{"gene":"STOM","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2020,"finding":"STOM inhibits ASIC3 gating by requiring two distinct sites on ASIC3: the distal C-terminus (critical for forming the STOM-ASIC3 complex) and the first transmembrane domain TM1 (required only for the regulatory effect). STOM does not alter surface expression of ASIC3 or shift pH dependence of activation, but a desensitization-blocking point mutation (Q269G) also prevents STOM regulation, suggesting STOM stabilizes the desensitized state of the channel.","method":"Chimeric channel analysis, patch-clamp electrophysiology, FRET, site-directed mutagenesis","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis and FRET, multiple orthogonal methods in single rigorous study","pmids":["32012213"],"is_preprint":false},{"year":2021,"finding":"DRAM (damage-regulated autophagy modulator) interacts with stomatin (STOM) upon fatty acid stimulation and promotes STOM lysosomal localization, which enhances lysosomal membrane permeabilization and exosome secretion from hepatocytes. DRAM knockout reversed high-fat diet-induced increase of secreted exosomes, and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice.","method":"Co-immunoprecipitation, knockout mouse model, knockdown cell model, lysosome inhibitor rescue experiments","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown, in vivo KO model plus pharmacological rescue, single lab","pmids":["34731006"],"is_preprint":false},{"year":2021,"finding":"STOM inhibits glucose uptake by restraining the glucose transporter GLUT1. PON2 releases GLUT1 from STOM-mediated inhibition to enable glucose uptake in B-ALL cells. Genetic deletion of STOM largely rescued the glucose uptake deficiency caused by PON2 deficiency, placing STOM as an inhibitor of GLUT1 activity upstream of PON2.","method":"Genetic deletion (STOM KO), epistasis rescue experiments, glucose uptake assays in murine and human B-ALL cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with STOM KO rescuing PON2 deficiency, replicated in murine and human cell models with functional metabolic readout","pmids":["33531346"],"is_preprint":false},{"year":2022,"finding":"STOM interacts with Pannexin 1 (PANX1) in human red blood cells, as demonstrated by Proximity Ligation Assay. RBCs from overhydrated hereditary stomatocytosis (OHSt) patients lacking stomatin show significantly reduced PANX1 permeability activity (dye uptake reduced ~50%), and K562 erythroid cells with stomatin knocked out show reduced PANX1 channel activity, suggesting stomatin promotes PANX1 pore opening via a caspase-independent mechanism.","method":"Proximity Ligation Assay, dye uptake (CF and TO-PRO-3) in patient RBCs and STOM-KO K562 cells, flow imaging","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PLA interaction plus functional loss-of-function with two distinct cell models (patient RBCs and engineered K562), single lab","pmids":["36012667"],"is_preprint":false},{"year":2022,"finding":"The NMR solution structure of the SPFH domain of human stomatin (hSTOM) was determined, revealing a cryptic phosphate-binding pocket not present in the mouse crystal structure. At high concentrations, hSTOM(SPFH) forms fibril-like assemblies (confirmed by electron microscopy), and phosphate binding inhibits dissolution of these assemblies, suggesting phosphate regulates SPFH-domain-mediated oligomerization relevant to membrane skeleton function.","method":"NMR structure determination, NMR chemical shift perturbation with phosphate, electron microscopy of fibrils, centrifugal ultrafiltration assembly assay","journal":"Current research in structural biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure with functional validation (phosphate binding, fibril assembly), single lab, no mutagenesis confirmation of phosphate site function","pmids":["35663930"],"is_preprint":false},{"year":2025,"finding":"STOM interacts with Prdx1 (peroxiredoxin 1) and promotes its degradation through the lysosomal pathway, thereby increasing intracellular ROS production and activating osteoclastogenesis. STOM-deficient mice show higher bone mass and reduced osteoclast differentiation. Targeted inhibition of macrophage STOM expression alleviates ovariectomy-induced bone loss in mice.","method":"Transcriptomic analysis, co-immunoprecipitation (STOM-Prdx1 interaction), STOM-deficient mouse model, lysosomal pathway inhibition, ROS measurement, osteoclast differentiation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for STOM-Prdx1 interaction, in vivo KO model with mechanistic rescue, multiple orthogonal methods","pmids":["40595453"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated depletion of STOM in human epithelial cells resulted in increased Salmonella typhimurium replication and dispersal of intracellular Salmonella microcolonies, indicating STOM plays a role in restricting intracellular Salmonella growth and maintaining microcolony integrity.","method":"SILAC-based quantitative proteomics, siRNA knockdown, intracellular Salmonella replication assay, microcolony imaging","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA KD with two distinct cellular phenotype readouts (replication and microcolony dispersal), single lab","pmids":["21919203"],"is_preprint":false},{"year":2022,"finding":"STOM interacts with VacA (vacuolating cytotoxin A from H. pylori) at the cell membrane; STOM and VacA co-immunoprecipitate and interact in vitro. Based on these results, STOM at the plasma membrane was proposed to capture VacA to form endosomes that allow VacA entry into cells targeting mitochondria.","method":"Pull-down assay, co-immunoprecipitation, protein-protein docking, LC-MS/MS","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and pulldown, mechanistic interpretation partially speculative, single lab","pmids":["35912184"],"is_preprint":false},{"year":2021,"finding":"STOM knockdown in LPS-treated mouse lung epithelial cells (MLE-12) reversed LPS-induced inhibition of cell viability and promotion of oxidative stress and inflammation. RNA immunoprecipitation confirmed that STOM interacts with and positively regulates CD36 expression; overexpression of CD36 rescued the protective effects of STOM knockdown.","method":"siRNA knockdown, CD36 overexpression, RNA immunoprecipitation (RIP), Cell Counting Kit-8 viability assay, ELISA for oxidative stress and inflammatory markers, western blotting","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP assay for STOM-CD36 interaction plus functional rescue epistasis, single lab","pmids":["34934440"],"is_preprint":false},{"year":2022,"finding":"STOM and STOML3 are co-expressed in olfactory sensory neuron (OSN) cilia, and STOML3 is necessary for STOM to properly localize to OSN cilia; without STOML3, STOM fails to reach the ciliary compartment.","method":"Immunofluorescence, confocal imaging, genetic loss-of-function (STOML3-deficient mice), subcellular localization analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by imaging with genetic loss-of-function showing STOML3 dependence for STOM ciliary targeting, single lab","pmids":["35794236"],"is_preprint":false},{"year":1995,"finding":"The human EPB72 gene (encoding stomatin) comprises seven exons spanning ~30 kb. The 5'-flanking region contains consensus sequences for ubiquitous transcription factors (Sp1, AP1, AP2, CP1/2, NF-κB, CREB, Ets-1, CACC/GT-BF) and imperfect erythroid factor sequences (EKLF, GATA-1), with no TATA box, consistent with a housekeeping gene promoter. Two polyadenylation signals produce two mRNA species.","method":"Genomic library cloning, sequencing, Southern blot, promoter analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct genomic characterization by sequencing and blotting, single lab, structural not functional validation","pmids":["8825639"],"is_preprint":false},{"year":1993,"finding":"The human EPB72 gene (stomatin) was mapped to chromosome band 9q34.1 by Southern blot analysis of somatic cell hybrid DNA panels.","method":"Southern blot analysis of somatic cell hybrid DNA panels","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct chromosomal mapping by established hybrid panel method, single lab","pmids":["8500356"],"is_preprint":false}],"current_model":"STOM (stomatin/EPB72) is a monotopic integral membrane protein and lipid raft component that acts as a multi-functional regulator: it inhibits acid-sensing ion channel 3 (ASIC3) by anchoring to its C-terminus and stabilizing the desensitized state via TM1; it restrains glucose transporter GLUT1 activity (released by PON2 in leukemia cells); it interacts with and promotes lysosomal degradation of Prdx1 to elevate ROS and drive osteoclastogenesis; it interacts with DRAM at lysosomes to facilitate lysosomal membrane permeabilization and exosome secretion; it promotes Pannexin 1 (PANX1) channel opening in red blood cells; it regulates CD36 expression under inflammatory conditions; and its ciliary localization in olfactory sensory neurons depends on STOML3."},"narrative":{"mechanistic_narrative":"STOM (stomatin/EPB72) is a lipid-raft-associated, monotopic membrane protein with an SPFH domain that functions as a multi-target regulator of membrane channels, transporters, and lysosomal/membrane homeostasis [PMID:32012213, PMID:33531346, PMID:35663930]. As a channel regulator, it binds the distal C-terminus of acid-sensing ion channel ASIC3 and, through its first transmembrane domain, stabilizes the channel's desensitized state to inhibit gating without altering surface expression [PMID:32012213], and in red blood cells it physically associates with Pannexin 1 to promote pore opening through a caspase-independent mechanism [PMID:36012667]. STOM also restrains the glucose transporter GLUT1, with PON2 relieving this inhibition to permit glucose uptake in B-ALL cells [PMID:33531346]. At lysosomes, STOM drives degradative and membrane-permeabilization programs: it interacts with Prdx1 to promote its lysosomal degradation, elevating ROS to activate osteoclastogenesis [PMID:40595453], and partners with DRAM upon fatty-acid stimulation to enhance lysosomal membrane permeabilization and exosome secretion from hepatocytes [PMID:34731006]. Structurally, the SPFH domain harbors a cryptic phosphate-binding pocket and forms fibril-like assemblies whose dissolution is inhibited by phosphate, linking phosphate sensing to oligomerization [PMID:35663930]. STOM ciliary localization in olfactory sensory neurons depends on STOML3 [PMID:35794236]. The EPB72 gene maps to 9q34.1 and has a TATA-less, housekeeping-type promoter [PMID:8825639, PMID:8500356].","teleology":[{"year":1993,"claim":"Establishing the chromosomal location and genomic organization of the stomatin gene provided the molecular foundation for studying the protein and its disease associations.","evidence":"Southern blot of somatic cell hybrid panels mapping EPB72 to 9q34.1, followed by genomic cloning and promoter analysis","pmids":["8500356","8825639"],"confidence":"Medium","gaps":["Promoter elements identified by sequence only, not functionally validated","No link to protein function established at this stage"]},{"year":2011,"claim":"The question of whether STOM has a role in host defense was addressed by showing its loss permits intracellular bacterial growth, implicating STOM in restricting pathogen replication.","evidence":"SILAC proteomics with siRNA knockdown and intracellular Salmonella replication/microcolony imaging in epithelial cells","pmids":["21919203"],"confidence":"Medium","gaps":["Molecular mechanism of restriction unknown","No direct STOM-pathogen interaction defined","Single lab, single phenotype class"]},{"year":2020,"claim":"The mechanism by which STOM inhibits an ion channel was resolved, showing it binds the ASIC3 C-terminus and uses TM1 to stabilize the desensitized state rather than altering trafficking.","evidence":"Chimeric channel analysis, patch-clamp, FRET, and site-directed mutagenesis in heterologous expression","pmids":["32012213"],"confidence":"High","gaps":["No structure of the STOM-ASIC3 complex","Stoichiometry of regulation undefined","Physiological context in native neurons not tested"]},{"year":2021,"claim":"STOM was placed in glucose metabolism as a brake on GLUT1, with genetic epistasis showing PON2 relieves this inhibition in leukemia cells.","evidence":"STOM genetic deletion and epistasis rescue of PON2-deficient glucose uptake in murine and human B-ALL cells","pmids":["33531346"],"confidence":"High","gaps":["Direct STOM-GLUT1 physical interaction not biochemically resolved","Mechanism of PON2-mediated release unknown"]},{"year":2021,"claim":"STOM was connected to lysosomal membrane dynamics and inflammatory signaling through distinct partners, defining roles in exosome secretion and CD36 regulation.","evidence":"Co-IP plus DRAM knockout mouse and lysosome-inhibitor rescue for exosome secretion; RIP and CD36-overexpression rescue in LPS-treated lung epithelial cells","pmids":["34731006","34934440"],"confidence":"Medium","gaps":["Mechanism by which STOM permeabilizes lysosomal membranes undefined","Nature of the STOM-CD36 RNA/protein interaction unclear","Both from single labs"]},{"year":2022,"claim":"Structural and additional interaction studies expanded STOM's mechanistic picture, revealing a phosphate-sensitive SPFH oligomerization domain, a role in Pannexin 1 pore opening, STOML3-dependent ciliary targeting, and a candidate toxin-capture interaction.","evidence":"NMR structure with fibril/phosphate assays; PLA and loss-of-function in OHSt RBCs and K562; immunofluorescence in STOML3-deficient mice; Co-IP/pull-down with H. pylori VacA","pmids":["35663930","36012667","35794236","35912184"],"confidence":"Medium","gaps":["Phosphate-binding site not validated by mutagenesis","Mechanism linking STOM to PANX1 opening undefined","VacA interaction based on single Co-IP/pull-down with speculative interpretation"]},{"year":2025,"claim":"A lysosomal-degradation mechanism linking STOM to redox-driven bone resorption was established, defining Prdx1 as a STOM target and STOM as a driver of osteoclastogenesis.","evidence":"Reciprocal Co-IP, STOM-deficient mice, lysosomal pathway inhibition, ROS measurement, and osteoclast differentiation assays","pmids":["40595453"],"confidence":"High","gaps":["How STOM routes Prdx1 to lysosomes mechanistically is unresolved","Whether ROS elevation is solely Prdx1-dependent untested"]},{"year":null,"claim":"It remains unknown how STOM achieves selectivity across its diverse targets (ion channels, transporters, lysosomal substrates) and whether its SPFH-domain oligomerization underlies a unified scaffolding mechanism.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural model of STOM target engagement","No reconstituted system linking oligomerization state to regulatory output","Tissue-specific partner repertoires uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2]}],"complexes":[],"partners":["ASIC3","GLUT1","PANX1","PRDX1","DRAM","CD36","STOML3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P27105","full_name":"Stomatin","aliases":["Erythrocyte band 7 integral membrane protein","Erythrocyte membrane protein band 7.2","Protein 7.2b"],"length_aa":288,"mass_kda":31.7,"function":"Regulates ion channel activity and transmembrane ion transport. Regulates ASIC2 and ASIC3 channel activity","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton; Cell membrane; Membrane raft; Melanosome; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/P27105/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STOM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCNB1","stoichiometry":10.0},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"ARHGAP11AB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STOM","total_profiled":1310},"omim":[{"mim_id":"608885","title":"STOMATIN-DEFICIENT CRYOHYDROCYTOSIS WITH NEUROLOGIC DEFECTS; SDCHCN","url":"https://www.omim.org/entry/608885"},{"mim_id":"608327","title":"STOMATIN-LIKE PROTEIN 3; STOML3","url":"https://www.omim.org/entry/608327"},{"mim_id":"608326","title":"STOMATIN-LIKE PROTEIN 1; STOML1","url":"https://www.omim.org/entry/608326"},{"mim_id":"608292","title":"STOMATIN-LIKE PROTEIN 2; STOML2","url":"https://www.omim.org/entry/608292"},{"mim_id":"185020","title":"CRYOHYDROCYTOSIS; CHC","url":"https://www.omim.org/entry/185020"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STOM"},"hgnc":{"alias_symbol":["BND7"],"prev_symbol":["EPB7","EPB72"]},"alphafold":{"accession":"P27105","domains":[{"cath_id":"-","chopping":"35-94","consensus_level":"high","plddt":86.5232,"start":35,"end":94},{"cath_id":"3.30.479.30","chopping":"98-199","consensus_level":"high","plddt":94.7632,"start":98,"end":199}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P27105","model_url":"https://alphafold.ebi.ac.uk/files/AF-P27105-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P27105-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STOM","jax_strain_url":"https://www.jax.org/strain/search?query=STOM"},"sequence":{"accession":"P27105","fasta_url":"https://rest.uniprot.org/uniprotkb/P27105.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P27105/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P27105"}},"corpus_meta":[{"pmid":"11739726","id":"PMC_11739726","title":"Mammalian 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STOM does not alter surface expression of ASIC3 or shift pH dependence of activation, but a desensitization-blocking point mutation (Q269G) also prevents STOM regulation, suggesting STOM stabilizes the desensitized state of the channel.\",\n      \"method\": \"Chimeric channel analysis, patch-clamp electrophysiology, FRET, site-directed mutagenesis\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro electrophysiology with mutagenesis and FRET, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"32012213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DRAM (damage-regulated autophagy modulator) interacts with stomatin (STOM) upon fatty acid stimulation and promotes STOM lysosomal localization, which enhances lysosomal membrane permeabilization and exosome secretion from hepatocytes. DRAM knockout reversed high-fat diet-induced increase of secreted exosomes, and lysosome inhibitor reversed the down-regulation of exosome release in DRAM knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, knockout mouse model, knockdown cell model, lysosome inhibitor rescue experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown, in vivo KO model plus pharmacological rescue, single lab\",\n      \"pmids\": [\"34731006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOM inhibits glucose uptake by restraining the glucose transporter GLUT1. PON2 releases GLUT1 from STOM-mediated inhibition to enable glucose uptake in B-ALL cells. Genetic deletion of STOM largely rescued the glucose uptake deficiency caused by PON2 deficiency, placing STOM as an inhibitor of GLUT1 activity upstream of PON2.\",\n      \"method\": \"Genetic deletion (STOM KO), epistasis rescue experiments, glucose uptake assays in murine and human B-ALL cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with STOM KO rescuing PON2 deficiency, replicated in murine and human cell models with functional metabolic readout\",\n      \"pmids\": [\"33531346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STOM interacts with Pannexin 1 (PANX1) in human red blood cells, as demonstrated by Proximity Ligation Assay. RBCs from overhydrated hereditary stomatocytosis (OHSt) patients lacking stomatin show significantly reduced PANX1 permeability activity (dye uptake reduced ~50%), and K562 erythroid cells with stomatin knocked out show reduced PANX1 channel activity, suggesting stomatin promotes PANX1 pore opening via a caspase-independent mechanism.\",\n      \"method\": \"Proximity Ligation Assay, dye uptake (CF and TO-PRO-3) in patient RBCs and STOM-KO K562 cells, flow imaging\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PLA interaction plus functional loss-of-function with two distinct cell models (patient RBCs and engineered K562), single lab\",\n      \"pmids\": [\"36012667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The NMR solution structure of the SPFH domain of human stomatin (hSTOM) was determined, revealing a cryptic phosphate-binding pocket not present in the mouse crystal structure. At high concentrations, hSTOM(SPFH) forms fibril-like assemblies (confirmed by electron microscopy), and phosphate binding inhibits dissolution of these assemblies, suggesting phosphate regulates SPFH-domain-mediated oligomerization relevant to membrane skeleton function.\",\n      \"method\": \"NMR structure determination, NMR chemical shift perturbation with phosphate, electron microscopy of fibrils, centrifugal ultrafiltration assembly assay\",\n      \"journal\": \"Current research in structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure with functional validation (phosphate binding, fibril assembly), single lab, no mutagenesis confirmation of phosphate site function\",\n      \"pmids\": [\"35663930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STOM interacts with Prdx1 (peroxiredoxin 1) and promotes its degradation through the lysosomal pathway, thereby increasing intracellular ROS production and activating osteoclastogenesis. STOM-deficient mice show higher bone mass and reduced osteoclast differentiation. Targeted inhibition of macrophage STOM expression alleviates ovariectomy-induced bone loss in mice.\",\n      \"method\": \"Transcriptomic analysis, co-immunoprecipitation (STOM-Prdx1 interaction), STOM-deficient mouse model, lysosomal pathway inhibition, ROS measurement, osteoclast differentiation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for STOM-Prdx1 interaction, in vivo KO model with mechanistic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40595453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated depletion of STOM in human epithelial cells resulted in increased Salmonella typhimurium replication and dispersal of intracellular Salmonella microcolonies, indicating STOM plays a role in restricting intracellular Salmonella growth and maintaining microcolony integrity.\",\n      \"method\": \"SILAC-based quantitative proteomics, siRNA knockdown, intracellular Salmonella replication assay, microcolony imaging\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA KD with two distinct cellular phenotype readouts (replication and microcolony dispersal), single lab\",\n      \"pmids\": [\"21919203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STOM interacts with VacA (vacuolating cytotoxin A from H. pylori) at the cell membrane; STOM and VacA co-immunoprecipitate and interact in vitro. Based on these results, STOM at the plasma membrane was proposed to capture VacA to form endosomes that allow VacA entry into cells targeting mitochondria.\",\n      \"method\": \"Pull-down assay, co-immunoprecipitation, protein-protein docking, LC-MS/MS\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and pulldown, mechanistic interpretation partially speculative, single lab\",\n      \"pmids\": [\"35912184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOM knockdown in LPS-treated mouse lung epithelial cells (MLE-12) reversed LPS-induced inhibition of cell viability and promotion of oxidative stress and inflammation. RNA immunoprecipitation confirmed that STOM interacts with and positively regulates CD36 expression; overexpression of CD36 rescued the protective effects of STOM knockdown.\",\n      \"method\": \"siRNA knockdown, CD36 overexpression, RNA immunoprecipitation (RIP), Cell Counting Kit-8 viability assay, ELISA for oxidative stress and inflammatory markers, western blotting\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP assay for STOM-CD36 interaction plus functional rescue epistasis, single lab\",\n      \"pmids\": [\"34934440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STOM and STOML3 are co-expressed in olfactory sensory neuron (OSN) cilia, and STOML3 is necessary for STOM to properly localize to OSN cilia; without STOML3, STOM fails to reach the ciliary compartment.\",\n      \"method\": \"Immunofluorescence, confocal imaging, genetic loss-of-function (STOML3-deficient mice), subcellular localization analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by imaging with genetic loss-of-function showing STOML3 dependence for STOM ciliary targeting, single lab\",\n      \"pmids\": [\"35794236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human EPB72 gene (encoding stomatin) comprises seven exons spanning ~30 kb. The 5'-flanking region contains consensus sequences for ubiquitous transcription factors (Sp1, AP1, AP2, CP1/2, NF-κB, CREB, Ets-1, CACC/GT-BF) and imperfect erythroid factor sequences (EKLF, GATA-1), with no TATA box, consistent with a housekeeping gene promoter. Two polyadenylation signals produce two mRNA species.\",\n      \"method\": \"Genomic library cloning, sequencing, Southern blot, promoter analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct genomic characterization by sequencing and blotting, single lab, structural not functional validation\",\n      \"pmids\": [\"8825639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human EPB72 gene (stomatin) was mapped to chromosome band 9q34.1 by Southern blot analysis of somatic cell hybrid DNA panels.\",\n      \"method\": \"Southern blot analysis of somatic cell hybrid DNA panels\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct chromosomal mapping by established hybrid panel method, single lab\",\n      \"pmids\": [\"8500356\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STOM (stomatin/EPB72) is a monotopic integral membrane protein and lipid raft component that acts as a multi-functional regulator: it inhibits acid-sensing ion channel 3 (ASIC3) by anchoring to its C-terminus and stabilizing the desensitized state via TM1; it restrains glucose transporter GLUT1 activity (released by PON2 in leukemia cells); it interacts with and promotes lysosomal degradation of Prdx1 to elevate ROS and drive osteoclastogenesis; it interacts with DRAM at lysosomes to facilitate lysosomal membrane permeabilization and exosome secretion; it promotes Pannexin 1 (PANX1) channel opening in red blood cells; it regulates CD36 expression under inflammatory conditions; and its ciliary localization in olfactory sensory neurons depends on STOML3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STOM (stomatin/EPB72) is a lipid-raft-associated, monotopic membrane protein with an SPFH domain that functions as a multi-target regulator of membrane channels, transporters, and lysosomal/membrane homeostasis [#0, #2, #4]. As a channel regulator, it binds the distal C-terminus of acid-sensing ion channel ASIC3 and, through its first transmembrane domain, stabilizes the channel's desensitized state to inhibit gating without altering surface expression [#0], and in red blood cells it physically associates with Pannexin 1 to promote pore opening through a caspase-independent mechanism [#3]. STOM also restrains the glucose transporter GLUT1, with PON2 relieving this inhibition to permit glucose uptake in B-ALL cells [#2]. At lysosomes, STOM drives degradative and membrane-permeabilization programs: it interacts with Prdx1 to promote its lysosomal degradation, elevating ROS to activate osteoclastogenesis [#5], and partners with DRAM upon fatty-acid stimulation to enhance lysosomal membrane permeabilization and exosome secretion from hepatocytes [#1]. Structurally, the SPFH domain harbors a cryptic phosphate-binding pocket and forms fibril-like assemblies whose dissolution is inhibited by phosphate, linking phosphate sensing to oligomerization [#4]. STOM ciliary localization in olfactory sensory neurons depends on STOML3 [#9]. The EPB72 gene maps to 9q34.1 and has a TATA-less, housekeeping-type promoter [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the chromosomal location and genomic organization of the stomatin gene provided the molecular foundation for studying the protein and its disease associations.\",\n      \"evidence\": \"Southern blot of somatic cell hybrid panels mapping EPB72 to 9q34.1, followed by genomic cloning and promoter analysis\",\n      \"pmids\": [\"8500356\", \"8825639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Promoter elements identified by sequence only, not functionally validated\", \"No link to protein function established at this stage\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The question of whether STOM has a role in host defense was addressed by showing its loss permits intracellular bacterial growth, implicating STOM in restricting pathogen replication.\",\n      \"evidence\": \"SILAC proteomics with siRNA knockdown and intracellular Salmonella replication/microcolony imaging in epithelial cells\",\n      \"pmids\": [\"21919203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of restriction unknown\", \"No direct STOM-pathogen interaction defined\", \"Single lab, single phenotype class\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The mechanism by which STOM inhibits an ion channel was resolved, showing it binds the ASIC3 C-terminus and uses TM1 to stabilize the desensitized state rather than altering trafficking.\",\n      \"evidence\": \"Chimeric channel analysis, patch-clamp, FRET, and site-directed mutagenesis in heterologous expression\",\n      \"pmids\": [\"32012213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the STOM-ASIC3 complex\", \"Stoichiometry of regulation undefined\", \"Physiological context in native neurons not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"STOM was placed in glucose metabolism as a brake on GLUT1, with genetic epistasis showing PON2 relieves this inhibition in leukemia cells.\",\n      \"evidence\": \"STOM genetic deletion and epistasis rescue of PON2-deficient glucose uptake in murine and human B-ALL cells\",\n      \"pmids\": [\"33531346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct STOM-GLUT1 physical interaction not biochemically resolved\", \"Mechanism of PON2-mediated release unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"STOM was connected to lysosomal membrane dynamics and inflammatory signaling through distinct partners, defining roles in exosome secretion and CD36 regulation.\",\n      \"evidence\": \"Co-IP plus DRAM knockout mouse and lysosome-inhibitor rescue for exosome secretion; RIP and CD36-overexpression rescue in LPS-treated lung epithelial cells\",\n      \"pmids\": [\"34731006\", \"34934440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which STOM permeabilizes lysosomal membranes undefined\", \"Nature of the STOM-CD36 RNA/protein interaction unclear\", \"Both from single labs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural and additional interaction studies expanded STOM's mechanistic picture, revealing a phosphate-sensitive SPFH oligomerization domain, a role in Pannexin 1 pore opening, STOML3-dependent ciliary targeting, and a candidate toxin-capture interaction.\",\n      \"evidence\": \"NMR structure with fibril/phosphate assays; PLA and loss-of-function in OHSt RBCs and K562; immunofluorescence in STOML3-deficient mice; Co-IP/pull-down with H. pylori VacA\",\n      \"pmids\": [\"35663930\", \"36012667\", \"35794236\", \"35912184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphate-binding site not validated by mutagenesis\", \"Mechanism linking STOM to PANX1 opening undefined\", \"VacA interaction based on single Co-IP/pull-down with speculative interpretation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A lysosomal-degradation mechanism linking STOM to redox-driven bone resorption was established, defining Prdx1 as a STOM target and STOM as a driver of osteoclastogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, STOM-deficient mice, lysosomal pathway inhibition, ROS measurement, and osteoclast differentiation assays\",\n      \"pmids\": [\"40595453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STOM routes Prdx1 to lysosomes mechanistically is unresolved\", \"Whether ROS elevation is solely Prdx1-dependent untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how STOM achieves selectivity across its diverse targets (ion channels, transporters, lysosomal substrates) and whether its SPFH-domain oligomerization underlies a unified scaffolding mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural model of STOM target engagement\", \"No reconstituted system linking oligomerization state to regulatory output\", \"Tissue-specific partner repertoires uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ASIC3\", \"GLUT1\", \"PANX1\", \"PRDX1\", \"DRAM\", \"CD36\", \"STOML3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}