{"gene":"FAM177A1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2021,"finding":"FAM177A1 acts as a negative regulator of IL-1β-induced NF-κB signaling by competitively binding to the E3 ubiquitin ligase TRAF6 and impairing its interaction with the E2-conjugating enzyme Ubc13, thereby inhibiting TRAF6-mediated polyubiquitination and downstream signaling molecule recruitment.","method":"Overexpression and knockdown in human cells; co-immunoprecipitation to show FAM177A1-TRAF6 binding and impaired TRAF6-Ubc13 association; NF-κB reporter assays; inflammatory gene transcription assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and functional assays (OE/KD) in a single lab with multiple orthogonal methods","pmids":["34799425"],"is_preprint":false},{"year":2024,"finding":"FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells, and its loss causes delayed Golgi complex reformation after Brefeldin A-induced disruption, phenocopying the loss of its interactor VPS13B; in zebrafish, vps13b and fam177a1 genetically interact.","method":"Immunofluorescence/super-resolution imaging for Golgi localization; Brefeldin A washout assay in FAM177A1 KO and VPS13B KO cells; zebrafish genetic interaction (double mutant/knockdown epistasis); reported VPS13B–FAM177A1 protein interaction","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (imaging, BFA functional assay, zebrafish epistasis) with KO controls across two model systems, replicated from preprint","pmids":["39331042"],"is_preprint":false},{"year":2023,"finding":"FAM177A1 is a Golgi complex protein that physically interacts with VPS13B (a bulk lipid transfer protein) and functionally partners with it; loss of FAM177A1 delays Golgi membrane reformation after Brefeldin A treatment, and fam177a1 genetically interacts with vps13b in zebrafish.","method":"Super-resolution imaging; BFA washout assay in KO cells; zebrafish genetic interaction; reported protein–protein interaction with VPS13B","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods but preprint version of the published study","pmids":["38187698"],"is_preprint":true},{"year":2024,"finding":"FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells; loss-of-function in human fibroblasts and zebrafish larvae causes dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation, as determined by RNA sequencing and metabolomics.","method":"Subcellular localization by immunofluorescence; RNA-seq and metabolomics on FAM177A1-deficient human fibroblasts and zebrafish larvae; loss-of-function zebrafish model","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment plus multi-omic functional characterization in two model systems, single lab","pmids":["38767059"],"is_preprint":false},{"year":2009,"finding":"FAM177A1 (c14orf24) is predominantly expressed in the cytoplasm, is highly expressed in proliferating cells, and its expression is gradually decreased during neurogenesis; it is a target of miR-124a-mediated translational repression.","method":"qRT-PCR; luciferase reporter assays with 3′-UTR of c14orf24; subcellular fractionation/imaging in P19 mouse embryonic carcinoma cells; miR-124a overexpression","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct localization and in vitro luciferase 3′-UTR assay establishing miRNA-mediated regulation and cytoplasmic localization, single lab","pmids":["19663910"],"is_preprint":false},{"year":2026,"finding":"FAM177A1 disrupts SIRT3-SOD2 binding, leading to elevated SOD2 K68 acetylation, decreased SOD2 activity and stability, increased mitochondrial ROS, impaired oxidative phosphorylation, and enhanced glycolytic flux, thereby driving vascular smooth muscle cell (VSMC) phenotypic switching; FAM177A1 deficiency suppresses neointimal hyperplasia and atherosclerosis in multiple rodent models.","method":"Global Fam177a1 KO rats with carotid balloon injury; VSMC-specific AAV-mediated Fam177a1 knockdown in carotid artery ligation mice; ApoE−/− mice with high-fat diet; in vitro PDGF-BB-stimulated VSMCs; Co-IP for SIRT3-SOD2 interaction; SOD2 acetylation (K68) mass spectrometry/immunoblot; mitochondrial functional assays (ROS, ΔΨm, mtDNA, OXPHOS, glycolysis)","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 1–2 — multiple in vivo models plus in vitro mechanistic dissection of SIRT3-SOD2 axis with molecular and functional readouts, single lab","pmids":["41943851"],"is_preprint":false}],"current_model":"FAM177A1 is a cytoplasm-localized Golgi complex protein that (1) acts as a functional partner of the lipid transfer protein VPS13B at the proximal-distal Golgi interface to support Golgi membrane dynamics, (2) inhibits IL-1β/NF-κB inflammatory signaling by competitively binding TRAF6 and blocking its interaction with Ubc13, and (3) disrupts the SIRT3-SOD2 deacetylation axis in vascular smooth muscle cells to elevate mitochondrial ROS and drive phenotypic switching, while its expression is post-transcriptionally regulated by miR-124a during neurogenesis."},"narrative":{"teleology":[{"year":2009,"claim":"Before any functional role was known, the expression pattern and regulation of FAM177A1 (then c14orf24) were established: it is a cytoplasmic protein highly expressed in proliferating cells whose levels decline during neurogenesis via miR-124a-mediated translational repression, framing it as a differentiation-responsive gene.","evidence":"qRT-PCR, 3′-UTR luciferase reporter assays with miR-124a, subcellular fractionation/imaging in P19 mouse embryonic carcinoma cells","pmids":["19663910"],"confidence":"Medium","gaps":["No molecular function or pathway assignment was made","miR-124a regulation demonstrated only in one cell line with a single reporter system","Endogenous protein–protein interactions unknown"]},{"year":2021,"claim":"The first molecular function was identified: FAM177A1 negatively regulates NF-κB signaling by competitively binding TRAF6 and disrupting the TRAF6–Ubc13 E2–E3 interaction, establishing it as an anti-inflammatory modulator.","evidence":"Overexpression/knockdown in human cells; co-immunoprecipitation of FAM177A1–TRAF6 and impaired TRAF6–Ubc13 association; NF-κB luciferase reporter and inflammatory gene transcription assays","pmids":["34799425"],"confidence":"Medium","gaps":["Binding interface between FAM177A1 and TRAF6 not mapped; competitive mechanism inferred from Co-IP without structural data","In vivo relevance of the anti-inflammatory function not tested","Relationship between Golgi localization and TRAF6 binding unexplored"]},{"year":2024,"claim":"FAM177A1 was localized to the Golgi complex and shown to be a functional partner of the lipid transfer protein VPS13B: loss of FAM177A1 delays Golgi reformation after Brefeldin A treatment, phenocopying VPS13B loss, and the two genes genetically interact in zebrafish, establishing FAM177A1 as a Golgi membrane dynamics factor.","evidence":"Super-resolution imaging for Golgi localization; BFA washout assay in FAM177A1 KO and VPS13B KO human cells; zebrafish double-mutant/knockdown epistasis; protein–protein interaction with VPS13B","pmids":["39331042","38767059"],"confidence":"High","gaps":["Mechanism by which FAM177A1 supports VPS13B-mediated lipid transfer is unknown","No structural basis for the FAM177A1–VPS13B interaction","Whether Golgi dysfunction accounts for the inflammatory and metabolic transcriptomic changes seen in FAM177A1-deficient cells is unclear"]},{"year":2026,"claim":"A distinct mitochondrial-metabolic mechanism was uncovered: FAM177A1 disrupts SIRT3–SOD2 binding, increasing SOD2 K68 acetylation and mitochondrial ROS while shifting metabolism from oxidative phosphorylation to glycolysis, thereby driving vascular smooth muscle cell phenotypic switching and neointimal hyperplasia in vivo.","evidence":"Global Fam177a1 KO rats (carotid balloon injury), VSMC-specific AAV knockdown in mice (carotid ligation), ApoE−/− mice on high-fat diet; Co-IP for SIRT3–SOD2; SOD2 K68 acetylation by mass spectrometry/immunoblot; mitochondrial functional assays","pmids":["41943851"],"confidence":"High","gaps":["Direct physical interaction between FAM177A1 and SIRT3 or SOD2 not demonstrated—disruption of the SIRT3–SOD2 axis could be indirect","How a Golgi-localized protein influences a mitochondrial deacetylation axis is mechanistically unexplained","Relevance of the SIRT3–SOD2 mechanism to non-vascular cell types is untested"]},{"year":null,"claim":"It remains unknown how FAM177A1's Golgi-localized function with VPS13B, its cytoplasmic anti-inflammatory role via TRAF6, and its effect on the mitochondrial SIRT3–SOD2 axis are mechanistically integrated—whether these reflect independent activities, context-dependent pools of the protein, or a unified membrane-trafficking mechanism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or domain-level information to explain multifunctionality","No disease-causing mutations in humans have been mechanistically characterized","Tissue-specific and cell-type-specific functions are poorly resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":["VPS13B","TRAF6","SIRT3","SOD2"],"other_free_text":[]},"mechanistic_narrative":"FAM177A1 is a Golgi-localized protein that functions at the intersection of Golgi membrane dynamics, inflammatory signaling, and mitochondrial redox homeostasis. It physically interacts with the bulk lipid transfer protein VPS13B at the Golgi complex, and its loss delays Golgi membrane reformation after Brefeldin A-induced disruption, phenocopying VPS13B deficiency; genetic interaction between fam177a1 and vps13b is confirmed in zebrafish [PMID:39331042]. FAM177A1 negatively regulates IL-1β/NF-κB signaling by competitively binding the E3 ubiquitin ligase TRAF6 and blocking its interaction with the E2-conjugating enzyme Ubc13, thereby inhibiting TRAF6-mediated polyubiquitination [PMID:34799425]. In vascular smooth muscle cells, FAM177A1 disrupts the SIRT3–SOD2 deacetylation axis, elevating SOD2 K68 acetylation and mitochondrial ROS to drive phenotypic switching, and its deficiency suppresses neointimal hyperplasia and atherosclerosis in rodent models [PMID:41943851]."},"prefetch_data":{"uniprot":{"accession":"Q8N128","full_name":"Protein FAM177A1","aliases":[],"length_aa":213,"mass_kda":23.8,"function":"","subcellular_location":"Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q8N128/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FAM177A1","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FAM177A1","total_profiled":1310},"omim":[{"mim_id":"621152","title":"NEURODEVELOPMENTAL DISORDER WITH WHITE MATTER ABNORMALITIES AND GAIT DISTURBANCE; NEDWMG","url":"https://www.omim.org/entry/621152"},{"mim_id":"619181","title":"FAMILY WITH SEQUENCE SIMILARITY 177, MEMBER A1; FAM177A1","url":"https://www.omim.org/entry/619181"},{"mim_id":"615239","title":"MICRO RNA 7-1; MIR7-1","url":"https://www.omim.org/entry/615239"},{"mim_id":"609327","title":"MICRO RNA 124-1; MIR124-1","url":"https://www.omim.org/entry/609327"},{"mim_id":"607817","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG B; VPS13B","url":"https://www.omim.org/entry/607817"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FAM177A1"},"hgnc":{"alias_symbol":[],"prev_symbol":["C14orf24"]},"alphafold":{"accession":"Q8N128","domains":[{"cath_id":"-","chopping":"85-130","consensus_level":"medium","plddt":77.9537,"start":85,"end":130},{"cath_id":"1.20.5","chopping":"131-172","consensus_level":"medium","plddt":90.9395,"start":131,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N128","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N128-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N128-F1-predicted_aligned_error_v6.png","plddt_mean":63.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FAM177A1","jax_strain_url":"https://www.jax.org/strain/search?query=FAM177A1"},"sequence":{"accession":"Q8N128","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N128.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N128/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N128"}},"corpus_meta":[{"pmid":"25558065","id":"PMC_25558065","title":"Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25558065","citation_count":378,"is_preprint":false},{"pmid":"29228969","id":"PMC_29228969","title":"Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study.","date":"2017","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/29228969","citation_count":45,"is_preprint":false},{"pmid":"19663910","id":"PMC_19663910","title":"Noninvasive imaging of microRNA124a-mediated repression of the chromosome 14 ORF 24 gene during neurogenesis.","date":"2009","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/19663910","citation_count":28,"is_preprint":false},{"pmid":"15205934","id":"PMC_15205934","title":"Microsatellite genotyping of chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves' disease in the Latvian population.","date":"2004","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/15205934","citation_count":13,"is_preprint":false},{"pmid":"39331042","id":"PMC_39331042","title":"VPS13B is localized at the interface between Golgi cisternae and is a functional partner of FAM177A1.","date":"2024","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39331042","citation_count":11,"is_preprint":false},{"pmid":"34799425","id":"PMC_34799425","title":"FAM177A1 Inhibits IL-1β-Induced Signaling by Impairing TRAF6-Ubc13 Association.","date":"2021","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/34799425","citation_count":11,"is_preprint":false},{"pmid":"38767059","id":"PMC_38767059","title":"Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.","date":"2024","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38767059","citation_count":9,"is_preprint":false},{"pmid":"36825008","id":"PMC_36825008","title":"A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36825008","citation_count":8,"is_preprint":false},{"pmid":"20136554","id":"PMC_20136554","title":"Identification of a novel candidate locus for juvenile idiopathic arthritis at 14q13.2 in the Latvian population by association analysis with microsatellite markers.","date":"2010","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20136554","citation_count":8,"is_preprint":false},{"pmid":"40113264","id":"PMC_40113264","title":"Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.","date":"2025","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/40113264","citation_count":7,"is_preprint":false},{"pmid":"38585781","id":"PMC_38585781","title":"Integration of transcriptomics and long-read genomics prioritizes structural variants in rare disease.","date":"2024","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38585781","citation_count":6,"is_preprint":false},{"pmid":"27488439","id":"PMC_27488439","title":"Co-stimulatory CD28 and transcription factor NFKB1 gene variants affect idiopathic recurrent miscarriages.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27488439","citation_count":4,"is_preprint":false},{"pmid":"38187698","id":"PMC_38187698","title":"VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38187698","citation_count":3,"is_preprint":false},{"pmid":"34659352","id":"PMC_34659352","title":"Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34659352","citation_count":3,"is_preprint":false},{"pmid":"41943851","id":"PMC_41943851","title":"FAM177A1 disrupts SIRT3-SOD2 signaling to drive mitochondrial dysfunction-mediated VSMC phenotypic switching in vascular remodeling.","date":"2026","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41943851","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9379,"output_tokens":1754,"usd":0.027224},"stage2":{"model":"claude-opus-4-6","input_tokens":5034,"output_tokens":1874,"usd":0.10803},"total_usd":0.135254,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM177A1 acts as a negative regulator of IL-1β-induced NF-κB signaling by competitively binding to the E3 ubiquitin ligase TRAF6 and impairing its interaction with the E2-conjugating enzyme Ubc13, thereby inhibiting TRAF6-mediated polyubiquitination and downstream signaling molecule recruitment.\",\n      \"method\": \"Overexpression and knockdown in human cells; co-immunoprecipitation to show FAM177A1-TRAF6 binding and impaired TRAF6-Ubc13 association; NF-κB reporter assays; inflammatory gene transcription assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and functional assays (OE/KD) in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34799425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells, and its loss causes delayed Golgi complex reformation after Brefeldin A-induced disruption, phenocopying the loss of its interactor VPS13B; in zebrafish, vps13b and fam177a1 genetically interact.\",\n      \"method\": \"Immunofluorescence/super-resolution imaging for Golgi localization; Brefeldin A washout assay in FAM177A1 KO and VPS13B KO cells; zebrafish genetic interaction (double mutant/knockdown epistasis); reported VPS13B–FAM177A1 protein interaction\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (imaging, BFA functional assay, zebrafish epistasis) with KO controls across two model systems, replicated from preprint\",\n      \"pmids\": [\"39331042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM177A1 is a Golgi complex protein that physically interacts with VPS13B (a bulk lipid transfer protein) and functionally partners with it; loss of FAM177A1 delays Golgi membrane reformation after Brefeldin A treatment, and fam177a1 genetically interacts with vps13b in zebrafish.\",\n      \"method\": \"Super-resolution imaging; BFA washout assay in KO cells; zebrafish genetic interaction; reported protein–protein interaction with VPS13B\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but preprint version of the published study\",\n      \"pmids\": [\"38187698\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells; loss-of-function in human fibroblasts and zebrafish larvae causes dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation, as determined by RNA sequencing and metabolomics.\",\n      \"method\": \"Subcellular localization by immunofluorescence; RNA-seq and metabolomics on FAM177A1-deficient human fibroblasts and zebrafish larvae; loss-of-function zebrafish model\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment plus multi-omic functional characterization in two model systems, single lab\",\n      \"pmids\": [\"38767059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FAM177A1 (c14orf24) is predominantly expressed in the cytoplasm, is highly expressed in proliferating cells, and its expression is gradually decreased during neurogenesis; it is a target of miR-124a-mediated translational repression.\",\n      \"method\": \"qRT-PCR; luciferase reporter assays with 3′-UTR of c14orf24; subcellular fractionation/imaging in P19 mouse embryonic carcinoma cells; miR-124a overexpression\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct localization and in vitro luciferase 3′-UTR assay establishing miRNA-mediated regulation and cytoplasmic localization, single lab\",\n      \"pmids\": [\"19663910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAM177A1 disrupts SIRT3-SOD2 binding, leading to elevated SOD2 K68 acetylation, decreased SOD2 activity and stability, increased mitochondrial ROS, impaired oxidative phosphorylation, and enhanced glycolytic flux, thereby driving vascular smooth muscle cell (VSMC) phenotypic switching; FAM177A1 deficiency suppresses neointimal hyperplasia and atherosclerosis in multiple rodent models.\",\n      \"method\": \"Global Fam177a1 KO rats with carotid balloon injury; VSMC-specific AAV-mediated Fam177a1 knockdown in carotid artery ligation mice; ApoE−/− mice with high-fat diet; in vitro PDGF-BB-stimulated VSMCs; Co-IP for SIRT3-SOD2 interaction; SOD2 acetylation (K68) mass spectrometry/immunoblot; mitochondrial functional assays (ROS, ΔΨm, mtDNA, OXPHOS, glycolysis)\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple in vivo models plus in vitro mechanistic dissection of SIRT3-SOD2 axis with molecular and functional readouts, single lab\",\n      \"pmids\": [\"41943851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FAM177A1 is a cytoplasm-localized Golgi complex protein that (1) acts as a functional partner of the lipid transfer protein VPS13B at the proximal-distal Golgi interface to support Golgi membrane dynamics, (2) inhibits IL-1β/NF-κB inflammatory signaling by competitively binding TRAF6 and blocking its interaction with Ubc13, and (3) disrupts the SIRT3-SOD2 deacetylation axis in vascular smooth muscle cells to elevate mitochondrial ROS and drive phenotypic switching, while its expression is post-transcriptionally regulated by miR-124a during neurogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FAM177A1 is a Golgi-localized protein that functions at the intersection of Golgi membrane dynamics, inflammatory signaling, and mitochondrial redox homeostasis. It physically interacts with the bulk lipid transfer protein VPS13B at the Golgi complex, and its loss delays Golgi membrane reformation after Brefeldin A-induced disruption, phenocopying VPS13B deficiency; genetic interaction between fam177a1 and vps13b is confirmed in zebrafish [PMID:39331042]. FAM177A1 negatively regulates IL-1β/NF-κB signaling by competitively binding the E3 ubiquitin ligase TRAF6 and blocking its interaction with the E2-conjugating enzyme Ubc13, thereby inhibiting TRAF6-mediated polyubiquitination [PMID:34799425]. In vascular smooth muscle cells, FAM177A1 disrupts the SIRT3–SOD2 deacetylation axis, elevating SOD2 K68 acetylation and mitochondrial ROS to drive phenotypic switching, and its deficiency suppresses neointimal hyperplasia and atherosclerosis in rodent models [PMID:41943851].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Before any functional role was known, the expression pattern and regulation of FAM177A1 (then c14orf24) were established: it is a cytoplasmic protein highly expressed in proliferating cells whose levels decline during neurogenesis via miR-124a-mediated translational repression, framing it as a differentiation-responsive gene.\",\n      \"evidence\": \"qRT-PCR, 3′-UTR luciferase reporter assays with miR-124a, subcellular fractionation/imaging in P19 mouse embryonic carcinoma cells\",\n      \"pmids\": [\"19663910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular function or pathway assignment was made\",\n        \"miR-124a regulation demonstrated only in one cell line with a single reporter system\",\n        \"Endogenous protein–protein interactions unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The first molecular function was identified: FAM177A1 negatively regulates NF-κB signaling by competitively binding TRAF6 and disrupting the TRAF6–Ubc13 E2–E3 interaction, establishing it as an anti-inflammatory modulator.\",\n      \"evidence\": \"Overexpression/knockdown in human cells; co-immunoprecipitation of FAM177A1–TRAF6 and impaired TRAF6–Ubc13 association; NF-κB luciferase reporter and inflammatory gene transcription assays\",\n      \"pmids\": [\"34799425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface between FAM177A1 and TRAF6 not mapped; competitive mechanism inferred from Co-IP without structural data\",\n        \"In vivo relevance of the anti-inflammatory function not tested\",\n        \"Relationship between Golgi localization and TRAF6 binding unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"FAM177A1 was localized to the Golgi complex and shown to be a functional partner of the lipid transfer protein VPS13B: loss of FAM177A1 delays Golgi reformation after Brefeldin A treatment, phenocopying VPS13B loss, and the two genes genetically interact in zebrafish, establishing FAM177A1 as a Golgi membrane dynamics factor.\",\n      \"evidence\": \"Super-resolution imaging for Golgi localization; BFA washout assay in FAM177A1 KO and VPS13B KO human cells; zebrafish double-mutant/knockdown epistasis; protein–protein interaction with VPS13B\",\n      \"pmids\": [\"39331042\", \"38767059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which FAM177A1 supports VPS13B-mediated lipid transfer is unknown\",\n        \"No structural basis for the FAM177A1–VPS13B interaction\",\n        \"Whether Golgi dysfunction accounts for the inflammatory and metabolic transcriptomic changes seen in FAM177A1-deficient cells is unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A distinct mitochondrial-metabolic mechanism was uncovered: FAM177A1 disrupts SIRT3–SOD2 binding, increasing SOD2 K68 acetylation and mitochondrial ROS while shifting metabolism from oxidative phosphorylation to glycolysis, thereby driving vascular smooth muscle cell phenotypic switching and neointimal hyperplasia in vivo.\",\n      \"evidence\": \"Global Fam177a1 KO rats (carotid balloon injury), VSMC-specific AAV knockdown in mice (carotid ligation), ApoE−/− mice on high-fat diet; Co-IP for SIRT3–SOD2; SOD2 K68 acetylation by mass spectrometry/immunoblot; mitochondrial functional assays\",\n      \"pmids\": [\"41943851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interaction between FAM177A1 and SIRT3 or SOD2 not demonstrated—disruption of the SIRT3–SOD2 axis could be indirect\",\n        \"How a Golgi-localized protein influences a mitochondrial deacetylation axis is mechanistically unexplained\",\n        \"Relevance of the SIRT3–SOD2 mechanism to non-vascular cell types is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how FAM177A1's Golgi-localized function with VPS13B, its cytoplasmic anti-inflammatory role via TRAF6, and its effect on the mitochondrial SIRT3–SOD2 axis are mechanistically integrated—whether these reflect independent activities, context-dependent pools of the protein, or a unified membrane-trafficking mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or domain-level information to explain multifunctionality\",\n        \"No disease-causing mutations in humans have been mechanistically characterized\",\n        \"Tissue-specific and cell-type-specific functions are poorly resolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VPS13B\",\n      \"TRAF6\",\n      \"SIRT3\",\n      \"SOD2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}