{"gene":"KNOP1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"TSG118 (KNOP1) localizes to the dense fibrillar component of the nucleolus during interphase (co-localizing with fibrillarin) and re-localizes to the surface of condensed chromosomes during mitosis, indicating cell-cycle-dependent subcellular redistribution.","method":"Indirect immunofluorescence microscopy with affinity-purified anti-Tsg118 serum; co-localization with fibrillarin as nucleolar marker","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional implication of cell-cycle regulation, single lab, two markers used orthogonally","pmids":["10430019"],"is_preprint":false},{"year":2005,"finding":"TSG118 (KNOP1) physically interacts with the C-terminal WD40 repeat domain of ZFP106 and co-localizes with ZFP106 in the nucleolus; rapid downregulation of TSG118 during terminal differentiation in vitro coincides with loss of nucleolar ZFP106, indicating TSG118 is required for nucleolar retention of ZFP106.","method":"Yeast two-hybrid, co-localization by immunofluorescence, deletion analysis of ZFP106 domains, in vitro differentiation assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction mapped by two-hybrid and deletion analysis, co-localization confirmed, functional consequence (loss of ZFP106 nucleolar targeting) demonstrated in one lab","pmids":["15833274"],"is_preprint":false},{"year":2025,"finding":"KNOP1 directly interacts with NMNAT1 to maintain intracellular NAD+ homeostasis, which inhibits FoxO1 phosphorylation and promotes FoxO1 nuclear retention, thereby facilitating GPX4 transcription and suppressing ferroptosis in breast cancer cells; KNOP1 knockdown reduces NAD+ levels, induces FoxO1 nuclear export, downregulates GPX4, and enhances ferroptosis, all reversible by Ferrostatin-1 treatment or NMNAT1 overexpression.","method":"Co-immunoprecipitation (co-IP), ChIP assay, NAD+ quantification, CCK-8/EdU/transwell assays, ROS detection, tumor xenograft models, rescue experiments with Ferrostatin-1 and NMNAT1 overexpression, NMNAT1 knockdown epistasis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, ChIP, NAD+ quantification, genetic rescue) in a single lab; not yet independently replicated","pmids":["40784594"],"is_preprint":false}],"current_model":"KNOP1 (TSG118) is a nucleolar protein that redistributes to condensed chromosomes during mitosis, recruits ZFP106 to the nucleolus via interaction with its WD40 domain, and in breast cancer cells forms a complex with NMNAT1 to sustain NAD+ levels, thereby suppressing FoxO1 phosphorylation, promoting GPX4 transcription, and inhibiting ferroptosis."},"narrative":{"mechanistic_narrative":"KNOP1 (TSG118) is a nucleolar protein that undergoes cell-cycle-dependent redistribution, occupying the dense fibrillar component of the nucleolus in interphase—where it co-localizes with fibrillarin—and relocating to the surface of condensed chromosomes during mitosis [PMID:10430019]. Within the nucleolus it serves as a retention factor for ZFP106, binding the C-terminal WD40 repeat domain of ZFP106 and being required for its nucleolar localization [PMID:15833274]. Beyond this structural role, KNOP1 has a metabolic function in breast cancer cells, where it directly interacts with NMNAT1 to sustain intracellular NAD+ levels; this NAD+ homeostasis suppresses FoxO1 phosphorylation and promotes FoxO1 nuclear retention, driving GPX4 transcription and thereby suppressing ferroptosis [PMID:40784594]. KNOP1 loss reduces NAD+, drives FoxO1 nuclear export, downregulates GPX4, and sensitizes cells to ferroptosis [PMID:40784594].","teleology":[{"year":1999,"claim":"Established KNOP1 as a nucleolar protein with a dynamic, cell-cycle-coupled localization, raising the possibility of distinct interphase and mitotic functions.","evidence":"Indirect immunofluorescence with affinity-purified antibody, co-localization with fibrillarin in interphase and with condensed chromosomes in mitosis","pmids":["10430019"],"confidence":"Medium","gaps":["Molecular function within the nucleolus not defined","Mechanism driving chromosome surface relocalization at mitosis unknown","Single lab, antibody-based localization only"]},{"year":2005,"claim":"Assigned KNOP1 a concrete molecular role as a nucleolar retention factor for ZFP106, answering what protein partner it acts upon in the nucleolus.","evidence":"Yeast two-hybrid, ZFP106 domain deletion mapping, co-localization, and an in vitro differentiation assay linking KNOP1 loss to loss of nucleolar ZFP106","pmids":["15833274"],"confidence":"Medium","gaps":["Functional consequence of ZFP106 nucleolar retention not defined","Interaction not confirmed by reciprocal endogenous co-IP or structure","Biological role of the differentiation-coupled downregulation unresolved"]},{"year":2025,"claim":"Revealed a metabolic axis linking KNOP1 to NAD+ homeostasis and ferroptosis resistance, defining a disease-relevant function distinct from its nucleolar role.","evidence":"Co-IP, ChIP, NAD+ quantification, ROS detection, proliferation/migration assays, xenografts, and rescue/epistasis with Ferrostatin-1 and NMNAT1 in breast cancer cells","pmids":["40784594"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Whether the NMNAT1 axis connects to the nucleolar/ZFP106 functions is unknown","Direct biochemical basis for how KNOP1 sustains NMNAT1-dependent NAD+ output not resolved"]},{"year":null,"claim":"How KNOP1's nucleolar structural role relates to its metabolic NAD+/ferroptosis function, and whether either represents a unified molecular activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or enzymatic activity defined for KNOP1","No mechanism connecting the ZFP106 and NMNAT1 interactions","Physiological role outside cancer cells uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["ZFP106","NMNAT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q1ED39","full_name":"Lysine-rich nucleolar protein 1","aliases":["Protein FAM191A","Testis-specific gene 118 protein"],"length_aa":458,"mass_kda":51.6,"function":"","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q1ED39/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KNOP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"PTMA","stoichiometry":0.2},{"gene":"RTCB","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KNOP1","total_profiled":1310},"omim":[{"mim_id":"621293","title":"LYSINE-RICH NUCLEOLAR PROTEIN 1; KNOP1","url":"https://www.omim.org/entry/621293"},{"mim_id":"603988","title":"ZINC FINGER PROTEIN 106; ZNF106","url":"https://www.omim.org/entry/603988"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KNOP1"},"hgnc":{"alias_symbol":["101F10.1","FAM191A","TSG118"],"prev_symbol":["C16orf88"]},"alphafold":{"accession":"Q1ED39","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1ED39","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q1ED39-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q1ED39-F1-predicted_aligned_error_v6.png","plddt_mean":53.41},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KNOP1","jax_strain_url":"https://www.jax.org/strain/search?query=KNOP1"},"sequence":{"accession":"Q1ED39","fasta_url":"https://rest.uniprot.org/uniprotkb/Q1ED39.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q1ED39/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1ED39"}},"corpus_meta":[{"pmid":"24821223","id":"PMC_24821223","title":"Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.","date":"2014","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24821223","citation_count":234,"is_preprint":false},{"pmid":"33947463","id":"PMC_33947463","title":"Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer's disease.","date":"2021","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33947463","citation_count":57,"is_preprint":false},{"pmid":"15833274","id":"PMC_15833274","title":"Subcellular recruitment by TSG118 and TSPYL implicates a role for zinc finger protein 106 in a novel developmental pathway.","date":"2005","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15833274","citation_count":27,"is_preprint":false},{"pmid":"33627773","id":"PMC_33627773","title":"Transcriptome-wide association study identifies multiple genes associated with childhood body mass index.","date":"2021","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/33627773","citation_count":13,"is_preprint":false},{"pmid":"10430019","id":"PMC_10430019","title":"Characterization of a novel nucleolar protein that transiently associates with the condensed chromosomes in mitotic cells.","date":"1999","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10430019","citation_count":13,"is_preprint":false},{"pmid":"35779338","id":"PMC_35779338","title":"EARS2 significantly coexpresses with PALB2 in breast and pancreatic cancer.","date":"2022","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/35779338","citation_count":8,"is_preprint":false},{"pmid":"39455528","id":"PMC_39455528","title":"Identification of JAZF1, KNOP1, and PLEKHA1 as causally associated genes and drug targets for Alzheimer's disease: a summary data-based Mendelian randomization study.","date":"2024","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39455528","citation_count":2,"is_preprint":false},{"pmid":"40784594","id":"PMC_40784594","title":"KNOP1 interacts with NMNAT1 to govern ferroptosis and tumor growth in breast cancer via regulating FoxO1-dependent GPX4 transcription.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40784594","citation_count":1,"is_preprint":false},{"pmid":"41277170","id":"PMC_41277170","title":"Comprehensive Genome-Wide Analysis of Shared Genetic Factors in Gastrointestinal and Neurodegenerative Diseases.","date":"2025","source":"Brain and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/41277170","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7167,"output_tokens":917,"usd":0.017628,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7431,"output_tokens":1577,"usd":0.03829,"stage2_stop_reason":"end_turn"},"total_usd":0.055918,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TSG118 (KNOP1) localizes to the dense fibrillar component of the nucleolus during interphase (co-localizing with fibrillarin) and re-localizes to the surface of condensed chromosomes during mitosis, indicating cell-cycle-dependent subcellular redistribution.\",\n      \"method\": \"Indirect immunofluorescence microscopy with affinity-purified anti-Tsg118 serum; co-localization with fibrillarin as nucleolar marker\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional implication of cell-cycle regulation, single lab, two markers used orthogonally\",\n      \"pmids\": [\"10430019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TSG118 (KNOP1) physically interacts with the C-terminal WD40 repeat domain of ZFP106 and co-localizes with ZFP106 in the nucleolus; rapid downregulation of TSG118 during terminal differentiation in vitro coincides with loss of nucleolar ZFP106, indicating TSG118 is required for nucleolar retention of ZFP106.\",\n      \"method\": \"Yeast two-hybrid, co-localization by immunofluorescence, deletion analysis of ZFP106 domains, in vitro differentiation assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction mapped by two-hybrid and deletion analysis, co-localization confirmed, functional consequence (loss of ZFP106 nucleolar targeting) demonstrated in one lab\",\n      \"pmids\": [\"15833274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KNOP1 directly interacts with NMNAT1 to maintain intracellular NAD+ homeostasis, which inhibits FoxO1 phosphorylation and promotes FoxO1 nuclear retention, thereby facilitating GPX4 transcription and suppressing ferroptosis in breast cancer cells; KNOP1 knockdown reduces NAD+ levels, induces FoxO1 nuclear export, downregulates GPX4, and enhances ferroptosis, all reversible by Ferrostatin-1 treatment or NMNAT1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation (co-IP), ChIP assay, NAD+ quantification, CCK-8/EdU/transwell assays, ROS detection, tumor xenograft models, rescue experiments with Ferrostatin-1 and NMNAT1 overexpression, NMNAT1 knockdown epistasis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, ChIP, NAD+ quantification, genetic rescue) in a single lab; not yet independently replicated\",\n      \"pmids\": [\"40784594\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KNOP1 (TSG118) is a nucleolar protein that redistributes to condensed chromosomes during mitosis, recruits ZFP106 to the nucleolus via interaction with its WD40 domain, and in breast cancer cells forms a complex with NMNAT1 to sustain NAD+ levels, thereby suppressing FoxO1 phosphorylation, promoting GPX4 transcription, and inhibiting ferroptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KNOP1 (TSG118) is a nucleolar protein that undergoes cell-cycle-dependent redistribution, occupying the dense fibrillar component of the nucleolus in interphase—where it co-localizes with fibrillarin—and relocating to the surface of condensed chromosomes during mitosis [#0]. Within the nucleolus it serves as a retention factor for ZFP106, binding the C-terminal WD40 repeat domain of ZFP106 and being required for its nucleolar localization [#1]. Beyond this structural role, KNOP1 has a metabolic function in breast cancer cells, where it directly interacts with NMNAT1 to sustain intracellular NAD+ levels; this NAD+ homeostasis suppresses FoxO1 phosphorylation and promotes FoxO1 nuclear retention, driving GPX4 transcription and thereby suppressing ferroptosis [#2]. KNOP1 loss reduces NAD+, drives FoxO1 nuclear export, downregulates GPX4, and sensitizes cells to ferroptosis [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established KNOP1 as a nucleolar protein with a dynamic, cell-cycle-coupled localization, raising the possibility of distinct interphase and mitotic functions.\",\n      \"evidence\": \"Indirect immunofluorescence with affinity-purified antibody, co-localization with fibrillarin in interphase and with condensed chromosomes in mitosis\",\n      \"pmids\": [\"10430019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function within the nucleolus not defined\", \"Mechanism driving chromosome surface relocalization at mitosis unknown\", \"Single lab, antibody-based localization only\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Assigned KNOP1 a concrete molecular role as a nucleolar retention factor for ZFP106, answering what protein partner it acts upon in the nucleolus.\",\n      \"evidence\": \"Yeast two-hybrid, ZFP106 domain deletion mapping, co-localization, and an in vitro differentiation assay linking KNOP1 loss to loss of nucleolar ZFP106\",\n      \"pmids\": [\"15833274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ZFP106 nucleolar retention not defined\", \"Interaction not confirmed by reciprocal endogenous co-IP or structure\", \"Biological role of the differentiation-coupled downregulation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a metabolic axis linking KNOP1 to NAD+ homeostasis and ferroptosis resistance, defining a disease-relevant function distinct from its nucleolar role.\",\n      \"evidence\": \"Co-IP, ChIP, NAD+ quantification, ROS detection, proliferation/migration assays, xenografts, and rescue/epistasis with Ferrostatin-1 and NMNAT1 in breast cancer cells\",\n      \"pmids\": [\"40784594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Whether the NMNAT1 axis connects to the nucleolar/ZFP106 functions is unknown\", \"Direct biochemical basis for how KNOP1 sustains NMNAT1-dependent NAD+ output not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KNOP1's nucleolar structural role relates to its metabolic NAD+/ferroptosis function, and whether either represents a unified molecular activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or enzymatic activity defined for KNOP1\", \"No mechanism connecting the ZFP106 and NMNAT1 interactions\", \"Physiological role outside cancer cells uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"ZFP106\", \"NMNAT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}