{"gene":"UBFD1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2009,"finding":"UBFD1 was identified as a novel polyubiquitin binding protein using protein array screening with polyubiquitin as bait.","method":"Protein array screening with polyubiquitin as bait","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein array binding assay, single lab, single method, but replicated alongside multiple known polyubiquitin binders as positive controls","pmids":["19285159"],"is_preprint":false},{"year":2025,"finding":"UBFD1 is a CoA-binding protein that scaffolds HIF-1α for proteasomal degradation; CoAsy deficiency disrupts the UBFD1–HIF-1α–proteasome association, stabilizing HIF-1α and HIF-2α independently of the canonical oxygen-sensing pathway. UBFD1's PH domain mediates CoA-dependent interaction with HIFα and undergoes CoAlation (a post-translational modification by CoA).","method":"Proximity-labelling proteomics (BioID/APEX), loss-of-function (CoAsy knockdown/knockout), domain mutagenesis, CoAlation assay","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity-labelling proteomics combined with functional loss-of-function and PTM identification in single preprint lab, multiple orthogonal methods but not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"UBFD1 is a polyubiquitin-binding protein whose PH domain binds Coenzyme A (and undergoes CoAlation), enabling it to scaffold HIF-1α for proteasomal degradation; disruption of CoAsy-mediated CoA homeostasis abrogates this UBFD1–HIFα–proteasome interaction, stabilizing HIF activity independently of canonical oxygen sensing."},"narrative":{"mechanistic_narrative":"UBFD1 is a polyubiquitin-binding protein that links coenzyme A metabolism to the regulation of hypoxia-inducible factor stability [PMID:19285159]. It was first identified as a novel polyubiquitin binder in protein array screening [PMID:19285159]. UBFD1 binds coenzyme A through its PH domain, which itself undergoes CoAlation, and in a CoA-dependent manner scaffolds HIF-1α for proteasomal degradation. Disruption of CoA homeostasis through CoAsy deficiency abrogates the UBFD1–HIFα–proteasome association, stabilizing both HIF-1α and HIF-2α independently of the canonical oxygen-sensing pathway. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Established UBFD1 as a previously uncharacterized protein with the capacity to engage the ubiquitin system, framing it as a candidate adaptor in ubiquitin-dependent processes.","evidence":"Protein array screening with polyubiquitin as bait alongside known polyubiquitin binders as controls","pmids":["19285159"],"confidence":"Medium","gaps":["Single binding-assay method without cellular validation of the interaction","No linkage assigned for the polyubiquitin chains bound","No physiological substrate or pathway identified"]},{"year":2025,"claim":"Connected UBFD1 to CoA metabolism and HIF regulation, showing it scaffolds HIFα for proteasomal degradation in a CoA-dependent manner and defining a non-canonical, oxygen-independent route to HIF stabilization.","evidence":"Proximity-labelling proteomics, CoAsy loss-of-function, PH-domain mutagenesis, and CoAlation assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Not yet peer-reviewed","Mechanism connecting polyubiquitin binding (2009) to the CoA/HIF scaffolding role is not resolved","Structural basis of CoA binding and CoAlation of the PH domain not defined"]},{"year":null,"claim":"How UBFD1's polyubiquitin-binding activity mechanistically integrates with its CoA-dependent HIFα scaffolding function, and whether it acts more broadly in ubiquitin-dependent degradation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconciliation of the ubiquitin-binding and CoA-binding activities","No structural model of UBFD1 or its complexes","No additional substrates or interactors validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1]}],"complexes":[],"partners":["HIF1A","HIF2A","COASY"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14562","full_name":"Ubiquitin domain-containing protein UBFD1","aliases":["Ubiquitin-binding protein homolog"],"length_aa":309,"mass_kda":33.4,"function":"May play a role as NF-kappa-B regulator","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O14562/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBFD1","classification":"Not Classified","n_dependent_lines":44,"n_total_lines":1208,"dependency_fraction":0.03642384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PSMC4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBFD1","total_profiled":1310},"omim":[{"mim_id":"621059","title":"UBIQUITIN FAMILY DOMAIN-CONTAINING PROTEIN 1; UBFD1","url":"https://www.omim.org/entry/621059"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":74.7}],"url":"https://www.proteinatlas.org/search/UBFD1"},"hgnc":{"alias_symbol":["FLJ42145","FLJ38870","UBPH"],"prev_symbol":[]},"alphafold":{"accession":"O14562","domains":[{"cath_id":"3.10.20.90","chopping":"86-159","consensus_level":"high","plddt":85.1519,"start":86,"end":159},{"cath_id":"2.30.29.30","chopping":"186-304","consensus_level":"high","plddt":84.5386,"start":186,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14562","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14562-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14562-F1-predicted_aligned_error_v6.png","plddt_mean":70.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBFD1","jax_strain_url":"https://www.jax.org/strain/search?query=UBFD1"},"sequence":{"accession":"O14562","fasta_url":"https://rest.uniprot.org/uniprotkb/O14562.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14562/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14562"}},"corpus_meta":[{"pmid":"19285159","id":"PMC_19285159","title":"Identification of polyubiquitin binding proteins involved in NF-kappaB signaling using protein arrays.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19285159","citation_count":57,"is_preprint":false},{"pmid":"38511057","id":"PMC_38511057","title":"LncRNA PCAT6 mediates UBFD1 expression via sponging miR-545-3p in breast cancer cells.","date":"2024","source":"Non-coding RNA research","url":"https://pubmed.ncbi.nlm.nih.gov/38511057","citation_count":4,"is_preprint":false},{"pmid":"39663698","id":"PMC_39663698","title":"Whole-exome sequencing reveals known and candidate genes for hearing impairment in Mali.","date":"2024","source":"HGG advances","url":"https://pubmed.ncbi.nlm.nih.gov/39663698","citation_count":1,"is_preprint":false},{"pmid":"39502647","id":"PMC_39502647","title":"Ustekinumab affects myofibroblast metabolism to alleviate intestinal fibrosis by targeting KDELC1 in Crohn's disease through multi-machine learning combined with single-cell sequencing analysis.","date":"2024","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39502647","citation_count":0,"is_preprint":false},{"pmid":"39954892","id":"PMC_39954892","title":"Fe ion coordination direction and refresh mechanism in off-line αKG-dependent hydroxylase.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39954892","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.18.660436","title":"Coenzyme A homeostasis regulates hypoxic signalling via UBFD1 in triple-negative breast cancer","date":"2025-06-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.18.660436","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5522,"output_tokens":559,"usd":0.012476,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6926,"output_tokens":1273,"usd":0.033228,"stage2_stop_reason":"end_turn"},"total_usd":0.045704,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"UBFD1 was identified as a novel polyubiquitin binding protein using protein array screening with polyubiquitin as bait.\",\n      \"method\": \"Protein array screening with polyubiquitin as bait\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein array binding assay, single lab, single method, but replicated alongside multiple known polyubiquitin binders as positive controls\",\n      \"pmids\": [\"19285159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UBFD1 is a CoA-binding protein that scaffolds HIF-1α for proteasomal degradation; CoAsy deficiency disrupts the UBFD1–HIF-1α–proteasome association, stabilizing HIF-1α and HIF-2α independently of the canonical oxygen-sensing pathway. UBFD1's PH domain mediates CoA-dependent interaction with HIFα and undergoes CoAlation (a post-translational modification by CoA).\",\n      \"method\": \"Proximity-labelling proteomics (BioID/APEX), loss-of-function (CoAsy knockdown/knockout), domain mutagenesis, CoAlation assay\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity-labelling proteomics combined with functional loss-of-function and PTM identification in single preprint lab, multiple orthogonal methods but not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"UBFD1 is a polyubiquitin-binding protein whose PH domain binds Coenzyme A (and undergoes CoAlation), enabling it to scaffold HIF-1α for proteasomal degradation; disruption of CoAsy-mediated CoA homeostasis abrogates this UBFD1–HIFα–proteasome interaction, stabilizing HIF activity independently of canonical oxygen sensing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBFD1 is a polyubiquitin-binding protein that links coenzyme A metabolism to the regulation of hypoxia-inducible factor stability [#0, #1]. It was first identified as a novel polyubiquitin binder in protein array screening [#0]. UBFD1 binds coenzyme A through its PH domain, which itself undergoes CoAlation, and in a CoA-dependent manner scaffolds HIF-1\\u03b1 for proteasomal degradation [#1]. Disruption of CoA homeostasis through CoAsy deficiency abrogates the UBFD1\\u2013HIF\\u03b1\\u2013proteasome association, stabilizing both HIF-1\\u03b1 and HIF-2\\u03b1 independently of the canonical oxygen-sensing pathway [#1]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established UBFD1 as a previously uncharacterized protein with the capacity to engage the ubiquitin system, framing it as a candidate adaptor in ubiquitin-dependent processes.\",\n      \"evidence\": \"Protein array screening with polyubiquitin as bait alongside known polyubiquitin binders as controls\",\n      \"pmids\": [\"19285159\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single binding-assay method without cellular validation of the interaction\",\n        \"No linkage assigned for the polyubiquitin chains bound\",\n        \"No physiological substrate or pathway identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected UBFD1 to CoA metabolism and HIF regulation, showing it scaffolds HIF\\u03b1 for proteasomal degradation in a CoA-dependent manner and defining a non-canonical, oxygen-independent route to HIF stabilization.\",\n      \"evidence\": \"Proximity-labelling proteomics, CoAsy loss-of-function, PH-domain mutagenesis, and CoAlation assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Not yet peer-reviewed\",\n        \"Mechanism connecting polyubiquitin binding (2009) to the CoA/HIF scaffolding role is not resolved\",\n        \"Structural basis of CoA binding and CoAlation of the PH domain not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBFD1's polyubiquitin-binding activity mechanistically integrates with its CoA-dependent HIF\\u03b1 scaffolding function, and whether it acts more broadly in ubiquitin-dependent degradation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No reconciliation of the ubiquitin-binding and CoA-binding activities\",\n        \"No structural model of UBFD1 or its complexes\",\n        \"No additional substrates or interactors validated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HIF1A\", \"HIF2A\", \"CoAsy\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"UBFD1","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"uncited_synthesis","uniprot_band":"sparse","rules_fired":"R8","issue":"R8: 2/4 claims uncited (50%)"},"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}