{"gene":"UBAC1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2005,"finding":"KPC2 (UBAC1) interacts with KPC1 through its UBL domain, with the 26S proteasome through its UBL and N-terminal UBA domains, and with polyubiquitylated proteins through its UBA domains, as shown by co-immunoprecipitation and domain-deletion experiments.","method":"Co-immunoprecipitation, domain deletion mutants, in vitro polyubiquitylation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro ubiquitylation, RNAi rescue) in a single focused study with domain-mapping rigor","pmids":["16227581"],"is_preprint":false},{"year":2005,"finding":"KPC2 (UBAC1) association with KPC1 stabilizes KPC1 in a manner dependent on the STI1 domain of KPC2, as demonstrated by expression of STI1-deletion mutants in cells.","method":"Domain deletion mutagenesis, protein stability assay (cycloheximide chase implied), co-expression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, domain deletion with functional readout (KPC1 stability), but single publication","pmids":["16227581"],"is_preprint":false},{"year":2005,"finding":"KPC2 (UBAC1) mutants lacking either the N-terminal or C-terminal UBA domain could still support polyubiquitylation of p27 in vitro, but a KPC2 derivative lacking the STI1 domain was greatly impaired in p27 polyubiquitylation.","method":"In vitro ubiquitylation assay with domain-deletion mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitylation assay with structure-function mutagenesis, single lab","pmids":["16227581"],"is_preprint":false},{"year":2005,"finding":"Depletion of KPC2 (UBAC1) by RNAi inhibited p27 degradation at G1 phase; rescue experiments with domain mutants revealed that the N-terminal UBA domain of KPC2 is essential for p27 degradation in cells.","method":"RNA interference (RNAi) knockdown, rescue with domain mutants, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with domain-specific rescue, multiple mutants tested, direct functional readout (p27 protein levels at G1)","pmids":["16227581"],"is_preprint":false},{"year":2021,"finding":"KPC2 (UBAC1) was identified as a novel interaction partner of CD95 (Fas) by unbiased proteomics; CD95/KPC2 interaction contributes to partial degradation of p105 (NF-κB1) and generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression independently of CD95L.","method":"Unbiased proteomics (pull-down/MS), co-immunoprecipitation, NF-κB reporter assay, p105/p50 immunoblot","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased proteomics plus reciprocal Co-IP and functional NF-κB readout, single lab","pmids":["34917906"],"is_preprint":false},{"year":2021,"finding":"KPC2 (UBAC1) interacts with the C-terminal region of CD95 and acts as an adaptor to recruit RelA (p65) and KPC1 (the E3 ubiquitin ligase), which promotes degradation of p105 into p50.","method":"Co-immunoprecipitation with deletion constructs, proximity ligation or co-IP of KPC1/RelA complex","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, single lab, mechanistic model supported by multiple co-IP experiments","pmids":["34917906"],"is_preprint":false},{"year":2021,"finding":"Loss of CD95 in triple-negative breast cancer (TNBC) cells releases KPC2 (UBAC1), limiting formation of the NF-κB inhibitory p50/p50 homodimer complex and promoting NF-κB activation and pro-inflammatory cytokine production.","method":"CD95 knockdown/knockout in TNBC cells, NF-κB activity measurement, cytokine ELISA","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (CD95 KO) with defined molecular phenotype (p50 homodimer loss, NF-κB activation), single lab","pmids":["34917906"],"is_preprint":false}],"current_model":"UBAC1 (KPC2) is a UBL-UBA-STI1 domain adaptor protein that forms the KPC ubiquitin ligase complex with KPC1: it binds KPC1 via its UBL domain to stabilize KPC1, recruits polyubiquitylated substrates (including the CDK inhibitor p27) via its UBA domains, and requires its STI1 domain for productive p27 polyubiquitylation and degradation at G1; additionally, UBAC1 is recruited to the cytoplasmic tail of CD95 (Fas) independently of CD95L, where it acts as an adaptor to recruit KPC1 and RelA, driving partial proteolysis of p105 to p50 and thereby suppressing NF-κB transcriptional activity in breast cancer cells."},"narrative":{"mechanistic_narrative":"UBAC1 (KPC2) is a multidomain adaptor subunit of the KPC ubiquitin ligase complex that couples polyubiquitylated substrates to E3-mediated degradation during cell cycle control [PMID:16227581]. It binds the catalytic subunit KPC1 through its UBL domain and engages the 26S proteasome through its UBL and N-terminal UBA domains, while its UBA domains capture polyubiquitylated cargo [PMID:16227581]; the KPC1 interaction stabilizes KPC1 in a manner requiring the UBAC1 STI1 domain [PMID:16227581]. Functionally, UBAC1 drives degradation of the CDK inhibitor p27 at G1: its STI1 domain is required for efficient p27 polyubiquitylation in vitro, and its N-terminal UBA domain is essential for p27 degradation in cells [PMID:16227581]. Beyond cell-cycle control, UBAC1 is recruited to the C-terminal cytoplasmic region of CD95 (Fas) independently of CD95L, where it acts as an adaptor to bring together KPC1 and RelA, promoting partial proteolysis of p105 (NF-κB1) into p50 and formation of inhibitory p50 homodimers that repress NF-κB transcription [PMID:34917906]; loss of CD95 releases UBAC1, limiting p50/p50 formation and de-repressing NF-κB-driven cytokine production in triple-negative breast cancer cells [PMID:34917906].","teleology":[{"year":2005,"claim":"Established UBAC1 as the substrate- and proteasome-bridging subunit of the KPC ligase by defining which domains contact KPC1, the proteasome, and ubiquitin chains.","evidence":"Co-immunoprecipitation, domain-deletion mutants, and in vitro polyubiquitylation in cells","pmids":["16227581"],"confidence":"High","gaps":["No structural model of the UBL/UBA-domain interactions","Affinity and chain-linkage selectivity of the UBA domains not quantified"]},{"year":2005,"claim":"Showed that UBAC1 binding does not merely scaffold but stabilizes the catalytic partner KPC1, identifying the STI1 domain as the determinant of this stabilization.","evidence":"STI1-deletion mutants with KPC1 protein-stability readout on co-expression","pmids":["16227581"],"confidence":"Medium","gaps":["Mechanism by which STI1 stabilizes KPC1 unresolved","Single publication, no orthogonal stability assay reported"]},{"year":2005,"claim":"Mapped the domain requirements for catalytic output versus cargo handling, distinguishing the STI1 domain (required for p27 polyubiquitylation) from individual UBA domains (dispensable in vitro).","evidence":"In vitro reconstituted ubiquitylation with domain-deletion mutants","pmids":["16227581"],"confidence":"High","gaps":["Why STI1 is needed for polyubiquitylation mechanistically unclear","In vitro requirements not fully matched to cellular requirements"]},{"year":2005,"claim":"Connected UBAC1 to a defined physiological output by demonstrating its requirement for G1 p27 degradation and pinpointing the N-terminal UBA domain as essential in cells.","evidence":"RNAi knockdown with domain-mutant rescue and cell-cycle analysis","pmids":["16227581"],"confidence":"High","gaps":["Other physiological substrates beyond p27 not identified","Discrepancy between cellular UBA requirement and in vitro dispensability unexplained"]},{"year":2021,"claim":"Extended UBAC1 function beyond the cell cycle by identifying it as a CD95 interactor that acts as an adaptor coupling KPC1 and RelA to control NF-κB signaling.","evidence":"Unbiased proteomics, reciprocal Co-IP with deletion constructs, and NF-κB reporter/p105-p50 immunoblot","pmids":["34917906"],"confidence":"Medium","gaps":["Direct UBAC1-CD95 binding interface not structurally defined","Whether p105-to-p50 processing uses the same KPC catalytic mechanism as p27 unknown","Single lab"]},{"year":2021,"claim":"Demonstrated the biological consequence of UBAC1 sequestration by showing CD95 loss releases UBAC1, reduces inhibitory p50 homodimers, and activates pro-inflammatory NF-κB output in TNBC.","evidence":"CD95 knockdown/knockout in TNBC cells with NF-κB activity and cytokine ELISA","pmids":["34917906"],"confidence":"Medium","gaps":["In vivo relevance to tumor behavior not established","Quantitative link between UBAC1 availability and p50 dimer abundance not measured"]},{"year":null,"claim":"The full substrate repertoire of the UBAC1-KPC complex and the structural basis for how a single adaptor switches between cell-cycle (p27) and NF-κB (p105) regulatory programs remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of UBAC1 in either complex","Regulation of UBAC1 partitioning between KPC and CD95 contexts unknown","Substrates beyond p27 and p105 uncharacterized in the available corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6]}],"complexes":["KPC ubiquitin ligase complex"],"partners":["KPC1","P27","CD95","RELA","NFKB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BSL1","full_name":"Ubiquitin-associated domain-containing protein 1","aliases":["Glialblastoma cell differentiation-related protein 1","Kip1 ubiquitination-promoting complex protein 2"],"length_aa":405,"mass_kda":45.3,"function":"Non-catalytic component of the KPC complex, a E3 ubiquitin-protein ligase complex that mediates polyubiquitination of target proteins, such as CDKN1B and NFKB1 (PubMed:15531880, PubMed:15746103, PubMed:16227581, PubMed:25860612). The KPC complex catalyzes polyubiquitination and proteasome-mediated degradation of CDKN1B during G1 phase of the cell cycle (PubMed:15531880, PubMed:15746103). The KPC complex also acts as a key regulator of the NF-kappa-B signaling by promoting maturation of the NFKB1 component of NF-kappa-B by catalyzing ubiquitination of the NFKB1 p105 precursor (PubMed:25860612). Within the KPC complex, UBAC1 acts as an adapter that promotes the transfer of target proteins that have been polyubiquitinated by RNF123/KPC1 to the 26S proteasome (PubMed:16227581)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BSL1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBAC1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBAC1","total_profiled":1310},"omim":[{"mim_id":"614472","title":"RING FINGER PROTEIN 123; RNF123","url":"https://www.omim.org/entry/614472"},{"mim_id":"608129","title":"UBA DOMAIN-CONTAINING PROTEIN 1; UBAC1","url":"https://www.omim.org/entry/608129"},{"mim_id":"602559","title":"EXPORTIN 1; XPO1","url":"https://www.omim.org/entry/602559"},{"mim_id":"601436","title":"S-PHASE KINASE-ASSOCIATED PROTEIN 2; SKP2","url":"https://www.omim.org/entry/601436"},{"mim_id":"600778","title":"CYCLIN-DEPENDENT KINASE INHIBITOR 1B; CDKN1B","url":"https://www.omim.org/entry/600778"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":290.9},{"tissue":"tongue","ntpm":159.7}],"url":"https://www.proteinatlas.org/search/UBAC1"},"hgnc":{"alias_symbol":["GBDR1","KPC2"],"prev_symbol":["UBADC1"]},"alphafold":{"accession":"Q9BSL1","domains":[{"cath_id":"3.10.20.90","chopping":"12-92","consensus_level":"high","plddt":85.5106,"start":12,"end":92},{"cath_id":"1.10.8.10","chopping":"191-230","consensus_level":"medium","plddt":81.8222,"start":191,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSL1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSL1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BSL1-F1-predicted_aligned_error_v6.png","plddt_mean":74.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBAC1","jax_strain_url":"https://www.jax.org/strain/search?query=UBAC1"},"sequence":{"accession":"Q9BSL1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BSL1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BSL1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BSL1"}},"corpus_meta":[{"pmid":"17562800","id":"PMC_17562800","title":"Emergence 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Resistance.","date":"2018","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/29356380","citation_count":25,"is_preprint":false},{"pmid":"34461917","id":"PMC_34461917","title":"Bloodstream Infections caused by Klebsiella pneumoniae and Serratia marcescens isolates co-harboring NDM-1 and KPC-2.","date":"2021","source":"Annals of clinical microbiology and antimicrobials","url":"https://pubmed.ncbi.nlm.nih.gov/34461917","citation_count":24,"is_preprint":false},{"pmid":"31572337","id":"PMC_31572337","title":"Emergence and Characterization of a Novel IncP-6 Plasmid Harboring bla KPC-2 and qnrS2 Genes in Aeromonas taiwanensis Isolates.","date":"2019","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31572337","citation_count":24,"is_preprint":false},{"pmid":"36972204","id":"PMC_36972204","title":"Tautomer-Specific Deacylation and Ω-Loop Flexibility Explain the Carbapenem-Hydrolyzing Broad-Spectrum Activity of the KPC-2 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Venezuelan Hospital.","date":"2016","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27770796","citation_count":21,"is_preprint":false},{"pmid":"34022225","id":"PMC_34022225","title":"Local interactions with the Glu166 base and the conformation of an active site loop play key roles in carbapenem hydrolysis by the KPC-2 β-lactamase.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34022225","citation_count":20,"is_preprint":false},{"pmid":"34007191","id":"PMC_34007191","title":"Ceftazidime-Avibactam Resistance in Klebsiella pneumoniae Sequence Type 11 Due to a Mutation in Plasmid-Borne bla kpc-2 to bla kpc-33, in Henan, China.","date":"2021","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/34007191","citation_count":19,"is_preprint":false},{"pmid":"34954336","id":"PMC_34954336","title":"Emergence of ST39 carbapenem-resistant Klebsiella pneumoniae producing VIM-1 and 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chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/33972237","citation_count":16,"is_preprint":false},{"pmid":"33536766","id":"PMC_33536766","title":"Distribution of β-Lactamase Genes and Genetic Context of bla KPC-2 in Clinical Carbapenemase-Producing Klebsiella pneumoniae Isolates.","date":"2021","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/33536766","citation_count":16,"is_preprint":false},{"pmid":"30543470","id":"PMC_30543470","title":"Endemicity of the High-Risk Clone Klebsiella pneumoniae ST340 Coproducing QnrB, CTX-M-15, and KPC-2 in a Brazilian Hospital.","date":"2018","source":"Microbial drug resistance (Larchmont, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30543470","citation_count":16,"is_preprint":false},{"pmid":"34858362","id":"PMC_34858362","title":"Deciphering the Epidemiological Characteristics and Molecular Features of bla KPC-2- or bla NDM-1-Positive Klebsiella pneumoniae Isolates in a Newly Established Hospital.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34858362","citation_count":16,"is_preprint":false},{"pmid":"21874606","id":"PMC_21874606","title":"Identification of bla KPC-2 on different plasmids of three Morganella morganii isolates.","date":"2011","source":"European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21874606","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56451,"output_tokens":1957,"usd":0.099354,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8457,"output_tokens":2373,"usd":0.050805,"stage2_stop_reason":"end_turn"},"total_usd":0.150159,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human/mammalian gene UBAC1 (also known as KPC2/GBDR1/UBADC1 in the context of the ubiquitin pathway protein) versus the bacterial beta-lactamase KPC-2.\n\nThe alias \"KPC2\" for UBAC1 refers to \"Kip1 ubiquitylation-promoting complex 2\" - a mammalian ubiquitin pathway protein. The vast majority of papers (1-22, 24-100) describe the bacterial carbapenemase enzyme KPC-2 (Klebsiella pneumoniae Carbapenemase-2), which is a completely different entity - a bacterial beta-lactamase resistance gene.\n\nOnly papers 23 and 79 describe the mammalian UBAC1/KPC2 protein:\n- Paper 23 (PMID:16227581): Directly about KPC2 (Kip1 ubiquitylation-promoting complex 2) / UBAC1\n- Paper 79 (PMID:34917906): About KPC2 interacting with CD95 in NF-κB regulation\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"KPC2 (UBAC1) interacts with KPC1 through its UBL domain, with the 26S proteasome through its UBL and N-terminal UBA domains, and with polyubiquitylated proteins through its UBA domains, as shown by co-immunoprecipitation and domain-deletion experiments.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, in vitro polyubiquitylation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vitro ubiquitylation, RNAi rescue) in a single focused study with domain-mapping rigor\",\n      \"pmids\": [\"16227581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KPC2 (UBAC1) association with KPC1 stabilizes KPC1 in a manner dependent on the STI1 domain of KPC2, as demonstrated by expression of STI1-deletion mutants in cells.\",\n      \"method\": \"Domain deletion mutagenesis, protein stability assay (cycloheximide chase implied), co-expression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, domain deletion with functional readout (KPC1 stability), but single publication\",\n      \"pmids\": [\"16227581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KPC2 (UBAC1) mutants lacking either the N-terminal or C-terminal UBA domain could still support polyubiquitylation of p27 in vitro, but a KPC2 derivative lacking the STI1 domain was greatly impaired in p27 polyubiquitylation.\",\n      \"method\": \"In vitro ubiquitylation assay with domain-deletion mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitylation assay with structure-function mutagenesis, single lab\",\n      \"pmids\": [\"16227581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Depletion of KPC2 (UBAC1) by RNAi inhibited p27 degradation at G1 phase; rescue experiments with domain mutants revealed that the N-terminal UBA domain of KPC2 is essential for p27 degradation in cells.\",\n      \"method\": \"RNA interference (RNAi) knockdown, rescue with domain mutants, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with domain-specific rescue, multiple mutants tested, direct functional readout (p27 protein levels at G1)\",\n      \"pmids\": [\"16227581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPC2 (UBAC1) was identified as a novel interaction partner of CD95 (Fas) by unbiased proteomics; CD95/KPC2 interaction contributes to partial degradation of p105 (NF-κB1) and generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression independently of CD95L.\",\n      \"method\": \"Unbiased proteomics (pull-down/MS), co-immunoprecipitation, NF-κB reporter assay, p105/p50 immunoblot\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased proteomics plus reciprocal Co-IP and functional NF-κB readout, single lab\",\n      \"pmids\": [\"34917906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPC2 (UBAC1) interacts with the C-terminal region of CD95 and acts as an adaptor to recruit RelA (p65) and KPC1 (the E3 ubiquitin ligase), which promotes degradation of p105 into p50.\",\n      \"method\": \"Co-immunoprecipitation with deletion constructs, proximity ligation or co-IP of KPC1/RelA complex\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, single lab, mechanistic model supported by multiple co-IP experiments\",\n      \"pmids\": [\"34917906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of CD95 in triple-negative breast cancer (TNBC) cells releases KPC2 (UBAC1), limiting formation of the NF-κB inhibitory p50/p50 homodimer complex and promoting NF-κB activation and pro-inflammatory cytokine production.\",\n      \"method\": \"CD95 knockdown/knockout in TNBC cells, NF-κB activity measurement, cytokine ELISA\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (CD95 KO) with defined molecular phenotype (p50 homodimer loss, NF-κB activation), single lab\",\n      \"pmids\": [\"34917906\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBAC1 (KPC2) is a UBL-UBA-STI1 domain adaptor protein that forms the KPC ubiquitin ligase complex with KPC1: it binds KPC1 via its UBL domain to stabilize KPC1, recruits polyubiquitylated substrates (including the CDK inhibitor p27) via its UBA domains, and requires its STI1 domain for productive p27 polyubiquitylation and degradation at G1; additionally, UBAC1 is recruited to the cytoplasmic tail of CD95 (Fas) independently of CD95L, where it acts as an adaptor to recruit KPC1 and RelA, driving partial proteolysis of p105 to p50 and thereby suppressing NF-κB transcriptional activity in breast cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBAC1 (KPC2) is a multidomain adaptor subunit of the KPC ubiquitin ligase complex that couples polyubiquitylated substrates to E3-mediated degradation during cell cycle control [#0, #3]. It binds the catalytic subunit KPC1 through its UBL domain and engages the 26S proteasome through its UBL and N-terminal UBA domains, while its UBA domains capture polyubiquitylated cargo [#0]; the KPC1 interaction stabilizes KPC1 in a manner requiring the UBAC1 STI1 domain [#1]. Functionally, UBAC1 drives degradation of the CDK inhibitor p27 at G1: its STI1 domain is required for efficient p27 polyubiquitylation in vitro, and its N-terminal UBA domain is essential for p27 degradation in cells [#2, #3]. Beyond cell-cycle control, UBAC1 is recruited to the C-terminal cytoplasmic region of CD95 (Fas) independently of CD95L, where it acts as an adaptor to bring together KPC1 and RelA, promoting partial proteolysis of p105 (NF-\\u03baB1) into p50 and formation of inhibitory p50 homodimers that repress NF-\\u03baB transcription [#4, #5]; loss of CD95 releases UBAC1, limiting p50/p50 formation and de-repressing NF-\\u03baB-driven cytokine production in triple-negative breast cancer cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established UBAC1 as the substrate- and proteasome-bridging subunit of the KPC ligase by defining which domains contact KPC1, the proteasome, and ubiquitin chains.\",\n      \"evidence\": \"Co-immunoprecipitation, domain-deletion mutants, and in vitro polyubiquitylation in cells\",\n      \"pmids\": [\"16227581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the UBL/UBA-domain interactions\", \"Affinity and chain-linkage selectivity of the UBA domains not quantified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that UBAC1 binding does not merely scaffold but stabilizes the catalytic partner KPC1, identifying the STI1 domain as the determinant of this stabilization.\",\n      \"evidence\": \"STI1-deletion mutants with KPC1 protein-stability readout on co-expression\",\n      \"pmids\": [\"16227581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which STI1 stabilizes KPC1 unresolved\", \"Single publication, no orthogonal stability assay reported\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped the domain requirements for catalytic output versus cargo handling, distinguishing the STI1 domain (required for p27 polyubiquitylation) from individual UBA domains (dispensable in vitro).\",\n      \"evidence\": \"In vitro reconstituted ubiquitylation with domain-deletion mutants\",\n      \"pmids\": [\"16227581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why STI1 is needed for polyubiquitylation mechanistically unclear\", \"In vitro requirements not fully matched to cellular requirements\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected UBAC1 to a defined physiological output by demonstrating its requirement for G1 p27 degradation and pinpointing the N-terminal UBA domain as essential in cells.\",\n      \"evidence\": \"RNAi knockdown with domain-mutant rescue and cell-cycle analysis\",\n      \"pmids\": [\"16227581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other physiological substrates beyond p27 not identified\", \"Discrepancy between cellular UBA requirement and in vitro dispensability unexplained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended UBAC1 function beyond the cell cycle by identifying it as a CD95 interactor that acts as an adaptor coupling KPC1 and RelA to control NF-\\u03baB signaling.\",\n      \"evidence\": \"Unbiased proteomics, reciprocal Co-IP with deletion constructs, and NF-\\u03baB reporter/p105-p50 immunoblot\",\n      \"pmids\": [\"34917906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct UBAC1-CD95 binding interface not structurally defined\", \"Whether p105-to-p50 processing uses the same KPC catalytic mechanism as p27 unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated the biological consequence of UBAC1 sequestration by showing CD95 loss releases UBAC1, reduces inhibitory p50 homodimers, and activates pro-inflammatory NF-\\u03baB output in TNBC.\",\n      \"evidence\": \"CD95 knockdown/knockout in TNBC cells with NF-\\u03baB activity and cytokine ELISA\",\n      \"pmids\": [\"34917906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to tumor behavior not established\", \"Quantitative link between UBAC1 availability and p50 dimer abundance not measured\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full substrate repertoire of the UBAC1-KPC complex and the structural basis for how a single adaptor switches between cell-cycle (p27) and NF-\\u03baB (p105) regulatory programs remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of UBAC1 in either complex\", \"Regulation of UBAC1 partitioning between KPC and CD95 contexts unknown\", \"Substrates beyond p27 and p105 uncharacterized in the available corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"complexes\": [\"KPC ubiquitin ligase complex\"],\n    \"partners\": [\"KPC1\", \"p27\", \"CD95\", \"RelA\", \"NFKB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}