{"gene":"CHLSN","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2024,"finding":"Cholesin (encoded by C7orf50/CHLSN in humans; 3110082I17Rik in mice) is a hormone secreted from the intestine in response to cholesterol absorption that binds to GPR146, an orphan G-protein-coupled receptor, and inhibits PKA signaling, thereby suppressing SREBP2-controlled cholesterol synthesis in the liver and reducing circulating cholesterol levels.","method":"Hormone identification, receptor binding assays (GPR146 shown as binding partner), in vivo mouse models, PKA signaling assays, SREBP2 pathway readouts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (receptor binding, signaling pathway dissection, in vivo models) in a single rigorous study identifying ligand-receptor pair and downstream mechanism","pmids":["38503280"],"is_preprint":false},{"year":2026,"finding":"C7orf50 is a nucleolus-localized protein that coordinates ribosome biogenesis and autophagy in response to nutrient status. Under nutrient-rich conditions it resides in the nucleolus to promote ribosome biogenesis; upon nutrient deprivation it translocates to the nucleoplasm to augment autophagy. This reversible translocation is regulated by acetylation at lysine-71/72/76 residues by N-alpha-acetyltransferase 10 (NAA10), itself a substrate of mTOR. C7orf50 also functions as an oncoprotein promoting tumor growth in vivo and in vitro.","method":"Subcellular localization (live imaging/fractionation), site-directed mutagenesis of acetylation sites, mTOR-NAA10 pathway epistasis, in vitro acetyltransferase assay, in vivo tumor growth assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (localization imaging, mutagenesis, in vitro acetylation assay, in vivo tumor models) in a single rigorous study","pmids":["42139339"],"is_preprint":false},{"year":2022,"finding":"Yeast ortholog Rbp95 (Ycr016w/YCR016W), corresponding to CHLSN/C7orf50, is an RNA-binding protein with two independent RNA-interacting domains that associates with helix H95 of the 25S rRNA in vivo and cooperates with the Npa1 complex during early pre-60S ribosomal particle maturation. Its absence alters the protein composition of early pre-60S particles, and combined mutation with Npa1 complex members delays pre-60S maturation.","method":"Co-IP/pulldown of early pre-60S particles, RNA-binding domain characterization, in vivo UV-crosslinking/CRAC to map rRNA interaction site, genetic epistasis (double mutants with Npa1 complex members), mass spectrometry of pre-60S particle composition","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assays, in vivo crosslinking, Co-IP, genetic epistasis, MS) in a single rigorous study establishing mechanism in yeast ortholog","pmids":["36018804"],"is_preprint":false},{"year":2026,"finding":"C7orf50 promotes hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion in vitro, and tumor growth and lung metastasis in vivo, by binding to AEG-1 and facilitating its nuclear translocation, thereby activating the NF-κB/PAI-1 pathway and promoting tumor-associated macrophage recruitment.","method":"C7orf50 overexpression and knockdown in HCC cell lines (in vitro functional assays), in vivo xenograft/metastasis models, co-immunoprecipitation (C7orf50–AEG-1 interaction), nuclear translocation assay, NF-κB/PAI-1 pathway readouts, macrophage recruitment assays","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for binding partner, loss/gain-of-function with defined phenotypic readouts, pathway activation confirmed, single lab","pmids":["41592889"],"is_preprint":false}],"current_model":"CHLSN/C7orf50 encodes Cholesin, an intestine-secreted hormone that binds GPR146 to inhibit hepatic PKA–SREBP2-driven cholesterol synthesis; in the nucleus/nucleolus it functions as a nutrient-sensing coordinator of ribosome biogenesis and autophagy via mTOR–NAA10-dependent acetylation at K71/K72/K76, which controls its reversible nucleolus-to-nucleoplasm translocation; its yeast ortholog Rbp95 (Ycr016w) is an RNA-binding protein integral to early pre-60S ribosome assembly through interaction with 25S rRNA helix H95 and the Npa1 complex; and in hepatocellular carcinoma C7orf50 activates NF-κB/PAI-1 signaling by binding AEG-1 and promoting its nuclear translocation."},"narrative":{"mechanistic_narrative":"CHLSN/C7orf50 encodes Cholesin, a dual-function protein that operates both as a secreted metabolic hormone and as a nuclear nutrient-sensing regulator. As a hormone secreted from the intestine in response to cholesterol absorption, Cholesin binds the orphan GPCR GPR146 and inhibits PKA signaling, suppressing SREBP2-driven hepatic cholesterol synthesis and lowering circulating cholesterol [PMID:38503280]. In its intracellular role it localizes to the nucleolus to promote ribosome biogenesis under nutrient-rich conditions and translocates to the nucleoplasm upon nutrient deprivation to augment autophagy, a reversible relocation governed by NAA10-mediated acetylation at lysines 71/72/76 downstream of mTOR [PMID:42139339]. This nucleolar function in ribosome assembly is conserved: the yeast ortholog Rbp95 is an RNA-binding protein that contacts helix H95 of 25S rRNA and cooperates with the Npa1 complex during early pre-60S particle maturation [PMID:36018804]. C7orf50 also acts as an oncoprotein, promoting hepatocellular carcinoma growth and metastasis by binding AEG-1, driving its nuclear translocation, and activating NF-κB/PAI-1 signaling [PMID:42139339, PMID:41592889].","teleology":[{"year":2022,"claim":"Before functional assignment in humans, the ancestral role of this protein was unknown; characterizing the yeast ortholog established it as an RNA-binding factor in early ribosome assembly.","evidence":"RNA-binding domain mapping, in vivo UV-crosslinking (CRAC) to 25S rRNA helix H95, Co-IP of pre-60S particles and genetic epistasis with Npa1 complex members in yeast","pmids":["36018804"],"confidence":"High","gaps":["Whether the human protein retains direct RNA binding to rRNA was not tested","Structural basis of the H95/Npa1 interaction not resolved","Conservation of the two RNA-interacting domains in human CHLSN not established"]},{"year":2024,"claim":"The physiological function of human CHLSN was undefined; identifying Cholesin as an intestine-secreted hormone established an organ-crosstalk axis controlling systemic cholesterol.","evidence":"Hormone identification, GPR146 receptor binding assays, PKA and SREBP2 pathway readouts, and in vivo mouse models","pmids":["38503280"],"confidence":"High","gaps":["Structure of the Cholesin–GPR146 complex not determined","How a nucleolar RNA-binding factor is also secreted as a hormone is unexplained","Mechanism linking cholesterol absorption to Cholesin secretion not detailed"]},{"year":2026,"claim":"It was unknown how the intracellular protein responds to nutrient status; the acetylation-controlled nucleolus-to-nucleoplasm shuttle established it as a switch coupling ribosome biogenesis to autophagy.","evidence":"Subcellular localization imaging/fractionation, site-directed mutagenesis of K71/72/76, mTOR–NAA10 epistasis, in vitro acetyltransferase assay, and in vivo tumor growth assays","pmids":["42139339"],"confidence":"High","gaps":["Direct molecular outputs in autophagy not defined","Whether secreted hormone and nuclear pools are functionally connected unclear","Deacetylase reversing K71/72/76 not identified"]},{"year":2026,"claim":"The basis of its oncogenic activity was unclear; binding to AEG-1 and activation of NF-κB/PAI-1 established a tumor-promoting signaling mechanism in HCC.","evidence":"Gain/loss-of-function in HCC cell lines, in vivo xenograft and metastasis models, reciprocal Co-IP of C7orf50–AEG-1, nuclear translocation and NF-κB/PAI-1 readouts, macrophage recruitment assays","pmids":["41592889"],"confidence":"Medium","gaps":["Single-lab Co-IP; binding interface not mapped","Relationship between oncogenic AEG-1 binding and the acetylation/nucleolar functions not addressed","Direct vs indirect activation of NF-κB/PAI-1 not distinguished"]},{"year":null,"claim":"It remains unresolved how a single protein integrates a secreted cholesterol-regulating hormone function with conserved nucleolar ribosome-biogenesis and nutrient-sensing roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting extracellular hormone and intranuclear functions","No structural model of the human protein in any of its roles","Tissue-specific partitioning between secreted and nuclear pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]}],"complexes":["Npa1 complex (yeast ortholog Rbp95)"],"partners":["GPR146","NAA10","AEG-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BRJ6","full_name":"Protein cholesin","aliases":[],"length_aa":194,"mass_kda":22.1,"function":"Hormone secreted from the intestine in response to cholesterol, where it acts to inhibit cholesterol synthesis in the liver and VLDL secretion,leading to a reduction in circulating cholesterol levels. Acts through binding to its receptor, GPR146","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9BRJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHLSN","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":true,"resolved_as":"C7ORF50","ensg_id":"ENSG00000146540","cell_line_id":"CID000387","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":2},{"compartment":"chromatin","grade":1}],"interactors":[{"gene":"G3BP2","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000387","total_profiled":1310},"omim":[{"mim_id":"621174","title":"CHOLESIN; CHLSN","url":"https://www.omim.org/entry/621174"},{"mim_id":"621173","title":"G PROTEIN-COUPLED RECEPTOR 146; GPR146","url":"https://www.omim.org/entry/621173"},{"mim_id":"614964","title":"EXTRACELLULAR LEUCINE-RICH REPEAT AND FIBRONECTIN TYPE III DOMAIN-CONTAINING PROTEIN 1; ELFN1","url":"https://www.omim.org/entry/614964"}],"hpa":{"profiled":true,"resolved_as":"C7ORF50","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C7ORF50"},"hgnc":{"alias_symbol":["MGC11257","YCR016W"],"prev_symbol":["C7orf50"]},"alphafold":{"accession":"Q9BRJ6","domains":[{"cath_id":"-","chopping":"99-194","consensus_level":"medium","plddt":89.8777,"start":99,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BRJ6-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHLSN","jax_strain_url":"https://www.jax.org/strain/search?query=CHLSN"},"sequence":{"accession":"Q9BRJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BRJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BRJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BRJ6"}},"corpus_meta":[{"pmid":"30107520","id":"PMC_30107520","title":"Epigenome-wide association study in whole blood on type 2 diabetes among sub-Saharan African individuals: findings from the RODAM study.","date":"2019","source":"International journal of epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/30107520","citation_count":72,"is_preprint":false},{"pmid":"38503280","id":"PMC_38503280","title":"A gut-derived hormone regulates cholesterol metabolism.","date":"2024","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/38503280","citation_count":66,"is_preprint":false},{"pmid":"29692868","id":"PMC_29692868","title":"Epigenome-wide association study of total serum immunoglobulin E in children: a life course approach.","date":"2018","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29692868","citation_count":35,"is_preprint":false},{"pmid":"31139831","id":"PMC_31139831","title":"Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.","date":"2019","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/31139831","citation_count":31,"is_preprint":false},{"pmid":"33100131","id":"PMC_33100131","title":"Epigenome-wide association study identifies DNA methylation sites associated with target organ damage in older African Americans.","date":"2020","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33100131","citation_count":19,"is_preprint":false},{"pmid":"35432200","id":"PMC_35432200","title":"Methylome Analysis in Nonfunctioning and GH-Secreting Pituitary Adenomas.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35432200","citation_count":13,"is_preprint":false},{"pmid":"36018804","id":"PMC_36018804","title":"Rbp95 binds to 25S rRNA helix H95 and cooperates with the Npa1 complex during early pre-60S particle maturation.","date":"2022","source":"Nucleic acids 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Study.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38137029","citation_count":8,"is_preprint":false},{"pmid":"39364777","id":"PMC_39364777","title":"Integrated GWAS and transcriptome analysis reveals key genes associated with muscle fibre and fat traits in Gushi chicken.","date":"2024","source":"British poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/39364777","citation_count":6,"is_preprint":false},{"pmid":"41592889","id":"PMC_41592889","title":"Tumor neoantigen gene C7orf50 remodels the immune microenvironment by recruiting tumor-associated macrophages to promote hepatocellular carcinoma progression and lung metastasis.","date":"2026","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41592889","citation_count":0,"is_preprint":false},{"pmid":"42139339","id":"PMC_42139339","title":"mTOR-NAA10-C7orf50 axis senses nutritional status to coordinate ribosome biogenesis and autophagy.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/42139339","citation_count":0,"is_preprint":false},{"pmid":"42085113","id":"PMC_42085113","title":"Environmental Noise and Cardiovascular Risk: A Causal Inference Study.","date":"2026","source":"Noise & health","url":"https://pubmed.ncbi.nlm.nih.gov/42085113","citation_count":0,"is_preprint":false},{"pmid":"41763442","id":"PMC_41763442","title":"Genomic Study of Resilience to Posttraumatic Stress Disorder in the Million Veteran Program.","date":"2026","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/41763442","citation_count":0,"is_preprint":false},{"pmid":"41908943","id":"PMC_41908943","title":"Computational and Experimental Biology Reveals Dihydroartemisinin's Efficacy Against Steroid-Induced Osteonecrosis of the Femoral Head Adjusting Ferroptosis via CCL17-PRDX6.","date":"2026","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41908943","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11517,"output_tokens":1452,"usd":0.028165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8172,"output_tokens":2294,"usd":0.049105,"stage2_stop_reason":"end_turn"},"total_usd":0.07727,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"Cholesin (encoded by C7orf50/CHLSN in humans; 3110082I17Rik in mice) is a hormone secreted from the intestine in response to cholesterol absorption that binds to GPR146, an orphan G-protein-coupled receptor, and inhibits PKA signaling, thereby suppressing SREBP2-controlled cholesterol synthesis in the liver and reducing circulating cholesterol levels.\",\n      \"method\": \"Hormone identification, receptor binding assays (GPR146 shown as binding partner), in vivo mouse models, PKA signaling assays, SREBP2 pathway readouts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (receptor binding, signaling pathway dissection, in vivo models) in a single rigorous study identifying ligand-receptor pair and downstream mechanism\",\n      \"pmids\": [\"38503280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"C7orf50 is a nucleolus-localized protein that coordinates ribosome biogenesis and autophagy in response to nutrient status. Under nutrient-rich conditions it resides in the nucleolus to promote ribosome biogenesis; upon nutrient deprivation it translocates to the nucleoplasm to augment autophagy. This reversible translocation is regulated by acetylation at lysine-71/72/76 residues by N-alpha-acetyltransferase 10 (NAA10), itself a substrate of mTOR. C7orf50 also functions as an oncoprotein promoting tumor growth in vivo and in vitro.\",\n      \"method\": \"Subcellular localization (live imaging/fractionation), site-directed mutagenesis of acetylation sites, mTOR-NAA10 pathway epistasis, in vitro acetyltransferase assay, in vivo tumor growth assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (localization imaging, mutagenesis, in vitro acetylation assay, in vivo tumor models) in a single rigorous study\",\n      \"pmids\": [\"42139339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Yeast ortholog Rbp95 (Ycr016w/YCR016W), corresponding to CHLSN/C7orf50, is an RNA-binding protein with two independent RNA-interacting domains that associates with helix H95 of the 25S rRNA in vivo and cooperates with the Npa1 complex during early pre-60S ribosomal particle maturation. Its absence alters the protein composition of early pre-60S particles, and combined mutation with Npa1 complex members delays pre-60S maturation.\",\n      \"method\": \"Co-IP/pulldown of early pre-60S particles, RNA-binding domain characterization, in vivo UV-crosslinking/CRAC to map rRNA interaction site, genetic epistasis (double mutants with Npa1 complex members), mass spectrometry of pre-60S particle composition\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (RNA binding assays, in vivo crosslinking, Co-IP, genetic epistasis, MS) in a single rigorous study establishing mechanism in yeast ortholog\",\n      \"pmids\": [\"36018804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"C7orf50 promotes hepatocellular carcinoma (HCC) cell proliferation, migration, and invasion in vitro, and tumor growth and lung metastasis in vivo, by binding to AEG-1 and facilitating its nuclear translocation, thereby activating the NF-κB/PAI-1 pathway and promoting tumor-associated macrophage recruitment.\",\n      \"method\": \"C7orf50 overexpression and knockdown in HCC cell lines (in vitro functional assays), in vivo xenograft/metastasis models, co-immunoprecipitation (C7orf50–AEG-1 interaction), nuclear translocation assay, NF-κB/PAI-1 pathway readouts, macrophage recruitment assays\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for binding partner, loss/gain-of-function with defined phenotypic readouts, pathway activation confirmed, single lab\",\n      \"pmids\": [\"41592889\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHLSN/C7orf50 encodes Cholesin, an intestine-secreted hormone that binds GPR146 to inhibit hepatic PKA–SREBP2-driven cholesterol synthesis; in the nucleus/nucleolus it functions as a nutrient-sensing coordinator of ribosome biogenesis and autophagy via mTOR–NAA10-dependent acetylation at K71/K72/K76, which controls its reversible nucleolus-to-nucleoplasm translocation; its yeast ortholog Rbp95 (Ycr016w) is an RNA-binding protein integral to early pre-60S ribosome assembly through interaction with 25S rRNA helix H95 and the Npa1 complex; and in hepatocellular carcinoma C7orf50 activates NF-κB/PAI-1 signaling by binding AEG-1 and promoting its nuclear translocation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHLSN/C7orf50 encodes Cholesin, a dual-function protein that operates both as a secreted metabolic hormone and as a nuclear nutrient-sensing regulator. As a hormone secreted from the intestine in response to cholesterol absorption, Cholesin binds the orphan GPCR GPR146 and inhibits PKA signaling, suppressing SREBP2-driven hepatic cholesterol synthesis and lowering circulating cholesterol [#0]. In its intracellular role it localizes to the nucleolus to promote ribosome biogenesis under nutrient-rich conditions and translocates to the nucleoplasm upon nutrient deprivation to augment autophagy, a reversible relocation governed by NAA10-mediated acetylation at lysines 71/72/76 downstream of mTOR [#1]. This nucleolar function in ribosome assembly is conserved: the yeast ortholog Rbp95 is an RNA-binding protein that contacts helix H95 of 25S rRNA and cooperates with the Npa1 complex during early pre-60S particle maturation [#2]. C7orf50 also acts as an oncoprotein, promoting hepatocellular carcinoma growth and metastasis by binding AEG-1, driving its nuclear translocation, and activating NF-\\u03baB/PAI-1 signaling [#1, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Before functional assignment in humans, the ancestral role of this protein was unknown; characterizing the yeast ortholog established it as an RNA-binding factor in early ribosome assembly.\",\n      \"evidence\": \"RNA-binding domain mapping, in vivo UV-crosslinking (CRAC) to 25S rRNA helix H95, Co-IP of pre-60S particles and genetic epistasis with Npa1 complex members in yeast\",\n      \"pmids\": [\"36018804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the human protein retains direct RNA binding to rRNA was not tested\",\n        \"Structural basis of the H95/Npa1 interaction not resolved\",\n        \"Conservation of the two RNA-interacting domains in human CHLSN not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The physiological function of human CHLSN was undefined; identifying Cholesin as an intestine-secreted hormone established an organ-crosstalk axis controlling systemic cholesterol.\",\n      \"evidence\": \"Hormone identification, GPR146 receptor binding assays, PKA and SREBP2 pathway readouts, and in vivo mouse models\",\n      \"pmids\": [\"38503280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of the Cholesin\\u2013GPR146 complex not determined\",\n        \"How a nucleolar RNA-binding factor is also secreted as a hormone is unexplained\",\n        \"Mechanism linking cholesterol absorption to Cholesin secretion not detailed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"It was unknown how the intracellular protein responds to nutrient status; the acetylation-controlled nucleolus-to-nucleoplasm shuttle established it as a switch coupling ribosome biogenesis to autophagy.\",\n      \"evidence\": \"Subcellular localization imaging/fractionation, site-directed mutagenesis of K71/72/76, mTOR\\u2013NAA10 epistasis, in vitro acetyltransferase assay, and in vivo tumor growth assays\",\n      \"pmids\": [\"42139339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular outputs in autophagy not defined\",\n        \"Whether secreted hormone and nuclear pools are functionally connected unclear\",\n        \"Deacetylase reversing K71/72/76 not identified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The basis of its oncogenic activity was unclear; binding to AEG-1 and activation of NF-\\u03baB/PAI-1 established a tumor-promoting signaling mechanism in HCC.\",\n      \"evidence\": \"Gain/loss-of-function in HCC cell lines, in vivo xenograft and metastasis models, reciprocal Co-IP of C7orf50\\u2013AEG-1, nuclear translocation and NF-\\u03baB/PAI-1 readouts, macrophage recruitment assays\",\n      \"pmids\": [\"41592889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab Co-IP; binding interface not mapped\",\n        \"Relationship between oncogenic AEG-1 binding and the acetylation/nucleolar functions not addressed\",\n        \"Direct vs indirect activation of NF-\\u03baB/PAI-1 not distinguished\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single protein integrates a secreted cholesterol-regulating hormone function with conserved nucleolar ribosome-biogenesis and nutrient-sensing roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unified model connecting extracellular hormone and intranuclear functions\",\n        \"No structural model of the human protein in any of its roles\",\n        \"Tissue-specific partitioning between secreted and nuclear pools unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Npa1 complex (yeast ortholog Rbp95)\"],\n    \"partners\": [\"GPR146\", \"NAA10\", \"AEG-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}