{"gene":"TMEM9B","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"TMEM9B is a glycosylated transmembrane protein localized in lysosomal membranes and partially in early endosomes, where it is required for TNF-, IL-1β-, and TLR ligand-induced production of proinflammatory cytokines but not for apoptotic cell death triggered by TNF or Fas ligand.","method":"siRNA knockdown, cytokine production assays, subcellular fractionation/localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, localization experiment; single lab, multiple orthogonal assays","pmids":["18541524"],"is_preprint":false},{"year":2008,"finding":"TMEM9B acts downstream of RIP1 and upstream of the MAPK and IκB kinases at the level of the TAK1 complex, placing it as an essential component of both the NF-κB and MAPK branches of TNF signaling.","method":"Genetic epistasis via siRNA knockdown combined with pathway-specific kinase activity assays and overexpression of pathway components","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis mapping with multiple pathway nodes, single lab","pmids":["18541524"],"is_preprint":false},{"year":2011,"finding":"TMEM9B is required as a downstream effector of the p53-p21 and p16-pRB tumour suppressor pathways for mediating cellular senescence; direct silencing of TMEM9B via shRNA bypassed senescence in conditionally immortalised human fibroblasts.","method":"RNAi screen followed by validation with lentiviral shRNA knockdown, senescence bypass assay","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined cellular phenotype (senescence bypass), single lab, single method validation","pmids":["21740549"],"is_preprint":false},{"year":2024,"finding":"TMEM9B strongly and specifically interacts with endosomal ClC-3 and ClC-4 transporters; co-expression of TMEM9B with ClC-3 or ClC-4 dramatically reduces transporter activity, and TMEM9B also induces a slow activation kinetics component in ClC-3, suggesting direct physical interaction. TMEM9B does not substantially affect ClC-7 or ClC-1 currents.","method":"Xenopus oocyte electrophysiology, HEK cell transfection + electrophysiology, FLIM-FRET imaging to detect direct protein–protein interaction","journal":"Life (Basel, Switzerland)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — functional reconstitution in two expression systems, FRET-based direct interaction measurement, specificity controls with ClC-1 and ClC-7, single lab","pmids":["39202776"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures reveal that TMEM9 (and TMEM9B) act as accessory β-subunits that directly interact with ClC-3, ClC-4, and ClC-5. TMEM9 inhibits ClC-3 by sealing the cytosolic entrance to the Cl⁻ ion pathway, and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) stabilizes the TMEM9–ClC-3 interaction and is required for proper regulation of ClC-3 activity.","method":"Cryo-electron microscopy structure determination, biochemical reconstitution, lipid-binding assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with mechanistic interpretation, replicated in preprint and peer-reviewed form, multiple orthogonal methods","pmids":["40670814"],"is_preprint":false}],"current_model":"TMEM9B is a lysosomal/endosomal single-span transmembrane glycoprotein that functions as an accessory β-subunit of endosomal CLC Cl⁻/H⁺ antiporters (ClC-3, ClC-4, ClC-5), inhibiting transporter activity by sealing the cytosolic Cl⁻ ion pathway in a manner stabilized by PtdIns(3,5)P2; it also modulates inflammatory signaling by acting downstream of RIP1 and upstream of the TAK1–IKK/MAPK axis in TNF, IL-1β, and TLR pathways, and is required as a downstream effector of the p53-p21 and p16-pRB senescence pathways."},"narrative":{"mechanistic_narrative":"TMEM9B is a glycosylated single-span transmembrane protein of the lysosomal and early endosomal membranes that serves as an accessory β-subunit of endosomal CLC chloride/proton antiporters and as a required component of inflammatory and senescence signaling [PMID:18541524]. It interacts strongly and specifically with the endosomal transporters ClC-3 and ClC-4, dramatically reducing their activity and imposing slow activation kinetics on ClC-3, while leaving ClC-7 and ClC-1 currents largely unaffected [PMID:39202776]. Cryo-EM structures show that TMEM9B (with its paralog TMEM9) inhibits ClC-3 by sealing the cytosolic entrance to the Cl⁻ ion pathway, an interaction stabilized by PtdIns(3,5)P2 that is required for proper regulation of transporter activity [PMID:40670814]. In parallel, TMEM9B is required for TNF-, IL-1β-, and TLR-ligand-induced proinflammatory cytokine production but not for TNF- or Fas-induced apoptosis, acting downstream of RIP1 and upstream of the TAK1 complex to engage both the NF-κB and MAPK branches of these pathways [PMID:18541524]. It additionally functions as a downstream effector of the p53-p21 and p16-pRB tumor suppressor pathways, where its silencing bypasses cellular senescence [PMID:21740549].","teleology":[{"year":2008,"claim":"Established that an uncharacterized lysosomal/endosomal transmembrane protein is selectively required for innate inflammatory cytokine output rather than cell death, defining its first cellular role.","evidence":"siRNA knockdown with cytokine assays and subcellular fractionation/localization","pmids":["18541524"],"confidence":"Medium","gaps":["Molecular partner mediating cytokine signaling not identified","single lab, knockdown-based phenotype only","mechanism connecting endosomal localization to signaling unclear"]},{"year":2008,"claim":"Placed TMEM9B within the TNF signaling hierarchy by epistasis, showing it acts downstream of RIP1 and upstream of the TAK1 complex to drive both NF-κB and MAPK branches.","evidence":"siRNA epistasis combined with kinase activity assays and pathway-component overexpression","pmids":["18541524"],"confidence":"Medium","gaps":["No direct biochemical interaction with RIP1 or TAK1 demonstrated","how a membrane protein couples to cytosolic kinase complex unresolved"]},{"year":2011,"claim":"Extended TMEM9B function to tumor-suppressor biology, identifying it as a required effector downstream of p53-p21 and p16-pRB whose loss bypasses senescence.","evidence":"RNAi screen with lentiviral shRNA validation and senescence bypass assay in conditionally immortalized fibroblasts","pmids":["21740549"],"confidence":"Medium","gaps":["Single-method validation in one cell system","mechanistic link between TMEM9B and senescence effectors undefined","relation to inflammatory role not addressed"]},{"year":2024,"claim":"Defined a biochemical activity for TMEM9B by showing direct, specific interaction with endosomal CLC transporters and functional inhibition of ClC-3/ClC-4.","evidence":"Xenopus oocyte and HEK cell electrophysiology with FLIM-FRET direct-interaction imaging and ClC-1/ClC-7 specificity controls","pmids":["39202776"],"confidence":"High","gaps":["Structural basis of inhibition not yet resolved","physiological consequence of CLC regulation in cells not tested","relationship to inflammatory/senescence roles unknown"]},{"year":2025,"claim":"Provided the structural mechanism of TMEM9B as a CLC accessory β-subunit, showing it seals the cytosolic Cl⁻ pathway of ClC-3 in a PtdIns(3,5)P2-stabilized manner.","evidence":"Cryo-EM structure determination with biochemical reconstitution and lipid-binding assays","pmids":["40670814"],"confidence":"High","gaps":["In vivo physiological role of the TMEM9B–CLC complex not established","connection between transporter regulation and signaling functions not bridged"]},{"year":null,"claim":"Whether TMEM9B's CLC-regulatory activity mechanistically underlies its roles in inflammatory signaling and senescence remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No experiment links CLC antiporter modulation to TAK1/NF-κB-MAPK signaling","no link between CLC regulation and p53/p16 senescence pathways","in vivo loss-of-function phenotype not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["CLCN3","CLCN4","CLCN5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NQ34","full_name":"Transmembrane protein 9B","aliases":[],"length_aa":198,"mass_kda":22.5,"function":"Enhances production of pro-inflammatory cytokines induced by TNF, IL1B, and TLR ligands. Has a role in TNF activation of both the NF-kappaB and MAPK pathways","subcellular_location":"Lysosome membrane; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NQ34/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM9B","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM9B","total_profiled":1310},"omim":[{"mim_id":"620293","title":"TMEM9 DOMAIN FAMILY, MEMBER B; TMEM9B","url":"https://www.omim.org/entry/620293"},{"mim_id":"616877","title":"TRANSMEMBRANE PROTEIN 9; TMEM9","url":"https://www.omim.org/entry/616877"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM9B"},"hgnc":{"alias_symbol":[],"prev_symbol":["C11orf15"]},"alphafold":{"accession":"Q9NQ34","domains":[{"cath_id":"3.10.20","chopping":"39-96","consensus_level":"high","plddt":89.0783,"start":39,"end":96},{"cath_id":"1.20.5","chopping":"98-143","consensus_level":"medium","plddt":76.1604,"start":98,"end":143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ34","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ34-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NQ34-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM9B","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM9B"},"sequence":{"accession":"Q9NQ34","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NQ34.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NQ34/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NQ34"}},"corpus_meta":[{"pmid":"18541524","id":"PMC_18541524","title":"The lysosomal transmembrane protein 9B regulates the activity of inflammatory signaling pathways.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18541524","citation_count":47,"is_preprint":false},{"pmid":"21740549","id":"PMC_21740549","title":"An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence.","date":"2011","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21740549","citation_count":35,"is_preprint":false},{"pmid":"36105009","id":"PMC_36105009","title":"LncRNA MIR4435-2HG promotes proliferation, migration, invasion and epithelial mesenchymal transition via targeting miR-22-3p/TMEM9B in breast cancer.","date":"2022","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/36105009","citation_count":9,"is_preprint":false},{"pmid":"39202776","id":"PMC_39202776","title":"TMEM9B Regulates Endosomal ClC-3 and ClC-4 Transporters.","date":"2024","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39202776","citation_count":7,"is_preprint":false},{"pmid":"39696495","id":"PMC_39696495","title":"Epigenetic regulation on left atrial function and disease recurrence after catheter ablation in atrial fibrillation.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39696495","citation_count":4,"is_preprint":false},{"pmid":"40632859","id":"PMC_40632859","title":"Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis.","date":"2025","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/40632859","citation_count":3,"is_preprint":false},{"pmid":"40670814","id":"PMC_40670814","title":"Structural basis of ClC-3 transporter inhibition by TMEM9 and PtdIns(3,5)P2.","date":"2025","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40670814","citation_count":3,"is_preprint":false},{"pmid":"38246423","id":"PMC_38246423","title":"Association of GAL-8 promoter methylation levels with coronary plaque inflammation.","date":"2024","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/38246423","citation_count":3,"is_preprint":false},{"pmid":"40093093","id":"PMC_40093093","title":"Structural basis of ClC-3 inhibition by TMEM9 and PI(3,5)P2.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40093093","citation_count":1,"is_preprint":false},{"pmid":"40356149","id":"PMC_40356149","title":"Cellular uptake and transport mechanism of flaxseed cyclic peptide CLB via clathrin-dependent endocytosis.","date":"2025","source":"Food research international (Ottawa, Ont.)","url":"https://pubmed.ncbi.nlm.nih.gov/40356149","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.05.602204","title":"Human-specific lncRNA TMEM9B-AS1 is downregulated in skeletal muscle of individuals with type 2 diabetes and regulates ribosomal biogenesis","date":"2024-07-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.05.602204","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.28.640562","title":"Structural basis of ClC-3 inhibition by TMEM9 and PI(3,5)P  <sub>2</sub>","date":"2025-03-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.640562","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8160,"output_tokens":1354,"usd":0.022395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8009,"output_tokens":2103,"usd":0.04631,"stage2_stop_reason":"end_turn"},"total_usd":0.068705,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"TMEM9B is a glycosylated transmembrane protein localized in lysosomal membranes and partially in early endosomes, where it is required for TNF-, IL-1β-, and TLR ligand-induced production of proinflammatory cytokines but not for apoptotic cell death triggered by TNF or Fas ligand.\",\n      \"method\": \"siRNA knockdown, cytokine production assays, subcellular fractionation/localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, localization experiment; single lab, multiple orthogonal assays\",\n      \"pmids\": [\"18541524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TMEM9B acts downstream of RIP1 and upstream of the MAPK and IκB kinases at the level of the TAK1 complex, placing it as an essential component of both the NF-κB and MAPK branches of TNF signaling.\",\n      \"method\": \"Genetic epistasis via siRNA knockdown combined with pathway-specific kinase activity assays and overexpression of pathway components\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis mapping with multiple pathway nodes, single lab\",\n      \"pmids\": [\"18541524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TMEM9B is required as a downstream effector of the p53-p21 and p16-pRB tumour suppressor pathways for mediating cellular senescence; direct silencing of TMEM9B via shRNA bypassed senescence in conditionally immortalised human fibroblasts.\",\n      \"method\": \"RNAi screen followed by validation with lentiviral shRNA knockdown, senescence bypass assay\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined cellular phenotype (senescence bypass), single lab, single method validation\",\n      \"pmids\": [\"21740549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM9B strongly and specifically interacts with endosomal ClC-3 and ClC-4 transporters; co-expression of TMEM9B with ClC-3 or ClC-4 dramatically reduces transporter activity, and TMEM9B also induces a slow activation kinetics component in ClC-3, suggesting direct physical interaction. TMEM9B does not substantially affect ClC-7 or ClC-1 currents.\",\n      \"method\": \"Xenopus oocyte electrophysiology, HEK cell transfection + electrophysiology, FLIM-FRET imaging to detect direct protein–protein interaction\",\n      \"journal\": \"Life (Basel, Switzerland)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional reconstitution in two expression systems, FRET-based direct interaction measurement, specificity controls with ClC-1 and ClC-7, single lab\",\n      \"pmids\": [\"39202776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures reveal that TMEM9 (and TMEM9B) act as accessory β-subunits that directly interact with ClC-3, ClC-4, and ClC-5. TMEM9 inhibits ClC-3 by sealing the cytosolic entrance to the Cl⁻ ion pathway, and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) stabilizes the TMEM9–ClC-3 interaction and is required for proper regulation of ClC-3 activity.\",\n      \"method\": \"Cryo-electron microscopy structure determination, biochemical reconstitution, lipid-binding assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with mechanistic interpretation, replicated in preprint and peer-reviewed form, multiple orthogonal methods\",\n      \"pmids\": [\"40670814\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM9B is a lysosomal/endosomal single-span transmembrane glycoprotein that functions as an accessory β-subunit of endosomal CLC Cl⁻/H⁺ antiporters (ClC-3, ClC-4, ClC-5), inhibiting transporter activity by sealing the cytosolic Cl⁻ ion pathway in a manner stabilized by PtdIns(3,5)P2; it also modulates inflammatory signaling by acting downstream of RIP1 and upstream of the TAK1–IKK/MAPK axis in TNF, IL-1β, and TLR pathways, and is required as a downstream effector of the p53-p21 and p16-pRB senescence pathways.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM9B is a glycosylated single-span transmembrane protein of the lysosomal and early endosomal membranes that serves as an accessory \\u03b2-subunit of endosomal CLC chloride/proton antiporters and as a required component of inflammatory and senescence signaling [#0]. It interacts strongly and specifically with the endosomal transporters ClC-3 and ClC-4, dramatically reducing their activity and imposing slow activation kinetics on ClC-3, while leaving ClC-7 and ClC-1 currents largely unaffected [#3]. Cryo-EM structures show that TMEM9B (with its paralog TMEM9) inhibits ClC-3 by sealing the cytosolic entrance to the Cl\\u207b ion pathway, an interaction stabilized by PtdIns(3,5)P2 that is required for proper regulation of transporter activity [#4]. In parallel, TMEM9B is required for TNF-, IL-1\\u03b2-, and TLR-ligand-induced proinflammatory cytokine production but not for TNF- or Fas-induced apoptosis, acting downstream of RIP1 and upstream of the TAK1 complex to engage both the NF-\\u03baB and MAPK branches of these pathways [#0, #1]. It additionally functions as a downstream effector of the p53-p21 and p16-pRB tumor suppressor pathways, where its silencing bypasses cellular senescence [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that an uncharacterized lysosomal/endosomal transmembrane protein is selectively required for innate inflammatory cytokine output rather than cell death, defining its first cellular role.\",\n      \"evidence\": \"siRNA knockdown with cytokine assays and subcellular fractionation/localization\",\n      \"pmids\": [\"18541524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partner mediating cytokine signaling not identified\", \"single lab, knockdown-based phenotype only\", \"mechanism connecting endosomal localization to signaling unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed TMEM9B within the TNF signaling hierarchy by epistasis, showing it acts downstream of RIP1 and upstream of the TAK1 complex to drive both NF-\\u03baB and MAPK branches.\",\n      \"evidence\": \"siRNA epistasis combined with kinase activity assays and pathway-component overexpression\",\n      \"pmids\": [\"18541524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction with RIP1 or TAK1 demonstrated\", \"how a membrane protein couples to cytosolic kinase complex unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended TMEM9B function to tumor-suppressor biology, identifying it as a required effector downstream of p53-p21 and p16-pRB whose loss bypasses senescence.\",\n      \"evidence\": \"RNAi screen with lentiviral shRNA validation and senescence bypass assay in conditionally immortalized fibroblasts\",\n      \"pmids\": [\"21740549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-method validation in one cell system\", \"mechanistic link between TMEM9B and senescence effectors undefined\", \"relation to inflammatory role not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a biochemical activity for TMEM9B by showing direct, specific interaction with endosomal CLC transporters and functional inhibition of ClC-3/ClC-4.\",\n      \"evidence\": \"Xenopus oocyte and HEK cell electrophysiology with FLIM-FRET direct-interaction imaging and ClC-1/ClC-7 specificity controls\",\n      \"pmids\": [\"39202776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of inhibition not yet resolved\", \"physiological consequence of CLC regulation in cells not tested\", \"relationship to inflammatory/senescence roles unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural mechanism of TMEM9B as a CLC accessory \\u03b2-subunit, showing it seals the cytosolic Cl\\u207b pathway of ClC-3 in a PtdIns(3,5)P2-stabilized manner.\",\n      \"evidence\": \"Cryo-EM structure determination with biochemical reconstitution and lipid-binding assays\",\n      \"pmids\": [\"40670814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological role of the TMEM9B\\u2013CLC complex not established\", \"connection between transporter regulation and signaling functions not bridged\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether TMEM9B's CLC-regulatory activity mechanistically underlies its roles in inflammatory signaling and senescence remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experiment links CLC antiporter modulation to TAK1/NF-\\u03baB-MAPK signaling\", \"no link between CLC regulation and p53/p16 senescence pathways\", \"in vivo loss-of-function phenotype not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLCN3\", \"CLCN4\", \"CLCN5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}