{"gene":"CIAO2A","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2013,"finding":"CIA2A (FAM96A) forms a complex with CIA1 (CIAO1) that specifically matures iron regulatory protein 1 (IRP1) by facilitating Fe/S cluster assembly on IRP1/cytosolic aconitase, distinct from the CIA2B-CIA1-MMS19 complex that handles most other cytosolic-nuclear Fe/S proteins.","method":"Co-immunoprecipitation, RNAi knockdown with defined phenotypic readouts (IRP1 Fe/S cluster maturation assay), genetic epistasis in human cells","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi knockdown with specific Fe/S assembly readout, multiple orthogonal methods, independently consistent with structural and biochemical follow-up studies","pmids":["23891004"],"is_preprint":false},{"year":2013,"finding":"CIA2A (FAM96A) binding stabilizes IRP2 protein even though IRP2 lacks an Fe/S cluster, revealing a second layer of iron regulation independent of Fe/S cluster insertion.","method":"Co-immunoprecipitation, RNAi knockdown with IRP2 protein stability measurements","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and KD with defined readout, single lab, two orthogonal methods","pmids":["23891004"],"is_preprint":false},{"year":2012,"finding":"Human FAM96A (CIAO1/Fam96a) exists as monomers and two distinct domain-swapped dimers in solution; one dimer form is stabilized by zinc binding; the protein is cytoplasmic (not secreted despite a predicted signal peptide); and it interacts tightly in vitro and in vivo with CIAO1.","method":"X-ray crystallography, size-exclusion chromatography, co-immunoprecipitation, cellular fractionation","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both monomer and dimer forms, in vitro biochemical interaction assay, confirmed by co-IP in vivo, multiple orthogonal methods in single study","pmids":["22683786"],"is_preprint":false},{"year":2018,"finding":"A heterotrimeric complex of two CIA2A molecules and one CIAO1 molecule binds one [4Fe-4S] cluster, with Cys90 of CIA2A serving as a cluster ligand; this holo-trimeric complex transfers the [4Fe-4S] cluster to apo-IRP1 to generate active aconitase.","method":"NMR spectroscopy, UV-vis absorption spectroscopy, EPR spectroscopy, in vitro Fe/S cluster transfer assay to apo-IRP1, site-directed mutagenesis (Cys90)","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal spectroscopic methods plus mutagenesis and in vitro reconstitution of cluster transfer, single lab","pmids":["29842905"],"is_preprint":false},{"year":2012,"finding":"NMR backbone resonance assignments established the secondary structure of the monomeric DUF59 domain (residues 31-157) of human FAM96A, confirming that the monomeric and dimeric forms have distinct structural conformations.","method":"NMR spectroscopy (backbone resonance assignments)","journal":"Biomolecular NMR assignments","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural characterization, single lab, single method, primarily structural annotation without functional mutagenesis","pmids":["22618863"],"is_preprint":false},{"year":2015,"finding":"FAM96A binds APAF1 (apoptotic peptidase activating factor 1), and this interaction enhances induction of mitochondrial apoptosis; the interaction was mapped by deletion mutants, GST pull-down, and co-immunoprecipitation, and confirmed by immunofluorescence co-localization.","method":"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, deletion mutant mapping, immunofluorescence, overexpression/knockdown apoptosis assays in cancer cells and zebrafish embryos","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (Y2H, GST-PD, Co-IP) plus functional apoptosis readout, single lab","pmids":["25716227"],"is_preprint":false},{"year":2022,"finding":"FAM96A deficiency in adipocytes disrupts intracellular iron homeostasis (without affecting systemic iron levels), promotes mTOR signaling leading to elevated de novo lipogenesis and fat accumulation, and causes mitochondrial defects (number, ultrastructure, redox activity) in brown adipocytes, reducing organismal energy expenditure.","method":"Global and adipocyte-selective FAM96A knockout mice, metabolic phenotyping, mTOR pathway western blotting, mitochondrial functional assays, lipogenesis measurements","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with defined mechanistic pathway readout (mTOR signaling, lipogenesis), single lab, multiple orthogonal phenotypic measurements","pmids":["36150559"],"is_preprint":false},{"year":2022,"finding":"FAM96A overexpression inhibits TGFβ-mediated EMT through the SMAD-mediated pathway and downregulates endogenous TGFβ1 expression, suppressing tumor cell migration and invasion in vitro and colonization/metastasis in vivo.","method":"FAM96A overexpression and knockout in tumor cell lines, migration/invasion assays, in vivo metastasis models, western blotting for SMAD pathway components and EMT markers, TGFβ1 expression analysis","journal":"Life sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by western blot of downstream markers without direct binding/epistasis experiment for TGFβ1 suppression mechanism","pmids":["35513087"],"is_preprint":false},{"year":2020,"finding":"FAM96A deficiency in macrophages promotes M2 polarization and shifts macrophage metabolism from oxidative phosphorylation to glycolysis; adoptive transfer experiments confirmed macrophages as the key cell type mediating the FAM96A effect on sepsis outcome.","method":"FAM96A knockout mice, CLP and endotoxicosis models, bone marrow-derived macrophage polarization assays, macrophage depletion and adoptive transfer, ROS and glucose uptake measurements","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo adoptive transfer epistasis plus in vitro macrophage polarization assay with metabolic readout, single lab","pmids":["33232517"],"is_preprint":false},{"year":2024,"finding":"Myeloid cell-specific Fam96a deletion disrupts intracellular iron homeostasis in macrophages and suppresses interferon/STAT1 signaling, inhibiting iNOS induction and impairing anti-Toxoplasma gondii immunity; the macrophage polarization defect was iron-dependent.","method":"Myeloid cell-specific Fam96a knockout mice, T. gondii infection model, STAT1 signaling western blots, iNOS expression, intracellular iron measurements, mitochondrial OXPHOS assays","journal":"PLoS neglected tropical diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myeloid-specific KO with defined signaling pathway readout (IFN/STAT1/iNOS), iron-dependence tested, single lab","pmids":["38713713"],"is_preprint":false},{"year":2026,"finding":"Secreted FAM96A binds the extracellular domain of transferrin receptor (TFRC), reducing TFRC-transferrin binding affinity to limit iron uptake; FAM96A-null mice show arrested erythroblast differentiation with iron overload and ferroptosis that is rescued by exogenous FAM96A protein application.","method":"FAM96A knockout mice, erythropoiesis assays (flow cytometry for erythroblast stages), FAM96A protein rescue experiments, binding assay between secreted FAM96A and TFRC extracellular domain, transferrin competition assay, iron measurement, oxidative stress and ferroptosis markers","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with rescue by exogenous protein plus direct binding assay to TFRC, single lab, multiple orthogonal methods","pmids":["41922801"],"is_preprint":false},{"year":2025,"finding":"CIAO2A can recruit CIA targeting complex (CTC) client proteins terminating in a C-terminal TCR (targeting complex recognition) tripeptide motif, docking at the interface of the Cia1-Cia2 subunits; mutations destabilizing the Cia1-CIAO2A interface disrupt TCR-based client recognition, indicating CIAO2A has a more general role in Fe/S protein maturation beyond IRP1.","method":"Computational modeling, biochemical binding assays, biophysical interaction measurements, mutagenesis of Cia1-Cia2 interface residues","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — computational plus biochemical/biophysical approaches with mutagenesis, preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.03.25.645274"],"is_preprint":true}],"current_model":"CIAO2A (FAM96A/CIA2A) is a cytoplasmic DUF59-domain protein that forms a heterotrimeric complex with CIAO1 (two CIA2A : one CIAO1), binds a [4Fe-4S] cluster via Cys90, and transfers this cluster to apo-IRP1/cytosolic aconitase to generate active enzyme; it also stabilizes IRP2 independently of Fe/S cluster insertion, binds APAF1 to promote mitochondrial apoptosis, and—in a newly recognized secreted form—binds the extracellular domain of the transferrin receptor TFRC to limit iron uptake and support erythropoiesis, with emerging evidence that it can also recruit a broader set of CIA targeting complex client proteins via their C-terminal TCR motif."},"narrative":{"mechanistic_narrative":"CIAO2A (FAM96A/CIA2A) is a cytoplasmic DUF59-domain protein that functions in cytosolic iron-sulfur (Fe/S) protein maturation and cellular iron homeostasis [PMID:23891004, PMID:22683786]. It forms a heterotrimeric complex with CIAO1 (two CIAO2A: one CIAO1) that binds a single [4Fe-4S] cluster through Cys90 of CIAO2A and transfers this cluster to apo-IRP1/cytosolic aconitase to generate active enzyme, a maturation branch distinct from the CIA2B-CIAO1-MMS19 complex serving most other cytosolic-nuclear Fe/S proteins [PMID:23891004, PMID:29842905]. CIAO2A additionally stabilizes IRP2 protein independently of Fe/S cluster insertion, defining a second layer of iron regulation [PMID:23891004]. The protein crystallizes as monomers and zinc-stabilized domain-swapped dimers and interacts tightly with CIAO1 [PMID:22683786, PMID:22618863]. Beyond Fe/S maturation, CIAO2A binds APAF1 to promote mitochondrial apoptosis [PMID:25716227], and across multiple tissue-specific mouse models its loss disrupts intracellular iron homeostasis with downstream consequences including dysregulated mTOR signaling and lipogenesis in adipocytes [PMID:36150559], altered macrophage polarization and metabolism in immunity to sepsis and Toxoplasma gondii [PMID:33232517, PMID:38713713], and arrested erythroblast differentiation with iron overload and ferroptosis [PMID:41922801]. A secreted form of FAM96A binds the extracellular domain of transferrin receptor TFRC to reduce transferrin binding affinity and limit iron uptake, supporting erythropoiesis [PMID:41922801].","teleology":[{"year":2012,"claim":"Before functional assignment, the basic biochemistry and oligomeric state of human FAM96A were undefined; structural work established it as a cytoplasmic DUF59 protein that dimerizes and binds CIAO1.","evidence":"X-ray crystallography, SEC, co-IP, cellular fractionation, and NMR backbone assignment of the DUF59 domain","pmids":["22683786","22618863"],"confidence":"High","gaps":["Functional consequence of monomer versus zinc-stabilized dimer not resolved","Role of CIAO1 interaction in catalysis not yet defined","Despite a predicted signal peptide the protein appeared cytoplasmic, leaving any secreted function unaddressed"]},{"year":2013,"claim":"It was unknown which CIA machinery matures IRP1; this established a dedicated CIA2A-CIAO1 branch that assembles the Fe/S cluster on IRP1/cytosolic aconitase, distinct from the CIA2B-CIAO1-MMS19 complex.","evidence":"Co-IP, RNAi knockdown with IRP1 Fe/S maturation readout and genetic epistasis in human cells","pmids":["23891004"],"confidence":"High","gaps":["Cluster-binding residues and stoichiometry not yet defined","Whether IRP1 is the only client unresolved"]},{"year":2013,"claim":"Iron regulation through IRP2 lacks an Fe/S cluster, so its connection to CIA2A was unclear; CIA2A binding was shown to stabilize IRP2 protein independently of cluster insertion, revealing a second regulatory layer.","evidence":"Co-IP and RNAi knockdown with IRP2 protein stability measurements","pmids":["23891004"],"confidence":"Medium","gaps":["Mechanism of stabilization (e.g. shielding from degradation) not defined","Single lab; not independently confirmed"]},{"year":2015,"claim":"A role outside iron metabolism was untested; FAM96A was found to bind APAF1 and enhance mitochondrial apoptosis, linking it to programmed cell death.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, deletion mapping, immunofluorescence, and apoptosis assays in cancer cells and zebrafish","pmids":["25716227"],"confidence":"Medium","gaps":["Whether the apoptotic role depends on Fe/S maturation activity unknown","Single lab"]},{"year":2018,"claim":"The molecular mechanism of cluster handoff was unresolved; reconstitution defined a two-CIA2A:one-CIAO1 holo-complex carrying one [4Fe-4S] cluster via Cys90 that transfers it to apo-IRP1.","evidence":"NMR, UV-vis, EPR spectroscopy, in vitro Fe/S transfer to apo-IRP1, and Cys90 site-directed mutagenesis","pmids":["29842905"],"confidence":"High","gaps":["Source of the cluster transferred to the complex not defined","Structural basis of IRP1 docking not resolved"]},{"year":2020,"claim":"Physiological consequences of FAM96A loss in immune cells were unknown; macrophage studies showed deficiency drives M2 polarization and a metabolic shift to glycolysis, controlling sepsis outcome.","evidence":"FAM96A knockout mice, CLP/endotoxicosis models, BMDM polarization assays, depletion and adoptive transfer, ROS and glucose uptake measurements","pmids":["33232517"],"confidence":"Medium","gaps":["Direct molecular link from FAM96A loss to polarization not defined","Iron-dependence not tested in this study"]},{"year":2022,"claim":"Tissue-level metabolic roles were untested; adipocyte-specific knockout linked FAM96A loss to disrupted intracellular iron homeostasis, elevated mTOR signaling, lipogenesis, and brown-fat mitochondrial defects.","evidence":"Global and adipocyte-selective knockout mice, metabolic phenotyping, mTOR western blotting, mitochondrial and lipogenesis assays","pmids":["36150559"],"confidence":"Medium","gaps":["Mechanistic link between local iron disruption and mTOR activation not defined","Single lab"]},{"year":2022,"claim":"A potential tumor-suppressive role was probed; FAM96A overexpression was reported to inhibit TGFβ/SMAD-driven EMT and downregulate TGFβ1, suppressing migration, invasion and metastasis.","evidence":"Overexpression and knockout in tumor lines, migration/invasion and in vivo metastasis assays, SMAD/EMT marker western blots","pmids":["35513087"],"confidence":"Low","gaps":["Pathway placement rests on downstream marker westerns without direct binding or epistasis for TGFβ1 suppression","Single lab; not independently confirmed"]},{"year":2024,"claim":"Whether macrophage effects were iron-dependent was unresolved; myeloid-specific deletion showed disrupted intracellular iron homeostasis suppresses IFN/STAT1/iNOS signaling and impairs anti-T. gondii immunity in an iron-dependent manner.","evidence":"Myeloid-specific Fam96a knockout mice, T. gondii infection, STAT1/iNOS western blots, intracellular iron and OXPHOS assays","pmids":["38713713"],"confidence":"Medium","gaps":["Which Fe/S client(s) mediate the iron-to-STAT1 link not identified","Single lab"]},{"year":2026,"claim":"A long-standing puzzle of FAM96A's predicted signal peptide was addressed; a secreted form was shown to bind the TFRC extracellular domain, lower transferrin affinity to limit iron uptake, and support erythroblast differentiation, with knockout causing iron overload and ferroptosis rescued by exogenous protein.","evidence":"FAM96A knockout mice, erythropoiesis flow cytometry, exogenous protein rescue, FAM96A-TFRC binding and transferrin competition assays, ferroptosis markers","pmids":["41922801"],"confidence":"Medium","gaps":["Mechanism of FAM96A secretion not defined","Relationship between secreted and cytoplasmic Fe/S-maturation pools unclear","Single lab"]},{"year":2025,"claim":"Whether CIAO2A serves only IRP1 was open; modeling and binding work indicate it can dock CTC client proteins bearing a C-terminal TCR motif at the Cia1-Cia2 interface, implying a broader Fe/S maturation role.","evidence":"Computational modeling, biochemical/biophysical binding assays, and mutagenesis of the Cia1-Cia2 interface (preprint)","pmids":["bio_10.1101_2025.03.25.645274"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Specific additional clients not enumerated","Whether TCR-based recruitment operates in cells not shown"]},{"year":null,"claim":"How CIAO2A's intracellular Fe/S-maturation function mechanistically connects to its secreted TFRC-binding role and to apoptotic signaling within a single coherent pathway remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cytosolic Fe/S assembly, IRP2 stabilization, APAF1 binding, and secreted TFRC regulation","Secretion mechanism and the relationship between secreted and cytoplasmic pools undefined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":["CIA targeting complex (CIAO2A-CIAO1)"],"partners":["CIAO1","IRP1/ACO1","IREB2/IRP2","APAF1","TFRC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H5X1","full_name":"Cytosolic iron-sulfur assembly component 2A","aliases":["MIP18 family protein FAM96A"],"length_aa":160,"mass_kda":18.4,"function":"Component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins (PubMed:23891004). As a CIA complex component and in collaboration with CIAO1 specifically matures ACO1 and stabilizes IREB2, connecting cytosolic iron-sulfur protein maturation with cellular iron regulation (PubMed:23891004). May play a role in chromosome segregation through establishment of sister chromatid cohesion. May induce apoptosis in collaboration with APAF1 (PubMed:25716227)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H5X1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CIAO2A","classification":"Not Classified","n_dependent_lines":326,"n_total_lines":1208,"dependency_fraction":0.26986754966887416},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CIAO2A","total_profiled":1310},"omim":[{"mim_id":"620960","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 10; MMDS10","url":"https://www.omim.org/entry/620960"},{"mim_id":"618382","title":"CYTOSOLIC IRON-SULFUR ASSEMBLY COMPONENT 2A; CIAO2A","url":"https://www.omim.org/entry/618382"},{"mim_id":"614778","title":"CYTOSOLIC IRON-SULFUR ASSEMBLY COMPONENT 2B; CIAO2B","url":"https://www.omim.org/entry/614778"},{"mim_id":"614777","title":"MMS19 HOMOLOG, CYTOSOLIC IRON-SULFUR ASSEMBLY COMPONENT; MMS19","url":"https://www.omim.org/entry/614777"},{"mim_id":"604333","title":"WD40 REPEAT-CONTAINING PROTEIN CIAO1; CIAO1","url":"https://www.omim.org/entry/604333"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":245.2}],"url":"https://www.proteinatlas.org/search/CIAO2A"},"hgnc":{"alias_symbol":["FLJ22875","CIA2A"],"prev_symbol":["FAM96A"]},"alphafold":{"accession":"Q9H5X1","domains":[{"cath_id":"3.30.300.130","chopping":"25-155","consensus_level":"high","plddt":92.4216,"start":25,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5X1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5X1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H5X1-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CIAO2A","jax_strain_url":"https://www.jax.org/strain/search?query=CIAO2A"},"sequence":{"accession":"Q9H5X1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H5X1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H5X1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H5X1"}},"corpus_meta":[{"pmid":"23891004","id":"PMC_23891004","title":"Human CIA2A-FAM96A and CIA2B-FAM96B integrate iron homeostasis and maturation of different subsets of cytosolic-nuclear iron-sulfur proteins.","date":"2013","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23891004","citation_count":142,"is_preprint":false},{"pmid":"25716227","id":"PMC_25716227","title":"FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors.","date":"2015","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25716227","citation_count":25,"is_preprint":false},{"pmid":"22683786","id":"PMC_22683786","title":"The mammalian DUF59 protein Fam96a forms two distinct types of domain-swapped dimer.","date":"2012","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/22683786","citation_count":22,"is_preprint":false},{"pmid":"31803631","id":"PMC_31803631","title":"FAM96A Protects Mice From Dextran Sulfate Sodium (DSS)-Induced Colitis by Preventing Microbial Dysbiosis.","date":"2019","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/31803631","citation_count":19,"is_preprint":false},{"pmid":"29842905","id":"PMC_29842905","title":"Investigating the role of the human CIA2A-CIAO1 complex in the maturation of aconitase.","date":"2018","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/29842905","citation_count":18,"is_preprint":false},{"pmid":"33232517","id":"PMC_33232517","title":"FAM96A knock-out promotes alternative macrophage polarization and protects mice against sepsis.","date":"2020","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33232517","citation_count":12,"is_preprint":false},{"pmid":"36165859","id":"PMC_36165859","title":"FAM96A and FAM96B function as new tumor suppressor genes in breast cancer through regulation of the Wnt/β-catenin signaling pathway.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36165859","citation_count":9,"is_preprint":false},{"pmid":"22618863","id":"PMC_22618863","title":"Backbone resonance assignments of the monomeric DUF59 domain of human Fam96a.","date":"2012","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/22618863","citation_count":8,"is_preprint":false},{"pmid":"28443470","id":"PMC_28443470","title":"A multi-target protein of hTERTR-FAM96A presents significant anticancer potent in the treatment of hepatocellular carcinoma.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28443470","citation_count":8,"is_preprint":false},{"pmid":"29399066","id":"PMC_29399066","title":"Combination therapy of hTERTR and FAM96A for hepatocellular carcinoma through enhancing apoptosis sensitivity.","date":"2017","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29399066","citation_count":6,"is_preprint":false},{"pmid":"36150559","id":"PMC_36150559","title":"FAM96A is essential for maintaining organismal energy balance and adipose tissue homeostasis in mice.","date":"2022","source":"Free radical biology & 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motif","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.25.645274","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10026,"output_tokens":3034,"usd":0.037794,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10520,"output_tokens":3899,"usd":0.075037,"stage2_stop_reason":"end_turn"},"total_usd":0.112831,"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\": 2013,\n      \"finding\": \"CIA2A (FAM96A) forms a complex with CIA1 (CIAO1) that specifically matures iron regulatory protein 1 (IRP1) by facilitating Fe/S cluster assembly on IRP1/cytosolic aconitase, distinct from the CIA2B-CIA1-MMS19 complex that handles most other cytosolic-nuclear Fe/S proteins.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown with defined phenotypic readouts (IRP1 Fe/S cluster maturation assay), genetic epistasis in human cells\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi knockdown with specific Fe/S assembly readout, multiple orthogonal methods, independently consistent with structural and biochemical follow-up studies\",\n      \"pmids\": [\"23891004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CIA2A (FAM96A) binding stabilizes IRP2 protein even though IRP2 lacks an Fe/S cluster, revealing a second layer of iron regulation independent of Fe/S cluster insertion.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown with IRP2 protein stability measurements\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and KD with defined readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"23891004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human FAM96A (CIAO1/Fam96a) exists as monomers and two distinct domain-swapped dimers in solution; one dimer form is stabilized by zinc binding; the protein is cytoplasmic (not secreted despite a predicted signal peptide); and it interacts tightly in vitro and in vivo with CIAO1.\",\n      \"method\": \"X-ray crystallography, size-exclusion chromatography, co-immunoprecipitation, cellular fractionation\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both monomer and dimer forms, in vitro biochemical interaction assay, confirmed by co-IP in vivo, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22683786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A heterotrimeric complex of two CIA2A molecules and one CIAO1 molecule binds one [4Fe-4S] cluster, with Cys90 of CIA2A serving as a cluster ligand; this holo-trimeric complex transfers the [4Fe-4S] cluster to apo-IRP1 to generate active aconitase.\",\n      \"method\": \"NMR spectroscopy, UV-vis absorption spectroscopy, EPR spectroscopy, in vitro Fe/S cluster transfer assay to apo-IRP1, site-directed mutagenesis (Cys90)\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal spectroscopic methods plus mutagenesis and in vitro reconstitution of cluster transfer, single lab\",\n      \"pmids\": [\"29842905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NMR backbone resonance assignments established the secondary structure of the monomeric DUF59 domain (residues 31-157) of human FAM96A, confirming that the monomeric and dimeric forms have distinct structural conformations.\",\n      \"method\": \"NMR spectroscopy (backbone resonance assignments)\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization, single lab, single method, primarily structural annotation without functional mutagenesis\",\n      \"pmids\": [\"22618863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FAM96A binds APAF1 (apoptotic peptidase activating factor 1), and this interaction enhances induction of mitochondrial apoptosis; the interaction was mapped by deletion mutants, GST pull-down, and co-immunoprecipitation, and confirmed by immunofluorescence co-localization.\",\n      \"method\": \"Yeast two-hybrid screen, GST pull-down, co-immunoprecipitation, deletion mutant mapping, immunofluorescence, overexpression/knockdown apoptosis assays in cancer cells and zebrafish embryos\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (Y2H, GST-PD, Co-IP) plus functional apoptosis readout, single lab\",\n      \"pmids\": [\"25716227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM96A deficiency in adipocytes disrupts intracellular iron homeostasis (without affecting systemic iron levels), promotes mTOR signaling leading to elevated de novo lipogenesis and fat accumulation, and causes mitochondrial defects (number, ultrastructure, redox activity) in brown adipocytes, reducing organismal energy expenditure.\",\n      \"method\": \"Global and adipocyte-selective FAM96A knockout mice, metabolic phenotyping, mTOR pathway western blotting, mitochondrial functional assays, lipogenesis measurements\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with defined mechanistic pathway readout (mTOR signaling, lipogenesis), single lab, multiple orthogonal phenotypic measurements\",\n      \"pmids\": [\"36150559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM96A overexpression inhibits TGFβ-mediated EMT through the SMAD-mediated pathway and downregulates endogenous TGFβ1 expression, suppressing tumor cell migration and invasion in vitro and colonization/metastasis in vivo.\",\n      \"method\": \"FAM96A overexpression and knockout in tumor cell lines, migration/invasion assays, in vivo metastasis models, western blotting for SMAD pathway components and EMT markers, TGFβ1 expression analysis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by western blot of downstream markers without direct binding/epistasis experiment for TGFβ1 suppression mechanism\",\n      \"pmids\": [\"35513087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM96A deficiency in macrophages promotes M2 polarization and shifts macrophage metabolism from oxidative phosphorylation to glycolysis; adoptive transfer experiments confirmed macrophages as the key cell type mediating the FAM96A effect on sepsis outcome.\",\n      \"method\": \"FAM96A knockout mice, CLP and endotoxicosis models, bone marrow-derived macrophage polarization assays, macrophage depletion and adoptive transfer, ROS and glucose uptake measurements\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo adoptive transfer epistasis plus in vitro macrophage polarization assay with metabolic readout, single lab\",\n      \"pmids\": [\"33232517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Myeloid cell-specific Fam96a deletion disrupts intracellular iron homeostasis in macrophages and suppresses interferon/STAT1 signaling, inhibiting iNOS induction and impairing anti-Toxoplasma gondii immunity; the macrophage polarization defect was iron-dependent.\",\n      \"method\": \"Myeloid cell-specific Fam96a knockout mice, T. gondii infection model, STAT1 signaling western blots, iNOS expression, intracellular iron measurements, mitochondrial OXPHOS assays\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myeloid-specific KO with defined signaling pathway readout (IFN/STAT1/iNOS), iron-dependence tested, single lab\",\n      \"pmids\": [\"38713713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Secreted FAM96A binds the extracellular domain of transferrin receptor (TFRC), reducing TFRC-transferrin binding affinity to limit iron uptake; FAM96A-null mice show arrested erythroblast differentiation with iron overload and ferroptosis that is rescued by exogenous FAM96A protein application.\",\n      \"method\": \"FAM96A knockout mice, erythropoiesis assays (flow cytometry for erythroblast stages), FAM96A protein rescue experiments, binding assay between secreted FAM96A and TFRC extracellular domain, transferrin competition assay, iron measurement, oxidative stress and ferroptosis markers\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with rescue by exogenous protein plus direct binding assay to TFRC, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41922801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CIAO2A can recruit CIA targeting complex (CTC) client proteins terminating in a C-terminal TCR (targeting complex recognition) tripeptide motif, docking at the interface of the Cia1-Cia2 subunits; mutations destabilizing the Cia1-CIAO2A interface disrupt TCR-based client recognition, indicating CIAO2A has a more general role in Fe/S protein maturation beyond IRP1.\",\n      \"method\": \"Computational modeling, biochemical binding assays, biophysical interaction measurements, mutagenesis of Cia1-Cia2 interface residues\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — computational plus biochemical/biophysical approaches with mutagenesis, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.03.25.645274\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CIAO2A (FAM96A/CIA2A) is a cytoplasmic DUF59-domain protein that forms a heterotrimeric complex with CIAO1 (two CIA2A : one CIAO1), binds a [4Fe-4S] cluster via Cys90, and transfers this cluster to apo-IRP1/cytosolic aconitase to generate active enzyme; it also stabilizes IRP2 independently of Fe/S cluster insertion, binds APAF1 to promote mitochondrial apoptosis, and—in a newly recognized secreted form—binds the extracellular domain of the transferrin receptor TFRC to limit iron uptake and support erythropoiesis, with emerging evidence that it can also recruit a broader set of CIA targeting complex client proteins via their C-terminal TCR motif.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CIAO2A (FAM96A/CIA2A) is a cytoplasmic DUF59-domain protein that functions in cytosolic iron-sulfur (Fe/S) protein maturation and cellular iron homeostasis [#0, #2]. It forms a heterotrimeric complex with CIAO1 (two CIAO2A : one CIAO1) that binds a single [4Fe-4S] cluster through Cys90 of CIAO2A and transfers this cluster to apo-IRP1/cytosolic aconitase to generate active enzyme, a maturation branch distinct from the CIA2B-CIAO1-MMS19 complex serving most other cytosolic-nuclear Fe/S proteins [#0, #3]. CIAO2A additionally stabilizes IRP2 protein independently of Fe/S cluster insertion, defining a second layer of iron regulation [#1]. The protein crystallizes as monomers and zinc-stabilized domain-swapped dimers and interacts tightly with CIAO1 [#2, #4]. Beyond Fe/S maturation, CIAO2A binds APAF1 to promote mitochondrial apoptosis [#5], and across multiple tissue-specific mouse models its loss disrupts intracellular iron homeostasis with downstream consequences including dysregulated mTOR signaling and lipogenesis in adipocytes [#6], altered macrophage polarization and metabolism in immunity to sepsis and Toxoplasma gondii [#8, #9], and arrested erythroblast differentiation with iron overload and ferroptosis [#10]. A secreted form of FAM96A binds the extracellular domain of transferrin receptor TFRC to reduce transferrin binding affinity and limit iron uptake, supporting erythropoiesis [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Before functional assignment, the basic biochemistry and oligomeric state of human FAM96A were undefined; structural work established it as a cytoplasmic DUF59 protein that dimerizes and binds CIAO1.\",\n      \"evidence\": \"X-ray crystallography, SEC, co-IP, cellular fractionation, and NMR backbone assignment of the DUF59 domain\",\n      \"pmids\": [\"22683786\", \"22618863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of monomer versus zinc-stabilized dimer not resolved\", \"Role of CIAO1 interaction in catalysis not yet defined\", \"Despite a predicted signal peptide the protein appeared cytoplasmic, leaving any secreted function unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"It was unknown which CIA machinery matures IRP1; this established a dedicated CIA2A-CIAO1 branch that assembles the Fe/S cluster on IRP1/cytosolic aconitase, distinct from the CIA2B-CIAO1-MMS19 complex.\",\n      \"evidence\": \"Co-IP, RNAi knockdown with IRP1 Fe/S maturation readout and genetic epistasis in human cells\",\n      \"pmids\": [\"23891004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cluster-binding residues and stoichiometry not yet defined\", \"Whether IRP1 is the only client unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Iron regulation through IRP2 lacks an Fe/S cluster, so its connection to CIA2A was unclear; CIA2A binding was shown to stabilize IRP2 protein independently of cluster insertion, revealing a second regulatory layer.\",\n      \"evidence\": \"Co-IP and RNAi knockdown with IRP2 protein stability measurements\",\n      \"pmids\": [\"23891004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of stabilization (e.g. shielding from degradation) not defined\", \"Single lab; not independently confirmed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A role outside iron metabolism was untested; FAM96A was found to bind APAF1 and enhance mitochondrial apoptosis, linking it to programmed cell death.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, deletion mapping, immunofluorescence, and apoptosis assays in cancer cells and zebrafish\",\n      \"pmids\": [\"25716227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the apoptotic role depends on Fe/S maturation activity unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The molecular mechanism of cluster handoff was unresolved; reconstitution defined a two-CIA2A:one-CIAO1 holo-complex carrying one [4Fe-4S] cluster via Cys90 that transfers it to apo-IRP1.\",\n      \"evidence\": \"NMR, UV-vis, EPR spectroscopy, in vitro Fe/S transfer to apo-IRP1, and Cys90 site-directed mutagenesis\",\n      \"pmids\": [\"29842905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of the cluster transferred to the complex not defined\", \"Structural basis of IRP1 docking not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Physiological consequences of FAM96A loss in immune cells were unknown; macrophage studies showed deficiency drives M2 polarization and a metabolic shift to glycolysis, controlling sepsis outcome.\",\n      \"evidence\": \"FAM96A knockout mice, CLP/endotoxicosis models, BMDM polarization assays, depletion and adoptive transfer, ROS and glucose uptake measurements\",\n      \"pmids\": [\"33232517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from FAM96A loss to polarization not defined\", \"Iron-dependence not tested in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Tissue-level metabolic roles were untested; adipocyte-specific knockout linked FAM96A loss to disrupted intracellular iron homeostasis, elevated mTOR signaling, lipogenesis, and brown-fat mitochondrial defects.\",\n      \"evidence\": \"Global and adipocyte-selective knockout mice, metabolic phenotyping, mTOR western blotting, mitochondrial and lipogenesis assays\",\n      \"pmids\": [\"36150559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between local iron disruption and mTOR activation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A potential tumor-suppressive role was probed; FAM96A overexpression was reported to inhibit TGFβ/SMAD-driven EMT and downregulate TGFβ1, suppressing migration, invasion and metastasis.\",\n      \"evidence\": \"Overexpression and knockout in tumor lines, migration/invasion and in vivo metastasis assays, SMAD/EMT marker western blots\",\n      \"pmids\": [\"35513087\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement rests on downstream marker westerns without direct binding or epistasis for TGFβ1 suppression\", \"Single lab; not independently confirmed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether macrophage effects were iron-dependent was unresolved; myeloid-specific deletion showed disrupted intracellular iron homeostasis suppresses IFN/STAT1/iNOS signaling and impairs anti-T. gondii immunity in an iron-dependent manner.\",\n      \"evidence\": \"Myeloid-specific Fam96a knockout mice, T. gondii infection, STAT1/iNOS western blots, intracellular iron and OXPHOS assays\",\n      \"pmids\": [\"38713713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which Fe/S client(s) mediate the iron-to-STAT1 link not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A long-standing puzzle of FAM96A's predicted signal peptide was addressed; a secreted form was shown to bind the TFRC extracellular domain, lower transferrin affinity to limit iron uptake, and support erythroblast differentiation, with knockout causing iron overload and ferroptosis rescued by exogenous protein.\",\n      \"evidence\": \"FAM96A knockout mice, erythropoiesis flow cytometry, exogenous protein rescue, FAM96A-TFRC binding and transferrin competition assays, ferroptosis markers\",\n      \"pmids\": [\"41922801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FAM96A secretion not defined\", \"Relationship between secreted and cytoplasmic Fe/S-maturation pools unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether CIAO2A serves only IRP1 was open; modeling and binding work indicate it can dock CTC client proteins bearing a C-terminal TCR motif at the Cia1-Cia2 interface, implying a broader Fe/S maturation role.\",\n      \"evidence\": \"Computational modeling, biochemical/biophysical binding assays, and mutagenesis of the Cia1-Cia2 interface (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.25.645274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Specific additional clients not enumerated\", \"Whether TCR-based recruitment operates in cells not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CIAO2A's intracellular Fe/S-maturation function mechanistically connects to its secreted TFRC-binding role and to apoptotic signaling within a single coherent pathway remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cytosolic Fe/S assembly, IRP2 stabilization, APAF1 binding, and secreted TFRC regulation\", \"Secretion mechanism and the relationship between secreted and cytoplasmic pools undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051536\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"CIA targeting complex (CIAO2A-CIAO1)\"],\n    \"partners\": [\"CIAO1\", \"IRP1/ACO1\", \"IREB2/IRP2\", \"APAF1\", \"TFRC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}