{"gene":"STOML3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2015,"finding":"STOML3 controls membrane mechanics by binding cholesterol and localizes to cholesterol-rich lipid rafts in sensory neurons. Depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. Intact STOML3 is required to maintain membrane stiffness to sensitize Piezo1 and Piezo2 mechanically gated ion channels in heterologous systems.","method":"Cholesterol depletion experiments, atomic force microscopy for membrane mechanics, electrophysiology of Piezo channels in heterologous systems, STOML3 knockout mouse model, lipid raft fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (membrane mechanics, channel electrophysiology, cholesterol depletion, KO mouse), findings replicated across cell types and in vivo","pmids":["26443885"],"is_preprint":false},{"year":2016,"finding":"STOML3 forms oligomers that are required for its function in controlling the sensitivity of mechanically gated currents in sensory neurons. Small-molecule inhibitors of STOML3 oligomerization reversibly reduce mechanically gated currents in sensory neurons, silence mechanoreceptors in vivo, and reverse mechanical hypersensitivity following nerve injury or diabetic neuropathy.","method":"Small-molecule inhibitor screens targeting STOML3 oligomerization, in vivo mechanoreceptor recordings, behavioral assays in nerve injury and diabetic neuropathy mouse models, electrophysiology of sensory neurons","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — small-molecule functional intervention with defined molecular target (oligomerization), replicated across in vitro electrophysiology and multiple in vivo pathophysiological models","pmids":["27941788"],"is_preprint":false},{"year":2012,"finding":"STOML3 interacts physically with stomatin and ASIC (acid-sensing ion channel) subunits, and this complex resides in a highly mobile Rab11-positive vesicle pool in dorsal root ganglia neurons and CHO cells. A hydrophobic region in the N-terminus of STOML3 is required for vesicular localization and regulates physical and functional interaction with ASICs. Uncoupling vesicles from microtubules leads to incorporation of STOML3 into the plasma membrane and increased acid-gated currents.","method":"Co-immunoprecipitation, live-cell imaging of vesicle mobility, fractionation, N-terminal deletion/mutation analysis, microtubule uncoupling experiments, Rab marker co-localization, electrophysiology of acid-gated currents","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, live imaging, functional electrophysiology readout, multiple orthogonal methods in one study","pmids":["22773952"],"is_preprint":false},{"year":2002,"finding":"SRO (STOML3) is specifically expressed in olfactory sensory neurons and is abundant in apical dendrites and olfactory cilia. Immunoprecipitation demonstrated that SRO associates with adenylyl cyclase type III and caveolin-1 in the low-density (lipid raft) membrane fraction of olfactory cilia. Anti-SRO antibodies stimulated cAMP production in fractionated cilia membranes, implicating SRO in modulating odorant signal transduction.","method":"Immunoprecipitation from olfactory cilia membrane fractions, low-density membrane (lipid raft) fractionation, antibody stimulation of cAMP production assay, immunolocalization","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with adenylyl cyclase III and caveolin-1, functional cAMP assay, but single lab and limited mechanistic follow-up","pmids":["12122055"],"is_preprint":false},{"year":2021,"finding":"STOML3 is expressed in the knob and proximal cilia of olfactory sensory neurons. Loose-patch recordings from Stoml3 knockout mice revealed reduced spontaneous firing activity, shifted interspike interval distributions, and reduced stimulus-evoked firing compared to wild-type. The primary deficit in STOML3-null neurons was at the level of olfactory transduction rather than action potential generation, establishing a functional role for STOML3 in olfactory sensory encoding.","method":"Stoml3 knockout mouse model, loose-patch electrophysiological recordings from olfactory sensory neurons, immunolocalization, control experiments distinguishing transduction vs. action potential generation deficits","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined electrophysiological phenotype and localization, single lab, controls to isolate transduction deficit","pmids":["33637538"],"is_preprint":false},{"year":2025,"finding":"STOML3 is required for functional mechanosensory plasticity following peripheral nerve regeneration. In a cross-anastomosis model, muscle afferents redirected to hairy skin in wild-type mice acquired normal cutaneous mechanoreceptor properties, but in Stoml3 knockout mice these afferents largely failed to form functional mechanosensitive receptive fields despite making anatomically appropriate skin endings. Central anatomical plasticity (somatotopic synaptic terminals in dorsal horn) was preserved in stoml3 mutants, demonstrating that STOML3 is specifically required for peripheral functional plasticity but not anatomical plasticity.","method":"Mouse cross-anastomosis nerve regeneration model, in vivo electrophysiological recordings from regenerated afferents, neuroanatomical tracing of central projections, Stoml3 knockout mouse","journal":"Experimental physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with defined functional and anatomical phenotype readouts, genetic epistasis between STOML3 and mechanosensory plasticity, single lab","pmids":["40163784"],"is_preprint":false},{"year":2012,"finding":"Amplification of the STOML3 gene at chromosomal locus 13q13.3-q14.1 is restricted to the mesenchymal tumor areas of gliosarcoma, not glial areas, and is associated with overexpression of STOML3 protein specifically in mesenchymal components, suggesting a role for STOML3 gene copy number gain in mesenchymal differentiation of gliosarcoma.","method":"Array comparative genomic hybridization (aCGH), quantitative PCR for gene amplification in 64 gliosarcoma cases, immunohistochemistry for STOML3 protein expression","journal":"The American journal of pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genomic amplification and IHC correlation, no direct functional experiment on STOML3 mechanism in these cells","pmids":["22538188"],"is_preprint":false}],"current_model":"STOML3 (stomatin-like protein-3) is an integral membrane protein that localizes to cholesterol-rich lipid rafts and mobile Rab11-positive vesicles in sensory neurons, where it controls membrane mechanics through cholesterol binding, forms functional oligomers, and acts as an essential sensitizer of mechanically gated Piezo1/Piezo2 and ASIC channels via a complex with stomatin; it is required for normal touch mechanoreception, olfactory transduction, and functional mechanosensory plasticity after nerve regeneration, and its oligomerization can be targeted pharmacologically to reverse pathological mechanical hypersensitivity."},"narrative":{"mechanistic_narrative":"STOML3 (stomatin-like protein-3) is an integral membrane protein of sensory neurons that sensitizes mechanically gated ion channels by tuning the mechanical properties of the lipid bilayer [PMID:26443885]. It binds cholesterol and partitions into cholesterol-rich lipid rafts, where it is required to maintain membrane stiffness; loss of STOML3 or depletion of cholesterol interdependently attenuates the sensitivity of Piezo1 and Piezo2 channels in heterologous systems [PMID:26443885]. STOML3 forms oligomers that are essential for setting the sensitivity of mechanically gated currents, and small-molecule inhibitors of oligomerization reversibly silence mechanoreceptors and reverse mechanical hypersensitivity in nerve-injury and diabetic-neuropathy models, identifying oligomerization as a druggable node [PMID:27941788]. STOML3 also associates physically with stomatin and ASIC subunits within a mobile Rab11-positive vesicle pool, with an N-terminal hydrophobic region directing vesicular localization and controlling acid-gated currents; uncoupling these vesicles from microtubules drives STOML3 into the plasma membrane and increases acid-gated currents [PMID:22773952]. Beyond touch, STOML3 is enriched in olfactory cilia where it associates with adenylyl cyclase type III and caveolin-1 in lipid-raft membranes and modulates cAMP-dependent odorant transduction [PMID:12122055], and STOML3-null olfactory neurons show a transduction-level deficit in spontaneous and evoked firing [PMID:33637538]. STOML3 is further required for peripheral functional mechanosensory plasticity after nerve regeneration without affecting central anatomical plasticity [PMID:40163784].","teleology":[{"year":2002,"claim":"Established the first cellular context for STOML3 by showing it operates within a lipid-raft signaling assembly in olfactory cilia, linking it to cAMP-based sensory transduction.","evidence":"Immunoprecipitation from olfactory cilia membrane fractions, lipid-raft fractionation, and antibody-stimulated cAMP assays","pmids":["12122055"],"confidence":"Medium","gaps":["Direct vs. indirect association with adenylyl cyclase III and caveolin-1 not resolved","No in vivo loss-of-function test of the cAMP modulation","Single lab with limited mechanistic follow-up"]},{"year":2012,"claim":"Defined STOML3 as part of a stomatin/ASIC complex sequestered in mobile vesicles, showing that trafficking governs how much STOML3 reaches the surface to regulate acid-gated currents.","evidence":"Reciprocal Co-IP, live-cell vesicle imaging, N-terminal deletion mutagenesis, Rab11 co-localization, and microtubule-uncoupling electrophysiology in DRG neurons and CHO cells","pmids":["22773952"],"confidence":"High","gaps":["Molecular machinery linking the N-terminal hydrophobic region to vesicle targeting unknown","Stoichiometry of the STOML3–stomatin–ASIC complex not determined"]},{"year":2012,"claim":"Raised a candidate disease association by correlating STOML3 amplification with mesenchymal differentiation in gliosarcoma, though without a functional test.","evidence":"Array CGH, qPCR for amplification across 64 gliosarcoma cases, and IHC for STOML3 protein","pmids":["22538188"],"confidence":"Low","gaps":["Correlative genomics with no functional experiment on STOML3 in tumor cells","Causal role of amplification in mesenchymal differentiation untested","No mechanistic link to mechanosensory function established"]},{"year":2015,"claim":"Resolved how STOML3 sensitizes mechanotransduction by demonstrating it binds cholesterol and sets membrane stiffness, mechanically coupling lipid-raft physics to Piezo1/Piezo2 gating.","evidence":"Cholesterol depletion, atomic force microscopy of membrane mechanics, Piezo electrophysiology in heterologous systems, and a Stoml3 knockout mouse","pmids":["26443885"],"confidence":"High","gaps":["Structural basis of cholesterol binding not defined","Direct physical interaction between STOML3 and Piezo channels not established"]},{"year":2016,"claim":"Identified STOML3 oligomerization as the functional unit controlling mechanosensitivity and validated it as a pharmacological target for reversing pathological mechanical hypersensitivity.","evidence":"Small-molecule oligomerization inhibitor screens, sensory-neuron electrophysiology, in vivo mechanoreceptor recordings, and behavioral assays in nerve-injury and diabetic-neuropathy mouse models","pmids":["27941788"],"confidence":"High","gaps":["Structure of the STOML3 oligomer unresolved","Whether oligomerization acts via membrane mechanics or direct channel contact unclear"]},{"year":2021,"claim":"Extended STOML3's sensory role to olfaction in vivo by localizing it to the cilia/knob and showing knockout produces a transduction-level firing deficit.","evidence":"Loose-patch recordings and immunolocalization in Stoml3 knockout olfactory sensory neurons","pmids":["33637538"],"confidence":"Medium","gaps":["Molecular target of STOML3 in the olfactory transduction cascade not pinpointed","Single lab; relationship to the 2002 adenylyl cyclase III link not directly tested"]},{"year":2025,"claim":"Demonstrated a developmental/regenerative requirement for STOML3, showing it is needed for peripheral functional mechanosensory plasticity but dispensable for central anatomical plasticity.","evidence":"Cross-anastomosis nerve regeneration model with in vivo afferent recordings and central projection tracing in Stoml3 knockout mice","pmids":["40163784"],"confidence":"Medium","gaps":["Mechanism dissociating functional from anatomical plasticity unknown","Whether the deficit reflects membrane-mechanics tuning or trafficking not resolved","Single lab"]},{"year":null,"claim":"How STOML3 oligomers, cholesterol binding, and vesicular trafficking are coordinated to physically engage Piezo and ASIC channels remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of STOML3 alone or in oligomeric/channel complex","Direct STOML3–Piezo interaction unproven","Mechanism of Rab11-vesicle regulation of surface delivery undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["STOM","ASIC","ADCY3","CAV1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAV4","full_name":"Stomatin-like protein 3","aliases":[],"length_aa":291,"mass_kda":32.1,"function":"Required for the function of many mechanoreceptors. Modulate mechanotransduction channels and acid-sensing ion channels (ASIC) proteins. Potentiates PIEZO1 and PIEZO2 function by increasing their sensitivity to mechanical stimulations","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8TAV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STOML3","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":[],"url":"https://opencell.sf.czbiohub.org/search/STOML3","total_profiled":1310},"omim":[{"mim_id":"608327","title":"STOMATIN-LIKE PROTEIN 3; STOML3","url":"https://www.omim.org/entry/608327"},{"mim_id":"600374","title":"BBS4 GENE; BBS4","url":"https://www.omim.org/entry/600374"},{"mim_id":"209901","title":"BBS1 GENE; BBS1","url":"https://www.omim.org/entry/209901"},{"mim_id":"209900","title":"BARDET-BIEDL SYNDROME 1; BBS1","url":"https://www.omim.org/entry/209900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":32.8}],"url":"https://www.proteinatlas.org/search/STOML3"},"hgnc":{"alias_symbol":["SRO","Epb7.2l"],"prev_symbol":[]},"alphafold":{"accession":"Q8TAV4","domains":[{"cath_id":"-","chopping":"25-91","consensus_level":"high","plddt":87.1809,"start":25,"end":91},{"cath_id":"3.30.479.30","chopping":"94-196","consensus_level":"high","plddt":94.7218,"start":94,"end":196},{"cath_id":"1.20.5","chopping":"198-248","consensus_level":"medium","plddt":93.7514,"start":198,"end":248}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAV4-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STOML3","jax_strain_url":"https://www.jax.org/strain/search?query=STOML3"},"sequence":{"accession":"Q8TAV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAV4"}},"corpus_meta":[{"pmid":"29180076","id":"PMC_29180076","title":"Delineation of the primary tumour Clinical Target Volumes (CTV-P) in laryngeal, hypopharyngeal, oropharyngeal and oral cavity squamous cell carcinoma: AIRO, CACA, DAHANCA, EORTC, GEORCC, GORTEC, HKNPCSG, HNCIG, IAG-KHT, LPRHHT, NCIC CTG, NCRI, NRG Oncology, PHNS, SBRT, SOMERA, SRO, SSHNO, TROG consensus guidelines.","date":"2017","source":"Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29180076","citation_count":318,"is_preprint":false},{"pmid":"26443885","id":"PMC_26443885","title":"Membrane stiffening by STOML3 facilitates mechanosensation in sensory neurons.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26443885","citation_count":133,"is_preprint":false},{"pmid":"20226034","id":"PMC_20226034","title":"The RST and PARP-like domain containing SRO protein family: analysis of protein structure, function and conservation in land plants.","date":"2010","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/20226034","citation_count":85,"is_preprint":false},{"pmid":"21185955","id":"PMC_21185955","title":"Bioactive SrO-SiO2 glass with well-ordered mesopores: characterization, physiochemistry and biological properties.","date":"2010","source":"Acta biomaterialia","url":"https://pubmed.ncbi.nlm.nih.gov/21185955","citation_count":77,"is_preprint":false},{"pmid":"20493283","id":"PMC_20493283","title":"Understanding the influence of MgO and SrO binary doping on the mechanical and biological properties of beta-TCP ceramics.","date":"2010","source":"Acta biomaterialia","url":"https://pubmed.ncbi.nlm.nih.gov/20493283","citation_count":76,"is_preprint":false},{"pmid":"27941788","id":"PMC_27941788","title":"Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity.","date":"2016","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27941788","citation_count":64,"is_preprint":false},{"pmid":"25045131","id":"PMC_25045131","title":"SrO- and MgO-doped microwave sintered 3D printed tricalcium phosphate scaffolds: mechanical properties and in vivo osteogenesis in a rabbit model.","date":"2014","source":"Journal of biomedical materials research. 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Depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. Intact STOML3 is required to maintain membrane stiffness to sensitize Piezo1 and Piezo2 mechanically gated ion channels in heterologous systems.\",\n      \"method\": \"Cholesterol depletion experiments, atomic force microscopy for membrane mechanics, electrophysiology of Piezo channels in heterologous systems, STOML3 knockout mouse model, lipid raft fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (membrane mechanics, channel electrophysiology, cholesterol depletion, KO mouse), findings replicated across cell types and in vivo\",\n      \"pmids\": [\"26443885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STOML3 forms oligomers that are required for its function in controlling the sensitivity of mechanically gated currents in sensory neurons. Small-molecule inhibitors of STOML3 oligomerization reversibly reduce mechanically gated currents in sensory neurons, silence mechanoreceptors in vivo, and reverse mechanical hypersensitivity following nerve injury or diabetic neuropathy.\",\n      \"method\": \"Small-molecule inhibitor screens targeting STOML3 oligomerization, in vivo mechanoreceptor recordings, behavioral assays in nerve injury and diabetic neuropathy mouse models, electrophysiology of sensory neurons\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — small-molecule functional intervention with defined molecular target (oligomerization), replicated across in vitro electrophysiology and multiple in vivo pathophysiological models\",\n      \"pmids\": [\"27941788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STOML3 interacts physically with stomatin and ASIC (acid-sensing ion channel) subunits, and this complex resides in a highly mobile Rab11-positive vesicle pool in dorsal root ganglia neurons and CHO cells. A hydrophobic region in the N-terminus of STOML3 is required for vesicular localization and regulates physical and functional interaction with ASICs. Uncoupling vesicles from microtubules leads to incorporation of STOML3 into the plasma membrane and increased acid-gated currents.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging of vesicle mobility, fractionation, N-terminal deletion/mutation analysis, microtubule uncoupling experiments, Rab marker co-localization, electrophysiology of acid-gated currents\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mutagenesis, live imaging, functional electrophysiology readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22773952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SRO (STOML3) is specifically expressed in olfactory sensory neurons and is abundant in apical dendrites and olfactory cilia. Immunoprecipitation demonstrated that SRO associates with adenylyl cyclase type III and caveolin-1 in the low-density (lipid raft) membrane fraction of olfactory cilia. Anti-SRO antibodies stimulated cAMP production in fractionated cilia membranes, implicating SRO in modulating odorant signal transduction.\",\n      \"method\": \"Immunoprecipitation from olfactory cilia membrane fractions, low-density membrane (lipid raft) fractionation, antibody stimulation of cAMP production assay, immunolocalization\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with adenylyl cyclase III and caveolin-1, functional cAMP assay, but single lab and limited mechanistic follow-up\",\n      \"pmids\": [\"12122055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STOML3 is expressed in the knob and proximal cilia of olfactory sensory neurons. Loose-patch recordings from Stoml3 knockout mice revealed reduced spontaneous firing activity, shifted interspike interval distributions, and reduced stimulus-evoked firing compared to wild-type. The primary deficit in STOML3-null neurons was at the level of olfactory transduction rather than action potential generation, establishing a functional role for STOML3 in olfactory sensory encoding.\",\n      \"method\": \"Stoml3 knockout mouse model, loose-patch electrophysiological recordings from olfactory sensory neurons, immunolocalization, control experiments distinguishing transduction vs. action potential generation deficits\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined electrophysiological phenotype and localization, single lab, controls to isolate transduction deficit\",\n      \"pmids\": [\"33637538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STOML3 is required for functional mechanosensory plasticity following peripheral nerve regeneration. In a cross-anastomosis model, muscle afferents redirected to hairy skin in wild-type mice acquired normal cutaneous mechanoreceptor properties, but in Stoml3 knockout mice these afferents largely failed to form functional mechanosensitive receptive fields despite making anatomically appropriate skin endings. Central anatomical plasticity (somatotopic synaptic terminals in dorsal horn) was preserved in stoml3 mutants, demonstrating that STOML3 is specifically required for peripheral functional plasticity but not anatomical plasticity.\",\n      \"method\": \"Mouse cross-anastomosis nerve regeneration model, in vivo electrophysiological recordings from regenerated afferents, neuroanatomical tracing of central projections, Stoml3 knockout mouse\",\n      \"journal\": \"Experimental physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with defined functional and anatomical phenotype readouts, genetic epistasis between STOML3 and mechanosensory plasticity, single lab\",\n      \"pmids\": [\"40163784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Amplification of the STOML3 gene at chromosomal locus 13q13.3-q14.1 is restricted to the mesenchymal tumor areas of gliosarcoma, not glial areas, and is associated with overexpression of STOML3 protein specifically in mesenchymal components, suggesting a role for STOML3 gene copy number gain in mesenchymal differentiation of gliosarcoma.\",\n      \"method\": \"Array comparative genomic hybridization (aCGH), quantitative PCR for gene amplification in 64 gliosarcoma cases, immunohistochemistry for STOML3 protein expression\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genomic amplification and IHC correlation, no direct functional experiment on STOML3 mechanism in these cells\",\n      \"pmids\": [\"22538188\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STOML3 (stomatin-like protein-3) is an integral membrane protein that localizes to cholesterol-rich lipid rafts and mobile Rab11-positive vesicles in sensory neurons, where it controls membrane mechanics through cholesterol binding, forms functional oligomers, and acts as an essential sensitizer of mechanically gated Piezo1/Piezo2 and ASIC channels via a complex with stomatin; it is required for normal touch mechanoreception, olfactory transduction, and functional mechanosensory plasticity after nerve regeneration, and its oligomerization can be targeted pharmacologically to reverse pathological mechanical hypersensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STOML3 (stomatin-like protein-3) is an integral membrane protein of sensory neurons that sensitizes mechanically gated ion channels by tuning the mechanical properties of the lipid bilayer [#0]. It binds cholesterol and partitions into cholesterol-rich lipid rafts, where it is required to maintain membrane stiffness; loss of STOML3 or depletion of cholesterol interdependently attenuates the sensitivity of Piezo1 and Piezo2 channels in heterologous systems [#0]. STOML3 forms oligomers that are essential for setting the sensitivity of mechanically gated currents, and small-molecule inhibitors of oligomerization reversibly silence mechanoreceptors and reverse mechanical hypersensitivity in nerve-injury and diabetic-neuropathy models, identifying oligomerization as a druggable node [#1]. STOML3 also associates physically with stomatin and ASIC subunits within a mobile Rab11-positive vesicle pool, with an N-terminal hydrophobic region directing vesicular localization and controlling acid-gated currents; uncoupling these vesicles from microtubules drives STOML3 into the plasma membrane and increases acid-gated currents [#2]. Beyond touch, STOML3 is enriched in olfactory cilia where it associates with adenylyl cyclase type III and caveolin-1 in lipid-raft membranes and modulates cAMP-dependent odorant transduction [#3], and STOML3-null olfactory neurons show a transduction-level deficit in spontaneous and evoked firing [#4]. STOML3 is further required for peripheral functional mechanosensory plasticity after nerve regeneration without affecting central anatomical plasticity [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the first cellular context for STOML3 by showing it operates within a lipid-raft signaling assembly in olfactory cilia, linking it to cAMP-based sensory transduction.\",\n      \"evidence\": \"Immunoprecipitation from olfactory cilia membrane fractions, lipid-raft fractionation, and antibody-stimulated cAMP assays\",\n      \"pmids\": [\"12122055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct vs. indirect association with adenylyl cyclase III and caveolin-1 not resolved\",\n        \"No in vivo loss-of-function test of the cAMP modulation\",\n        \"Single lab with limited mechanistic follow-up\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined STOML3 as part of a stomatin/ASIC complex sequestered in mobile vesicles, showing that trafficking governs how much STOML3 reaches the surface to regulate acid-gated currents.\",\n      \"evidence\": \"Reciprocal Co-IP, live-cell vesicle imaging, N-terminal deletion mutagenesis, Rab11 co-localization, and microtubule-uncoupling electrophysiology in DRG neurons and CHO cells\",\n      \"pmids\": [\"22773952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular machinery linking the N-terminal hydrophobic region to vesicle targeting unknown\",\n        \"Stoichiometry of the STOML3–stomatin–ASIC complex not determined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Raised a candidate disease association by correlating STOML3 amplification with mesenchymal differentiation in gliosarcoma, though without a functional test.\",\n      \"evidence\": \"Array CGH, qPCR for amplification across 64 gliosarcoma cases, and IHC for STOML3 protein\",\n      \"pmids\": [\"22538188\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Correlative genomics with no functional experiment on STOML3 in tumor cells\",\n        \"Causal role of amplification in mesenchymal differentiation untested\",\n        \"No mechanistic link to mechanosensory function established\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how STOML3 sensitizes mechanotransduction by demonstrating it binds cholesterol and sets membrane stiffness, mechanically coupling lipid-raft physics to Piezo1/Piezo2 gating.\",\n      \"evidence\": \"Cholesterol depletion, atomic force microscopy of membrane mechanics, Piezo electrophysiology in heterologous systems, and a Stoml3 knockout mouse\",\n      \"pmids\": [\"26443885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of cholesterol binding not defined\",\n        \"Direct physical interaction between STOML3 and Piezo channels not established\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified STOML3 oligomerization as the functional unit controlling mechanosensitivity and validated it as a pharmacological target for reversing pathological mechanical hypersensitivity.\",\n      \"evidence\": \"Small-molecule oligomerization inhibitor screens, sensory-neuron electrophysiology, in vivo mechanoreceptor recordings, and behavioral assays in nerve-injury and diabetic-neuropathy mouse models\",\n      \"pmids\": [\"27941788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of the STOML3 oligomer unresolved\",\n        \"Whether oligomerization acts via membrane mechanics or direct channel contact unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended STOML3's sensory role to olfaction in vivo by localizing it to the cilia/knob and showing knockout produces a transduction-level firing deficit.\",\n      \"evidence\": \"Loose-patch recordings and immunolocalization in Stoml3 knockout olfactory sensory neurons\",\n      \"pmids\": [\"33637538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular target of STOML3 in the olfactory transduction cascade not pinpointed\",\n        \"Single lab; relationship to the 2002 adenylyl cyclase III link not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated a developmental/regenerative requirement for STOML3, showing it is needed for peripheral functional mechanosensory plasticity but dispensable for central anatomical plasticity.\",\n      \"evidence\": \"Cross-anastomosis nerve regeneration model with in vivo afferent recordings and central projection tracing in Stoml3 knockout mice\",\n      \"pmids\": [\"40163784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism dissociating functional from anatomical plasticity unknown\",\n        \"Whether the deficit reflects membrane-mechanics tuning or trafficking not resolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STOML3 oligomers, cholesterol binding, and vesicular trafficking are coordinated to physically engage Piezo and ASIC channels remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of STOML3 alone or in oligomeric/channel complex\",\n        \"Direct STOML3–Piezo interaction unproven\",\n        \"Mechanism of Rab11-vesicle regulation of surface delivery undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"STOM\",\n      \"ASIC\",\n      \"ADCY3\",\n      \"CAV1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}