUG1 (PSMC5), a 26S proteasome regulatory component; Ad12 E1A 13S binds SUG1 via a region distinct from conserved region 1 (which mediates increased p53 expression), and E1A co-immunoprecipitates with SUG1 in human cells infected with Ad5; SV40 large T antigen also co-immunoprecipitates with SUG1.","method":"Co-immunoprecipitation, in vitro binding assay, virus infection, 26S proteasome peptidase activity assay","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and in vitro binding but mechanistic consequence of the interaction is limited; single lab","pmids":["9927201"],"is_preprint":false},{"year":2026,"finding":"PSMC5 promotes SMURF1-dependent K11-linked ubiquitination of METTL14 at K263, leading to METTL14 destabilization and global m⁶A remodeling; SMURF1 silencing restores METTL14 expression and attenuates PSMC5-driven tumor growth and lung metastasis in vivo.","method":"Ubiquitination assay with K11-linkage specificity, site-directed mutagenesis (K263), rescue/overexpression experiments, in vivo xenograft/metastasis model with SMURF1 siRNA","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site mutagenesis and in vivo rescue, single lab, mechanistic cascade defined","pmids":["42212325"],"is_preprint":false}],"current_model":"PSMC5 (SUG1/TRIP1/RPT6) is an AAA+ ATPase subunit of the 19S regulatory particle of the 26S proteasome that (1) provides essential ATPase and DNA helicase activities required for ubiquitin-dependent protein degradation; (2) directly contacts substrates and transcription factors (VDR, RARs, SRC-3, Sp1, c-Fos, ΔFosB, CIITA) at their activation domains to couple their proteasomal degradation with transcriptional activation; (3) binds and recruits the acetyltransferase CBP to promoters (e.g., MHC class I/II), regulating histone H3 acetylation and enhanceosome assembly; (4) interacts with signaling proteins (NLRC4/Ipaf, Shoc2, TLR4) to modulate ubiquitination-dependent signaling and spatial remodeling of scaffold complexes; (5) links proteasomal regulation to SMURF1-mediated K11-ubiquitination of METTL14; and (6) loss-of-function mutations impair 19S–20S proteasome assembly and cause neurodevelopmental proteasomopathies through protein aggregation, mitochondrial dysfunction, and immune dysregulation."},"narrative":{"mechanistic_narrative":"PSMC5 (SUG1/TRIP1/RPT6) is an essential AAA+ ATPase subunit of the 19S regulatory particle of the 26S proteasome that couples ATP-dependent protein degradation to the control of transcription, signaling, and cell fate [PMID:8628401, PMID:8710853]. Beyond its structural role in the proteasome, recombinant PSMC5 has intrinsic Mg2+-dependent ATPase activity that is stimulated specifically by poly(U)/poly(C) and poly(A)+ mRNA, and an ATP-binding-domain-dependent 3'→5' DNA helicase activity [PMID:9054406, PMID:9287326]. A recurrent theme is that PSMC5 docks onto the activation domains of transcription factors and nuclear receptors to couple their proteasomal turnover with transactivation: it binds the AF-2 domains of VDR and RARs and the coactivator SRC-3 in a ligand-dependent manner, and stimulates proteasome-dependent degradation of Sp1, with ATP hydrolysis required and ATPase-dead mutants acting as dominant negatives [PMID:9831079, PMID:10816420, PMID:12110588, PMID:19144644]. In the immune system, PSMC5 associates with the MHC class II transactivator CIITA and is recruited to MHC class I and II promoters, where it binds acetylated histone H3 and recruits the acetyltransferase CBP to drive promoter H3 acetylation and transcription [PMID:18215421, PMID:18662994, PMID:22771340]. PSMC5 also remodels signaling scaffolds and ubiquitination: it relocalizes the Shoc2–RAF-1 complex to endosomes and displaces the E3 ligase HUWE1 [PMID:26519477], engages NLRC4/Ipaf to promote caspase-8-dependent cell death [PMID:20085538, PMID:27974463], and drives SMURF1-dependent K11-ubiquitination of METTL14 to remodel m6A and promote tumor growth [PMID:42212325]. Loss-of-function mutations, including P320R and haploinsufficiency, weaken 19S–20S proteasome association and impair proteasome function, causing neurodevelopmental proteasomopathies characterized by protein aggregation, mitochondrial dysfunction, integrated-stress-response activation, and immune dysregulation [PMID:38776958, PMID:41298377].","teleology":[{"year":1996,"claim":"Resolved whether Sug1 belongs to the transcription machinery or the proteasome, establishing PSMC5 as a 26S proteasome subunit required for ubiquitin-dependent proteolysis.","evidence":"Biochemical co-purification and functional proteolysis assays in yeast mutants; nuclear fractionation, reciprocal Co-IP and antibody depletion in mammalian cells","pmids":["8628401","8710853"],"confidence":"High","gaps":["Did not define which substrates require Sug1 specifically","Structural position within the 19S particle not resolved"]},{"year":1997,"claim":"Defined PSMC5's intrinsic enzymatic activities—ATP-domain-dependent DNA helicase and RNA-stimulated ATPase—indicating activities beyond simple unfoldase function.","evidence":"In vitro helicase and ATPase assays with recombinant protein, ATPase-domain mutagenesis, UV cross-linking, RNA-stimulation panels","pmids":["9054406","9287326"],"confidence":"High","gaps":["Physiological relevance of helicase and RNA-stimulated ATPase activities in the assembled proteasome not established","No cellular substrate of the helicase activity identified"]},{"year":1997,"claim":"Linked PSMC5 to transcription/repair machinery via XPB/TFIIH, hinting at a role coupling proteolysis to transcription.","evidence":"Yeast two-hybrid, baculovirus co-expression, co-purification with TFIIH, in vivo overexpression phenotype","pmids":["9173976"],"confidence":"Medium","gaps":["Functional consequence of TFIIH association not separated from general proteasome effects","Single lab"]},{"year":1998,"claim":"Established the paradigm that PSMC5 couples ligand-dependent nuclear receptor degradation to transactivation, using VDR as the first example.","evidence":"Co-IP, transient overexpression, proteasome inhibitors, ATPase-dead K196H mutant, reporter assays, cycloheximide chase","pmids":["9831079"],"confidence":"High","gaps":["Whether degradation is required for activation or a parallel event not fully resolved","Generality beyond VDR untested at this stage"]},{"year":1998,"claim":"Identified PSMC5 (TRIP-1) as a TGF-beta type II receptor-associated, receptor-phosphorylated repressor of TGF-beta transcriptional output.","evidence":"Transient transfection, luciferase reporters, deletion mutagenesis, co-expression with Smads and constitutively active receptors","pmids":["9813058"],"confidence":"Medium","gaps":["Mechanism connecting receptor phosphorylation of TRIP-1 to repression unclear","Endogenous relevance not shown"]},{"year":2000,"claim":"Demonstrated mechanistically that PSMC5 ATP hydrolysis drives substrate degradation, using Sp1 and an ATPase-dead dominant negative.","evidence":"In vitro reconstituted degradation, Co-IP, in vivo overexpression, ATPase-mutant/truncation dominant-negative analysis","pmids":["10816420"],"confidence":"High","gaps":["Whether Sp1 degradation is direct via PSMC5 or requires full proteasome assembly not isolated","Ubiquitination requirement not detailed"]},{"year":2002,"claim":"Generalized the receptor-turnover/activation coupling to RAR-gamma2, integrating p38MAPK signaling with proteasome-dependent transactivation.","evidence":"Co-IP, proteasome and p38MAPK inhibitors, transcription reporter assays","pmids":["12110588"],"confidence":"Medium","gaps":["Direct vs indirect coupling of turnover to activation not dissected","Single lab"]},{"year":2006,"claim":"Tied PSMC5 proteasome function to mitotic spindle checkpoint integrity and chemosensitivity to spindle poisons.","evidence":"Dominant-negative truncation, siRNA knockdown, proteasome activity, mitotic index and apoptosis assays","pmids":["16432160"],"confidence":"Medium","gaps":["Mechanism linking PSMC5 to BubR1 levels unclear","General proteasome impairment vs specific role not separated"]},{"year":2009,"claim":"Extended the transcriptional role to immune gene regulation, showing PSMC5 promotes CIITA recruitment to the MHC II promoter independent of proteasome activity.","evidence":"Co-IP, ChIP, siRNA knockdown, reporter assays, proteasome inhibition","pmids":["18215421"],"confidence":"Medium","gaps":["Non-proteolytic mechanism of promoter recruitment incompletely defined","Single lab"]},{"year":2008,"claim":"Defined a chromatin-level mechanism by which PSMC5 binds acetylated H3 and recruits CBP to drive promoter acetylation for transcription initiation.","evidence":"Co-IP, ChIP, siRNA knockdown, histone acetylation assays","pmids":["18662994"],"confidence":"Medium","gaps":["Direct vs proteasome-mediated CBP recruitment not fully separated","Specificity for H3K18 mechanism unexplained"]},{"year":2011,"claim":"Showed PSMC5/TRIP-1 loss promotes TGF-beta-driven EMT through elevated TGF-beta receptor II, Smad3 phosphorylation, and SLUG induction.","evidence":"shRNA knockdown, western blotting, morphology/migration assays, EMT marker analysis","pmids":["21378021"],"confidence":"Medium","gaps":["Whether receptor accumulation is proteasome-dependent not directly tested","Single cell line"]},{"year":2012,"claim":"Broadened immune-gene regulation to MHC class I and HLA-DM/DO, with PSMC5 controlling CBP/CIITA recruitment and H3 acetylation.","evidence":"siRNA knockdown, ChIP, transcription assays","pmids":["22771340"],"confidence":"Medium","gaps":["Mechanistic distinction from MHC II regulation not addressed","Single lab"]},{"year":2014,"claim":"Distinguished a Smad-independent, AKT-mediated fibroblast-to-myofibroblast role for PSMC5/TRIP-1, separating its signaling outputs.","evidence":"siRNA, overexpression, AKT inhibitor and constitutively active AKT, alpha-SMA western, collagen contraction, Smad3 knockdown","pmids":["24528651"],"confidence":"Medium","gaps":["Molecular link from PSMC5 loss to AKT activation unresolved","Single lab"]},{"year":2015,"claim":"Revealed non-degradative scaffold remodeling: PSMC5 relocates Shoc2-RAF-1 to endosomes and displaces HUWE1 to tune ubiquitylation.","evidence":"Co-IP, live-cell imaging, subcellular fractionation, ubiquitylation assay, RASopathy mutant analysis","pmids":["26519477"],"confidence":"Medium","gaps":["How a proteasome ATPase displaces an E3 ligase mechanistically unclear","Single lab"]},{"year":2010,"claim":"Implicated PSMC5 in innate immune cell-death control via NLRC4/Ipaf ubiquitination and caspase-8 activation.","evidence":"Yeast two-hybrid, Co-IP, co-localization, ubiquitination and caspase-8 assays, RNAi, cell death assays","pmids":["20085538"],"confidence":"Medium","gaps":["Whether PSMC5 directly mediates Ipaf ubiquitination or recruits an E3 unknown","Single lab"]},{"year":2016,"claim":"Showed an autoinflammatory NLRC4 mutant depends on enhanced SUG1 interaction for phosphorylation-independent caspase-8/FADD-dependent apoptosis.","evidence":"Comparative Co-IP of NLRC4 mutants, caspase-8 and cell death assays, FADD dependency, ubiquitination assays","pmids":["27974463"],"confidence":"Medium","gaps":["Structural basis of enhanced mutant binding undefined","Single lab"]},{"year":2015,"claim":"Connected nuclear PSMC5 to behavioral plasticity through DeltaFosB complexes with gene-activating chromatin regulators in the nucleus accumbens.","evidence":"Yeast two-hybrid, endogenous Co-IP, subcellular fractionation, viral overexpression, behavioral locomotor assays","pmids":["25962134"],"confidence":"Medium","gaps":["Molecular mechanism by which PSMC5 modifies DeltaFosB transcriptional output unclear","Single lab"]},{"year":2015,"claim":"Linked PSMC5 proteasome function to p53/p21 stability and radiosensitivity via an AKT/MDM2 axis in lung cancer cells.","evidence":"siRNA, AKT inhibitor, MDM2 siRNA epistasis, western blotting, clonogenic survival after irradiation","pmids":["26592665"],"confidence":"Medium","gaps":["Direct PSMC5 targets upstream of AKT not identified","Single cell line"]},{"year":2020,"claim":"Showed hypoxia-induced PSMC5 drives CIITA acetylation/K63-ubiquitination, nuclear translocation, and MHC-II upregulation, affecting MSC immunoprivilege.","evidence":"Co-IP, ubiquitination/acetylation assays, siRNA, nuclear fractionation, in vivo myocardial infarction MSC transplantation model","pmids":["32770803"],"confidence":"Medium","gaps":["Direct enzymatic role of PSMC5 in CIITA PTMs vs adaptor role unresolved","Single lab"]},{"year":2024,"claim":"Established disease causality: the P320R mutation and haploinsufficiency weaken 19S-20S proteasome association and impair function, activating apoptosis in patient cells.","evidence":"Patient-derived cells, proteasome activity assays, 19S-20S interface Co-IP, apoptosis marker western blotting","pmids":["38776958"],"confidence":"Medium","gaps":["Structural mechanism of weakened 19S-20S docking not resolved","Genotype-phenotype correlation across variants not addressed"]},{"year":2025,"claim":"Defined the broad cellular pathology of PSMC5 loss-of-function proteasomopathy and a therapeutic entry point via integrated stress response kinase inhibition.","evidence":"Patient-derived cells, multi-omics, Drosophila knockdown, proteasome activity assays, neuronal morphology, PKR/GCN2 inhibition","pmids":["41298377"],"confidence":"Medium","gaps":["Causal chain from proteasome impairment to specific neural phenotypes incomplete","Durability/safety of ISR kinase inhibition unaddressed"]},{"year":2026,"claim":"Identified a pro-tumorigenic cascade in which PSMC5 drives SMURF1-dependent K11-ubiquitination of METTL14 to remodel m6A.","evidence":"K11-linkage-specific ubiquitination assay, K263 site mutagenesis, rescue experiments, in vivo xenograft/metastasis with SMURF1 siRNA","pmids":["42212325"],"confidence":"Medium","gaps":["How PSMC5 promotes SMURF1 activity toward METTL14 mechanistically unclear","Single lab"]},{"year":null,"claim":"How PSMC5's intrinsic biochemical activities (helicase, RNA-stimulated ATPase) and its many non-proteolytic scaffolding/transcriptional functions are mechanistically distinct from its role within the assembled 26S proteasome remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of PSMC5 engaging transcription-factor activation domains","Whether free-pool PSMC5 acts outside the proteasome not established","Direct E3-ligase recruitment partners for many ubiquitination events unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2,3,5,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a 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signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24012495","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27352,"output_tokens":7938,"usd":0.100563,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17314,"output_tokens":6397,"usd":0.123247,"stage2_stop_reason":"end_turn"},"total_usd":0.22381,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast Sug1 (ortholog of human PSMC5) is a subunit of the 26S proteasome, not of the RNA polymerase II holoenzyme; it co-purifies with the proteasome by conventional and nickel-chelate affinity chromatography, and sug1 mutations reduce ubiquitin-dependent proteolysis.\",\n      \"method\": \"Biochemical co-purification (conventional and affinity chromatography), functional proteolysis assays in yeast mutants\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution-level biochemical purification, replicated across multiple chromatography methods, consistent with parallel mammalian data\",\n      \"pmids\": [\"8628401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mammalian Sug1 (FZA-B/mSug1, ortholog of PSMC5) is present in the nuclear 26S proteasome and interacts with c-Fos through its leucine zipper motif; depletion of FZA-B by antibody removes peptidase activity, proteasomal proteins, and c-Fos from 26S proteasome preparations.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, subcellular fractionation, antibody-depletion of proteasome activity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro binding, fractionation, and functional depletion in a single study\",\n      \"pmids\": [\"8710853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SUG1 (PSMC5) possesses intrinsic 3′→5′ DNA helicase activity that is dependent on an intact ATP-binding domain; sedimentation heterogeneity suggests it is associated with distinct protein complexes.\",\n      \"method\": \"In vitro helicase assay with recombinant protein, ATPase domain mutagenesis, sedimentation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic reconstitution with mutagenesis in a single study\",\n      \"pmids\": [\"9054406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Recombinant rat SUG1 (PSMC5) has Mg²⁺-dependent ATPase activity (Km ~35 µM for ATP); this activity is specifically stimulated by poly(U) and poly(C) RNA and by cellular poly(A)⁺ mRNA, but not by poly(A), poly(G), or any DNA tested, suggesting SUG1 can interact specifically with mRNA.\",\n      \"method\": \"In vitro ATPase activity assay with purified recombinant protein, UV cross-linking with [α-³²P]ATP, RNA-stimulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with purified recombinant protein and multiple RNA substrates tested\",\n      \"pmids\": [\"9287326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SUG1 (PSMC5) directly interacts with XPB, a subunit of the DNA repair/transcription factor TFIIH; a portion of SUG1 co-purifies with the TFIIH holocomplex under non-overexpression conditions, and overexpression of SUG1 induces transcription arrest and chromatin collapse in normal fibroblasts.\",\n      \"method\": \"Yeast two-hybrid, baculovirus co-expression, co-purification, immunopurification, nickel-chelate affinity chromatography; in vivo overexpression phenotype\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding methods (yeast 2-hybrid, co-expression, co-purification) plus in vivo functional phenotype, single lab\",\n      \"pmids\": [\"9173976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PSMC5/mSUG1 interacts with the AF-2 domain of the vitamin D receptor (VDR) in a 1,25-(OH)₂D₃-dependent manner; overexpression of wild-type mSUG1 generates a novel ~50 kDa VDR proteolytic fragment that is blocked by proteasome inhibitors or non-hydrolyzable ATP analogue, whereas the K196H ATPase mutant that does not interact with VDR fails to produce this fragment or inhibit VDR-driven transcription.\",\n      \"method\": \"Co-immunoprecipitation, transient overexpression, proteasome inhibitor treatment, ATPase mutant (K196H), reporter gene assay, cycloheximide chase\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis (K196H) combined with proteasome inhibition and functional reporter assay, multiple orthogonal approaches\",\n      \"pmids\": [\"9831079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PSMC5 (TRIP-1) associates with and is phosphorylated by the TGF-β type II receptor kinase; overexpression of TRIP-1 represses TGF-β-induced transcription from the PAI-1 promoter and inhibits Smad-driven and constitutively active TβRI-driven PAI-1 expression; two distinct non-WD40 regions are required for inhibitory activity.\",\n      \"method\": \"Transient transfection, luciferase reporter assay, deletion mutagenesis, co-expression with Smads and constitutively active receptors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with deletion mutants across multiple TGF-β pathway components, single lab\",\n      \"pmids\": [\"9813058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human Sug1/PSMC5 interacts with the transcription factor Sp1 through the C-terminal ATPase-containing region of hSug1; full-length hSug1 stimulates proteasome-dependent degradation of Sp1 in vitro and in vivo, whereas an ATPase mutant of hSug1 still binds Sp1 but acts as a dominant negative, blocking Sp1 degradation; ATP hydrolysis by hSug1 is required for this process.\",\n      \"method\": \"In vitro binding, co-immunoprecipitation, in vitro reconstituted degradation assay, in vivo overexpression in NRK cells, ATPase mutant and truncation dominant-negative analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of degradation plus ATPase mutagenesis plus in vivo overexpression, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10816420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SUG-1 (PSMC5) is recruited to the AF-2 domain of RAR-γ2 and this interaction is required for RA-induced proteasome-mediated degradation of RAR-γ2; blocking either the p38MAPK pathway (which phosphorylates AF-1 of RAR-γ2) or 26S proteasome function impairs RA-induced transactivation by RAR-γ2, demonstrating that ligand-induced receptor turnover is coupled to transcriptional activation.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, p38MAPK inhibitor treatment, transcription reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP combined with pharmacological inhibition and functional transcription assays, single lab\",\n      \"pmids\": [\"12110588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The 19S proteasome ATPase Sug1 (PSMC5) associates with the MHC class II transactivator CIITA and with the MHC class II proximal promoter; reduction of Sug1 decreases HLA-DR promoter activity and MHC class II transcription, and dramatically reduces CIITA association with the MHC II promoter even under conditions of proteasome inhibition.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assay, proteasome inhibition\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus functional knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18215421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sug1 (PSMC5) binds acetylated histone H3 and the histone acetyltransferase CBP; absence of Sug1 decreases histone H3 acetylation (preferentially H3K18) at the MHC II proximal promoter and reduces CBP recruitment to that promoter, indicating Sug1 regulates chromatin acetylation to initiate MHC II transcription.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, histone acetylation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP demonstrating direct binding to acetylated histone H3 and CBP, single lab\",\n      \"pmids\": [\"18662994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SUG-1 (PSMC5) directly interacts with the coactivator SRC-3 and is recruited to promoters of retinoic acid target genes; SUG-1 mediates proteasomal degradation of SRC-3, and excess SUG-1 blocks RA-induced activation of RARα target genes by interfering with SRC-3 recruitment to the AF-2 domain of RARα.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, overexpression/dominant-negative analysis, transcription reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional reporter assays, single lab\",\n      \"pmids\": [\"19144644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sug1 (PSMC5) interacts with NLRC4/Ipaf (binding residues 91–253), enabling ubiquitination of Ipaf; co-expression of Sug1 with Ipaf leads to formation of cytoplasmic aggregates, caspase-8 activation, and caspase-8-dependent cell death; RNAi or dominant-negative Sug1 blocks Ipaf-induced and TNF-α/doxorubicin-induced cell death.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, ubiquitination assay, caspase-8 activation assay, RNAi knockdown, cell death assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast 2-hybrid, Co-IP, ubiquitination, caspase assays, RNAi), single lab\",\n      \"pmids\": [\"20085538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMC5 (AAA+ ATPase) binds to the scaffold protein Shoc2 and triggers translocation of Shoc2 to endosomes; at endosomes, PSMC5 displaces the E3 ligase HUWE1 from the Shoc2-RAF-1 complex, attenuating ubiquitylation of Shoc2 and RAF-1; a RASopathy mutation in Shoc2 that alters its subcellular distribution disrupts accessibility to PSMC5 and consequently alters Shoc2 ubiquitylation.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, ubiquitylation assay, RASopathy mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, live imaging, and ubiquitylation assay with mechanistic mutagenesis, single lab\",\n      \"pmids\": [\"26519477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMC5 interacts with ΔFosB in the nucleus accumbens; chronic cocaine increases nuclear (but not cytoplasmic) PSMC5 levels in the NAc; overexpression of PSMC5 in the NAc promotes locomotor responses to cocaine; endogenous PSMC5 and ΔFosB form complexes with chromatin regulatory proteins associated with gene activation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, subcellular fractionation, viral overexpression in vivo, behavioral locomotor assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP, subcellular fractionation, and in vivo behavioral readout, single lab\",\n      \"pmids\": [\"25962134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSMC5 depletion in H460 lung cancer cells decreases proteasome activity, enhances AKT activation and MDM2 transcription, promotes degradation of p53 and p21, and converts radiosensitive cells to a radioresistant phenotype; inhibition of AKT or knockdown of MDM2 restores p21 levels in PSMC5-knockdown cells.\",\n      \"method\": \"siRNA knockdown, AKT inhibitor (triciribine), MDM2 siRNA, western blotting, clonogenic survival assay after irradiation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis by double knockdown (PSMC5 + MDM2) with pharmacological inhibitor orthogonal validation, single lab\",\n      \"pmids\": [\"26592665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The autoinflammatory NLRC4 mutant H443P shows stronger interaction with SUG1 (PSMC5) and with ubiquitinated cellular proteins than wild-type NLRC4, and constitutively activates caspase-8 and induces FADD-dependent apoptosis without requiring Ser533 phosphorylation; the phosphomimetic NLRC4 S533D mutant does not require SUG1 activity for cell death induction.\",\n      \"method\": \"Co-immunoprecipitation with NLRC4 mutants, caspase-8 activation assay, cell death assay, FADD dependency analysis, ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative Co-IP of mutant vs. wild-type, caspase assays, multiple mutants tested, single lab\",\n      \"pmids\": [\"27974463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sug1 (PSMC5) binds to CIITA in mesenchymal stem cells (MSCs); hypoxia upregulates Sug1, which promotes acetylation and K63-ubiquitination of CIITA, leading to CIITA nuclear translocation and MHC-II upregulation; Sug1 knockdown inactivates MHC-II expression and preserves immunoprivilege under hypoxia in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination and acetylation assays, siRNA knockdown, nuclear fractionation, in vivo rat model of myocardial infarction with Sug1-knockdown MSC transplantation\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PTM assays, nuclear fractionation, and in vivo validation, single lab\",\n      \"pmids\": [\"32770803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PSMC5 P320R mutation (found in individuals with neurodevelopmental disorders) weakens the association between the 19S regulatory particle and the 20S core particle of the proteasome, impairing overall proteasome function and activating apoptosis; PSMC5 haploinsufficiency also impairs proteasome function.\",\n      \"method\": \"Patient-derived cells, proteasome activity assays, co-immunoprecipitation of 19S-20S interface, western blotting for apoptosis markers\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct proteasome activity assay and 19S-20S association Co-IP with disease mutant, single lab\",\n      \"pmids\": [\"38776958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSMC5 interacts with TLR4 (via residues Glu284, Met139, Leu127, Phe283 of PSMC5); PSMC5 knockdown reduces TLR4 expression and attenuates LPS-induced NF-κB activation (IκB-α and p65 phosphorylation) in microglia; PSMC5 site mutations reduce TLR4-mediated MyD88-dependent NF-κB activation and pro-inflammatory cytokine release.\",\n      \"method\": \"siRNA/shRNA knockdown, molecular dynamics simulation, site-directed mutagenesis, co-immunoprecipitation (implied by interaction characterization), NF-κB pathway western blotting, cytokine measurement, TLR4-/- mouse model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction supported primarily by computational docking and knockdown phenotype; direct binding biochemistry not clearly demonstrated in abstract\",\n      \"pmids\": [\"38001534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of PSMC5/RPT6 function (via 26 distinct patient variants) impairs proteasome activity leading to protein aggregation, disruption of mitochondrial homeostasis, dysregulation of lipid metabolism and immune signaling, compromised synaptic balance, neuritogenesis, and neural progenitor stemness; pharmacological inhibition of integrated stress response kinases PKR and GCN2 ameliorates immune dysregulation in patient-derived cells.\",\n      \"method\": \"Patient-derived cell models, multi-omics (transcriptomics, proteomics), Drosophila genetic knockdown, proteasome activity assays, neuronal morphology assays, pharmacological kinase inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with biochemical validation and cross-species genetic evidence, though mechanistic depth per individual finding is moderate\",\n      \"pmids\": [\"41298377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A dominant-negative truncated TRIP1/S8/hSug1 (PSMC5) decreases cellular proteasome activity, increases mitotic index, and enhances apoptosis in response to spindle poisons (Taxol, vinblastine) or proteasome inhibitors; siRNA knockdown of TRIP1/hSug1 similarly reduces proteasome activity and increases cell death after spindle poison treatment, coinciding with decreased BubR1 expression.\",\n      \"method\": \"Expression cloning, stable transfection of dominant-negative truncation, siRNA knockdown, proteasome activity assay, mitotic index measurement, apoptosis assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative and siRNA genetic approaches with proteasome activity measurement and defined cellular phenotype, single lab\",\n      \"pmids\": [\"16432160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sug1 (PSMC5) also regulates transcription of MHC class I and the atypical MHC II molecules HLA-DM and HLA-DO; reduction of Sug1 expression decreases recruitment of CBP and CIITA to MHC class I and HLA-DM/DO promoters and reduces histone H3 acetylation at these promoters.\",\n      \"method\": \"siRNA knockdown, ChIP, transcription assays\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with siRNA knockdown showing promoter occupancy changes, single lab, extends prior MHC II findings\",\n      \"pmids\": [\"22771340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIP-1 (PSMC5) knockdown in A549 lung epithelial cells promotes TGF-β1-induced epithelial-mesenchymal transition; mechanistically, TRIP-1 depletion leads to increased TGF-β type II receptor levels, enhanced Smad3 phosphorylation, and induction of the transcription factor SLUG.\",\n      \"method\": \"shRNA knockdown, western blotting, morphology and migration assays, Smad3 phosphorylation measurement, EMT marker analysis\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA loss-of-function with defined pathway (TGFβRII/Smad3/SLUG) and multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"21378021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRIP-1 (PSMC5) knockdown in primary human lung fibroblasts induces α-SMA expression and myofibroblast features; this effect is mediated through AKT phosphorylation (not through Smad3), as AKT inhibition prevents α-SMA induction in TRIP-1 knockdown cells and constitutively active AKT drives collagen contraction.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, AKT inhibitor, constitutively active AKT construct, α-SMA western blotting, collagen contraction assay, apoptosis assay, Smad3 knockdown\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via AKT inhibitor and constitutively active AKT orthogonally validated, loss-of-function phenotype, single lab\",\n      \"pmids\": [\"24528651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Phosducin-like protein (PhLP) interacts with mouse SUG1 (PSMC5); inhibition of proteasome function with lactacystin leads to accumulation of high-molecular-weight ubiquitin-immunoreactive protein precipitated by PhLP antiserum, suggesting PhLP/SUG1 interaction may target PhLP for proteasomal degradation.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay, co-immunoprecipitation, proteasome inhibitor (lactacystin) treatment\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/Co-IP with pharmacological inhibitor but no direct degradation reconstitution, single lab\",\n      \"pmids\": [\"9551090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse SUG1 (PSMC5) interacts with mouse Prp19 (a ubiquitin ligase involved in pre-mRNA splicing/DNA repair); the N-terminus (U-box domain) of mPrp19 binds the C-terminus of mSUG1; co-expression of mPrp19 increases cellular proteasome activity; GFP-mPrp19 co-localizes with mSUG1 in cytoplasmic speckle-like structures in the presence of proteasome inhibitor MG132.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, GFP co-localization, proteasome activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple binding assays confirmed but functional link based on overexpression and single proteasome activity measurement, single lab\",\n      \"pmids\": [\"17349974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Sug1 (PSMC5) interacts with the C-terminal tail of the unconventional myosin MYO18B; Sug1 knockdown or proteasome inhibitor treatment increases MYO18B protein levels, and MYO18B is polyubiquitinated in vivo, indicating MYO18B is a substrate targeted for proteasomal degradation via Sug1.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, siRNA knockdown, proteasome inhibitor treatment, ubiquitination assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple binding assays with siRNA and ubiquitination, but single lab and limited mechanistic depth\",\n      \"pmids\": [\"16499872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Adenovirus E1A 12S and 13S proteins bind directly to mammalian SUG1 (PSMC5), a 26S proteasome regulatory component; Ad12 E1A 13S binds SUG1 via a region distinct from conserved region 1 (which mediates increased p53 expression), and E1A co-immunoprecipitates with SUG1 in human cells infected with Ad5; SV40 large T antigen also co-immunoprecipitates with SUG1.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, virus infection, 26S proteasome peptidase activity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and in vitro binding but mechanistic consequence of the interaction is limited; single lab\",\n      \"pmids\": [\"9927201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PSMC5 promotes SMURF1-dependent K11-linked ubiquitination of METTL14 at K263, leading to METTL14 destabilization and global m⁶A remodeling; SMURF1 silencing restores METTL14 expression and attenuates PSMC5-driven tumor growth and lung metastasis in vivo.\",\n      \"method\": \"Ubiquitination assay with K11-linkage specificity, site-directed mutagenesis (K263), rescue/overexpression experiments, in vivo xenograft/metastasis model with SMURF1 siRNA\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site mutagenesis and in vivo rescue, single lab, mechanistic cascade defined\",\n      \"pmids\": [\"42212325\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSMC5 (SUG1/TRIP1/RPT6) is an AAA+ ATPase subunit of the 19S regulatory particle of the 26S proteasome that (1) provides essential ATPase and DNA helicase activities required for ubiquitin-dependent protein degradation; (2) directly contacts substrates and transcription factors (VDR, RARs, SRC-3, Sp1, c-Fos, ΔFosB, CIITA) at their activation domains to couple their proteasomal degradation with transcriptional activation; (3) binds and recruits the acetyltransferase CBP to promoters (e.g., MHC class I/II), regulating histone H3 acetylation and enhanceosome assembly; (4) interacts with signaling proteins (NLRC4/Ipaf, Shoc2, TLR4) to modulate ubiquitination-dependent signaling and spatial remodeling of scaffold complexes; (5) links proteasomal regulation to SMURF1-mediated K11-ubiquitination of METTL14; and (6) loss-of-function mutations impair 19S–20S proteasome assembly and cause neurodevelopmental proteasomopathies through protein aggregation, mitochondrial dysfunction, and immune dysregulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSMC5 (SUG1/TRIP1/RPT6) is an essential AAA+ ATPase subunit of the 19S regulatory particle of the 26S proteasome that couples ATP-dependent protein degradation to the control of transcription, signaling, and cell fate [#0, #1]. Beyond its structural role in the proteasome, recombinant PSMC5 has intrinsic Mg2+-dependent ATPase activity that is stimulated specifically by poly(U)/poly(C) and poly(A)+ mRNA, and an ATP-binding-domain-dependent 3'→5' DNA helicase activity [#2, #3]. A recurrent theme is that PSMC5 docks onto the activation domains of transcription factors and nuclear receptors to couple their proteasomal turnover with transactivation: it binds the AF-2 domains of VDR and RARs and the coactivator SRC-3 in a ligand-dependent manner, and stimulates proteasome-dependent degradation of Sp1, with ATP hydrolysis required and ATPase-dead mutants acting as dominant negatives [#5, #7, #8, #11]. In the immune system, PSMC5 associates with the MHC class II transactivator CIITA and is recruited to MHC class I and II promoters, where it binds acetylated histone H3 and recruits the acetyltransferase CBP to drive promoter H3 acetylation and transcription [#9, #10, #22]. PSMC5 also remodels signaling scaffolds and ubiquitination: it relocalizes the Shoc2–RAF-1 complex to endosomes and displaces the E3 ligase HUWE1 [#13], engages NLRC4/Ipaf to promote caspase-8-dependent cell death [#12, #16], and drives SMURF1-dependent K11-ubiquitination of METTL14 to remodel m6A and promote tumor growth [#29]. Loss-of-function mutations, including P320R and haploinsufficiency, weaken 19S–20S proteasome association and impair proteasome function, causing neurodevelopmental proteasomopathies characterized by protein aggregation, mitochondrial dysfunction, integrated-stress-response activation, and immune dysregulation [#18, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved whether Sug1 belongs to the transcription machinery or the proteasome, establishing PSMC5 as a 26S proteasome subunit required for ubiquitin-dependent proteolysis.\",\n      \"evidence\": \"Biochemical co-purification and functional proteolysis assays in yeast mutants; nuclear fractionation, reciprocal Co-IP and antibody depletion in mammalian cells\",\n      \"pmids\": [\"8628401\", \"8710853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which substrates require Sug1 specifically\", \"Structural position within the 19S particle not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined PSMC5's intrinsic enzymatic activities—ATP-domain-dependent DNA helicase and RNA-stimulated ATPase—indicating activities beyond simple unfoldase function.\",\n      \"evidence\": \"In vitro helicase and ATPase assays with recombinant protein, ATPase-domain mutagenesis, UV cross-linking, RNA-stimulation panels\",\n      \"pmids\": [\"9054406\", \"9287326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of helicase and RNA-stimulated ATPase activities in the assembled proteasome not established\", \"No cellular substrate of the helicase activity identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Linked PSMC5 to transcription/repair machinery via XPB/TFIIH, hinting at a role coupling proteolysis to transcription.\",\n      \"evidence\": \"Yeast two-hybrid, baculovirus co-expression, co-purification with TFIIH, in vivo overexpression phenotype\",\n      \"pmids\": [\"9173976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TFIIH association not separated from general proteasome effects\", \"Single lab\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the paradigm that PSMC5 couples ligand-dependent nuclear receptor degradation to transactivation, using VDR as the first example.\",\n      \"evidence\": \"Co-IP, transient overexpression, proteasome inhibitors, ATPase-dead K196H mutant, reporter assays, cycloheximide chase\",\n      \"pmids\": [\"9831079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether degradation is required for activation or a parallel event not fully resolved\", \"Generality beyond VDR untested at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified PSMC5 (TRIP-1) as a TGF-beta type II receptor-associated, receptor-phosphorylated repressor of TGF-beta transcriptional output.\",\n      \"evidence\": \"Transient transfection, luciferase reporters, deletion mutagenesis, co-expression with Smads and constitutively active receptors\",\n      \"pmids\": [\"9813058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting receptor phosphorylation of TRIP-1 to repression unclear\", \"Endogenous relevance not shown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated mechanistically that PSMC5 ATP hydrolysis drives substrate degradation, using Sp1 and an ATPase-dead dominant negative.\",\n      \"evidence\": \"In vitro reconstituted degradation, Co-IP, in vivo overexpression, ATPase-mutant/truncation dominant-negative analysis\",\n      \"pmids\": [\"10816420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Sp1 degradation is direct via PSMC5 or requires full proteasome assembly not isolated\", \"Ubiquitination requirement not detailed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Generalized the receptor-turnover/activation coupling to RAR-gamma2, integrating p38MAPK signaling with proteasome-dependent transactivation.\",\n      \"evidence\": \"Co-IP, proteasome and p38MAPK inhibitors, transcription reporter assays\",\n      \"pmids\": [\"12110588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect coupling of turnover to activation not dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tied PSMC5 proteasome function to mitotic spindle checkpoint integrity and chemosensitivity to spindle poisons.\",\n      \"evidence\": \"Dominant-negative truncation, siRNA knockdown, proteasome activity, mitotic index and apoptosis assays\",\n      \"pmids\": [\"16432160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PSMC5 to BubR1 levels unclear\", \"General proteasome impairment vs specific role not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the transcriptional role to immune gene regulation, showing PSMC5 promotes CIITA recruitment to the MHC II promoter independent of proteasome activity.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, reporter assays, proteasome inhibition\",\n      \"pmids\": [\"18215421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-proteolytic mechanism of promoter recruitment incompletely defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a chromatin-level mechanism by which PSMC5 binds acetylated H3 and recruits CBP to drive promoter acetylation for transcription initiation.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA knockdown, histone acetylation assays\",\n      \"pmids\": [\"18662994\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs proteasome-mediated CBP recruitment not fully separated\", \"Specificity for H3K18 mechanism unexplained\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PSMC5/TRIP-1 loss promotes TGF-beta-driven EMT through elevated TGF-beta receptor II, Smad3 phosphorylation, and SLUG induction.\",\n      \"evidence\": \"shRNA knockdown, western blotting, morphology/migration assays, EMT marker analysis\",\n      \"pmids\": [\"21378021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether receptor accumulation is proteasome-dependent not directly tested\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened immune-gene regulation to MHC class I and HLA-DM/DO, with PSMC5 controlling CBP/CIITA recruitment and H3 acetylation.\",\n      \"evidence\": \"siRNA knockdown, ChIP, transcription assays\",\n      \"pmids\": [\"22771340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic distinction from MHC II regulation not addressed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Distinguished a Smad-independent, AKT-mediated fibroblast-to-myofibroblast role for PSMC5/TRIP-1, separating its signaling outputs.\",\n      \"evidence\": \"siRNA, overexpression, AKT inhibitor and constitutively active AKT, alpha-SMA western, collagen contraction, Smad3 knockdown\",\n      \"pmids\": [\"24528651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link from PSMC5 loss to AKT activation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed non-degradative scaffold remodeling: PSMC5 relocates Shoc2-RAF-1 to endosomes and displaces HUWE1 to tune ubiquitylation.\",\n      \"evidence\": \"Co-IP, live-cell imaging, subcellular fractionation, ubiquitylation assay, RASopathy mutant analysis\",\n      \"pmids\": [\"26519477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a proteasome ATPase displaces an E3 ligase mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Implicated PSMC5 in innate immune cell-death control via NLRC4/Ipaf ubiquitination and caspase-8 activation.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, co-localization, ubiquitination and caspase-8 assays, RNAi, cell death assays\",\n      \"pmids\": [\"20085538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PSMC5 directly mediates Ipaf ubiquitination or recruits an E3 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed an autoinflammatory NLRC4 mutant depends on enhanced SUG1 interaction for phosphorylation-independent caspase-8/FADD-dependent apoptosis.\",\n      \"evidence\": \"Comparative Co-IP of NLRC4 mutants, caspase-8 and cell death assays, FADD dependency, ubiquitination assays\",\n      \"pmids\": [\"27974463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of enhanced mutant binding undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected nuclear PSMC5 to behavioral plasticity through DeltaFosB complexes with gene-activating chromatin regulators in the nucleus accumbens.\",\n      \"evidence\": \"Yeast two-hybrid, endogenous Co-IP, subcellular fractionation, viral overexpression, behavioral locomotor assays\",\n      \"pmids\": [\"25962134\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which PSMC5 modifies DeltaFosB transcriptional output unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked PSMC5 proteasome function to p53/p21 stability and radiosensitivity via an AKT/MDM2 axis in lung cancer cells.\",\n      \"evidence\": \"siRNA, AKT inhibitor, MDM2 siRNA epistasis, western blotting, clonogenic survival after irradiation\",\n      \"pmids\": [\"26592665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PSMC5 targets upstream of AKT not identified\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed hypoxia-induced PSMC5 drives CIITA acetylation/K63-ubiquitination, nuclear translocation, and MHC-II upregulation, affecting MSC immunoprivilege.\",\n      \"evidence\": \"Co-IP, ubiquitination/acetylation assays, siRNA, nuclear fractionation, in vivo myocardial infarction MSC transplantation model\",\n      \"pmids\": [\"32770803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic role of PSMC5 in CIITA PTMs vs adaptor role unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established disease causality: the P320R mutation and haploinsufficiency weaken 19S-20S proteasome association and impair function, activating apoptosis in patient cells.\",\n      \"evidence\": \"Patient-derived cells, proteasome activity assays, 19S-20S interface Co-IP, apoptosis marker western blotting\",\n      \"pmids\": [\"38776958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of weakened 19S-20S docking not resolved\", \"Genotype-phenotype correlation across variants not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the broad cellular pathology of PSMC5 loss-of-function proteasomopathy and a therapeutic entry point via integrated stress response kinase inhibition.\",\n      \"evidence\": \"Patient-derived cells, multi-omics, Drosophila knockdown, proteasome activity assays, neuronal morphology, PKR/GCN2 inhibition\",\n      \"pmids\": [\"41298377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from proteasome impairment to specific neural phenotypes incomplete\", \"Durability/safety of ISR kinase inhibition unaddressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a pro-tumorigenic cascade in which PSMC5 drives SMURF1-dependent K11-ubiquitination of METTL14 to remodel m6A.\",\n      \"evidence\": \"K11-linkage-specific ubiquitination assay, K263 site mutagenesis, rescue experiments, in vivo xenograft/metastasis with SMURF1 siRNA\",\n      \"pmids\": [\"42212325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PSMC5 promotes SMURF1 activity toward METTL14 mechanistically unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PSMC5's intrinsic biochemical activities (helicase, RNA-stimulated ATPase) and its many non-proteolytic scaffolding/transcriptional functions are mechanistically distinct from its role within the assembled 26S proteasome remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of PSMC5 engaging transcription-factor activation domains\", \"Whether free-pool PSMC5 acts outside the proteasome not established\", \"Direct E3-ligase recruitment partners for many ubiquitination events unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2, 3, 5, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5, 7, 27, 29]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 9, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12, 26]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 5, 7, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 9, 10, 11, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10, 12, 17, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 13, 23, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 16, 18, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 20]}\n    ],\n    \"complexes\": [\"26S proteasome\", \"19S regulatory particle\"],\n    \"partners\": [\"CIITA\", \"VDR\", \"Sp1\", \"SRC-3\", \"NLRC4\", \"Shoc2\", \"CBP\", \"c-Fos\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}