{"gene":"TMEM9","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2002,"finding":"TMEM9 localizes to late endosomes and lysosomes (co-localization with LAMP1) as well as ER when expressed in COS-1 cells. The protein has three N-glycosylation sites and is expressed as multiple glycosylated forms (~28, 31, 33 kDa) from a ~26 kDa backbone.","method":"Transfection of TMEM9-GFP in COS-1 cells, co-localization with LAMP1 by fluorescence microscopy; glycosylation assessment by SDS-PAGE","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization with co-expression marker, two orthogonal methods (GFP imaging + biochemical sizing), single lab","pmids":["12359240"],"is_preprint":false},{"year":2018,"finding":"TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), enhancing vesicular acidification and trafficking. TMEM9-v-ATPase promotes lysosomal degradation of APC (adenomatous polyposis coli), which hyperactivates Wnt/β-catenin signaling. In addition, β-catenin transactivates TMEM9, creating a positive feedback loop in colorectal cancer.","method":"Proteomic and biochemical analyses (Co-IP, pulldown), vesicular acidification assays, lysosomal degradation assays, genetic ablation in vitro/ex vivo/in vivo, v-ATPase inhibitor experiments in APC mouse models and patient-derived xenografts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, biochemical v-ATPase assembly assay, genetic KO models, pharmacological rescue, multiple orthogonal methods across in vitro and in vivo systems","pmids":["30374053"],"is_preprint":false},{"year":2018,"finding":"TMEM9 overexpression increases IL-6 and IL-1β secretion in TNF-α-stimulated LX-2 cells, and this is associated with upregulation of canonical Wnt/β-catenin signaling components (wnt2b, wnt3a, β-catenin). TMEM9 knockdown decreases these cytokines.","method":"Transfection with pEGFP-C2-TMEM9 or TMEM9-siRNA in LX-2 cells; cytokine measurement (ELISA implied); western blotting for Wnt pathway components","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression/knockdown with western blot readout, no mechanistic dissection of pathway placement","pmids":["30119033"],"is_preprint":false},{"year":2020,"finding":"TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal degradation of APC in hepatocytes. Tmem9 knockout in mice impairs hepatic regeneration with increased APC and reduced Wnt signaling. In HCC, TMEM9 maintains β-catenin hyperactivation by down-regulating APC via lysosomal degradation. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation stabilizes APC and retains β-catenin in the cytosol.","method":"Tmem9 knockout mouse model, pharmacological inhibition of v-ATPase and lysosomal degradation, western blot, Co-IP, hepatic regeneration assays","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo with defined phenotype, pharmacological rescue, biochemical pathway validation, replicates findings from earlier Nature Cell Biology paper in a different tissue context","pmids":["32380568"],"is_preprint":false},{"year":2024,"finding":"TMEM9 activates Rab9-dependent alternative autophagy (LC3-independent) through interaction with Beclin1. The cytosolic domain of TMEM9 binds Beclin1 via its Bcl-2-binding domain, displacing the autophagy-inhibitor Bcl-2 from Beclin1. TMEM9 colocalizes with Rab9 but not LC3 at late endosomes/lysosomes. N-glycosylation of TMEM9 is required for its lysosomal localization and, consequently, for its interaction with Beclin1 and activation of alternative autophagy.","method":"Co-IP demonstrating TMEM9–Beclin1 interaction and Bcl-2 displacement; colocalization studies (TMEM9 with Rab9 vs. LC3); glycosylation mutants; autophagy flux assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, glycosylation mutagenesis, colocalization, multiple orthogonal methods in single lab","pmids":["39078420"],"is_preprint":false},{"year":2024,"finding":"TMEM9 upregulates VEGF expression by activating the MEK/ERK/STAT3 pathway in lung adenocarcinoma cells, promoting angiogenesis and tumor cell migration. VEGF-neutralizing antibodies reversed HUVEC angiogenesis caused by TMEM9 overexpression, and recombinant VEGF rescued the inhibitory effect of TMEM9 knockdown.","method":"TMEM9 knockdown/overexpression in LUAD cell lines; cancer cell/HUVEC co-culture model; VEGF neutralizing antibody rescue; western blotting for MEK/ERK/STAT3 pathway; in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway activation by western blot, rescue experiments with neutralizing antibody and recombinant VEGF, in vitro and in vivo models, single lab","pmids":["38664392"],"is_preprint":false},{"year":2025,"finding":"TMEM9 inhibits ClC-3 (a CLC-family Cl-/H+ antiporter) by sealing the cytosolic entrance to the Cl- ion pathway, acting as an accessory β-subunit. Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) stabilizes the TMEM9–ClC-3 interaction and is required for proper regulation of ClC-3 by TMEM9. TMEM9 and TMEM9B also directly interact with ClC-4 and ClC-5.","method":"Cryo-electron microscopy structures of TMEM9–ClC-3 complex; biochemical interaction assays; lipid (PtdIns(3,5)P2) binding and functional studies","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional validation, multiple CLC family members tested, published in peer-reviewed journal with preprint confirmation","pmids":["40670814"],"is_preprint":false},{"year":2025,"finding":"TMEM9 knockdown in renal proximal tubule epithelial cells recapitulates key Dent's Disease type 1 characteristics including defective endocytosis and epithelial dedifferentiation, but paradoxically enhanced endosomal acidification. TMEM9 interacts with all forms of ClC-5 (wild-type and pathogenic mutants I524K, E527D, V523Δ). Loss of TMEM9 also causes enlarged endosomes and fragmented Golgi apparatus.","method":"Interactome analysis (Co-IP/MS); TMEM9 knockdown in renal proximal tubule cell lines; endocytosis assays; pH measurement; immunofluorescence for organelle morphology","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — interactome analysis plus KD with defined cellular phenotypes, preprint not yet peer-reviewed, single lab","pmids":["bio_10.1101_2025.11.03.686312"],"is_preprint":true},{"year":2025,"finding":"Physical exercise down-regulates microglial TMEM9 protein, which inhibits C1q activation and decreases C1q-dependent microglial synapse engulfment in Alzheimer's disease mouse models. Mechanistically, microglial TMEM9 contributes to complement activation by regulating ATP6V0D1, a V-ATPase subunit that controls V-ATPase assembly.","method":"5xFAD mouse model with exercise intervention; oAβ-treated BV2 cells with TMEM9 overexpression/knockdown; complement activation assays; synapse engulfment assays; western blot for ATP6V0D1 and V-ATPase components","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro plus in vivo exercise model, complement assay, two orthogonal systems, single lab","pmids":["39871402"],"is_preprint":false},{"year":2023,"finding":"TMEM9A (TMEM9) knockdown in breast cancer cells increases APC expression and decreases β-catenin, cyclin D1, and AXIN2, blocking Wnt/β-catenin signaling. Overexpression of constitutively active β-Catenin-S33Y rescues the proliferation/migration/invasion defects caused by TMEM9A knockdown, placing TMEM9A upstream of β-catenin in this pathway.","method":"Loss/gain-of-function experiments in BC cell lines; western blot for APC, β-catenin, cyclin D1, AXIN2; β-Catenin-S33Y rescue transfection; proliferation, migration, invasion, and apoptosis assays","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis by rescue experiment, multiple downstream markers assayed, single lab","pmids":["36596527"],"is_preprint":false}],"current_model":"TMEM9 is a lysosomal/late-endosomal transmembrane protein that acts on multiple fronts: it facilitates v-ATPase assembly to drive vesicular acidification, leading to lysosomal degradation of APC and consequent hyperactivation of Wnt/β-catenin signaling; it interacts with Beclin1 (displacing Bcl-2) to activate Rab9-dependent alternative autophagy; it functions as an accessory β-subunit that directly inhibits CLC-family Cl-/H+ antiporters (ClC-3/4/5) in a manner stabilized by PtdIns(3,5)P2; and in microglia it regulates complement activation via ATP6V0D1/V-ATPase to control synaptic pruning."},"narrative":{"mechanistic_narrative":"TMEM9 is a multiply-glycosylated late-endosomal/lysosomal transmembrane protein that couples organellar acidification to cell signaling, autophagy, and ion transport [PMID:12359240, PMID:30374053]. Its central characterized activity is binding to and facilitating assembly of the vacuolar-ATPase (v-ATPase), enhancing vesicular acidification and driving lysosomal degradation of the Wnt antagonist APC; the resulting loss of APC hyperactivates Wnt/β-catenin signaling, and β-catenin in turn transactivates TMEM9 to form a positive feedback loop in colorectal cancer [PMID:30374053]. This TMEM9–v-ATPase–APC axis operates across tissues, controlling hepatic regeneration and sustaining β-catenin hyperactivation in hepatocellular carcinoma, where pharmacological blockade of TMEM9-v-ATPase stabilizes APC and retains β-catenin in the cytosol [PMID:32380568]; epistasis experiments place TMEM9 upstream of β-catenin in cancer cells [PMID:36596527]. Through its cytosolic domain TMEM9 also binds Beclin1 via the Bcl-2-binding region, displacing Bcl-2 to activate Rab9-dependent, LC3-independent alternative autophagy, a function that requires N-glycosylation-dependent lysosomal localization [PMID:39078420]. Independently, TMEM9 acts as an accessory β-subunit of CLC-family Cl-/H+ antiporters, inhibiting ClC-3 by sealing the cytosolic entrance to the Cl- pathway in a manner stabilized by PtdIns(3,5)P2, and also engaging ClC-4 and ClC-5 [PMID:40670814]. In microglia TMEM9 promotes C1q-dependent complement activation and synaptic engulfment by regulating the V-ATPase subunit ATP6V0D1 [PMID:39871402].","teleology":[{"year":2002,"claim":"Establishing where TMEM9 resides was the first step toward any functional model; the protein was assigned to the endolysosomal system.","evidence":"TMEM9-GFP transfection in COS-1 cells with LAMP1 co-localization and glycosylation sizing by SDS-PAGE","pmids":["12359240"],"confidence":"Medium","gaps":["No molecular function assigned","Overexpression in a single cell line may not reflect endogenous distribution","ER signal may reflect biosynthetic transit rather than steady-state residence"]},{"year":2018,"claim":"The defining mechanistic advance: TMEM9 was shown to bind and assemble v-ATPase, driving lysosomal APC degradation and a β-catenin feedback loop, linking an endolysosomal protein to Wnt-driven colorectal cancer.","evidence":"Reciprocal Co-IP, v-ATPase assembly and acidification assays, genetic ablation, and v-ATPase inhibitor rescue in APC mouse models and patient-derived xenografts","pmids":["30374053"],"confidence":"High","gaps":["Stoichiometry of TMEM9 within the v-ATPase complex not defined","Mechanism by which acidification selects APC for degradation not resolved"]},{"year":2018,"claim":"An early correlative link tied TMEM9 to inflammatory cytokine output via Wnt components, hinting at a broader signaling role beyond cancer epithelium.","evidence":"Overexpression/knockdown in TNF-α-stimulated LX-2 cells with cytokine and Wnt-component western blots","pmids":["30119033"],"confidence":"Low","gaps":["Pathway placement not dissected mechanistically","Single lab, correlative readouts","No demonstration that cytokine effect requires v-ATPase/APC axis"]},{"year":2020,"claim":"Independent in vivo genetics confirmed the TMEM9-v-ATPase-APC-Wnt axis in a second tissue, showing it governs hepatic regeneration and HCC β-catenin activation.","evidence":"Tmem9 knockout mouse, pharmacological v-ATPase/lysosomal inhibition, Co-IP, and regeneration assays","pmids":["32380568"],"confidence":"High","gaps":["Whether the same mechanism operates in non-hepatic, non-colorectal contexts not addressed","Direct biochemical link between TMEM9 and APC turnover not fully reconstituted"]},{"year":2023,"claim":"Epistasis testing formally placed TMEM9 upstream of β-catenin in another cancer type, reinforcing the APC/β-catenin model.","evidence":"Loss/gain-of-function in breast cancer cells with constitutively active β-catenin-S33Y rescue and downstream marker westerns","pmids":["36596527"],"confidence":"Medium","gaps":["No direct biochemical interaction shown in this system","Single lab","Does not establish v-ATPase involvement in breast cancer context"]},{"year":2024,"claim":"A distinct function emerged: the TMEM9 cytosolic domain binds Beclin1 to displace Bcl-2 and trigger Rab9-dependent alternative autophagy, showing TMEM9 acts beyond v-ATPase assembly.","evidence":"Reciprocal Co-IP with Bcl-2 displacement, domain mapping, glycosylation mutants, and Rab9/LC3 colocalization with autophagy flux assays","pmids":["39078420"],"confidence":"High","gaps":["Relationship between the autophagy role and the v-ATPase/Wnt role not integrated","Physiological triggers of this pathway not defined"]},{"year":2024,"claim":"TMEM9 was linked to angiogenesis through MEK/ERK/STAT3-driven VEGF induction, expanding its pro-tumorigenic repertoire.","evidence":"Knockdown/overexpression in LUAD cells, HUVEC co-culture, VEGF neutralizing antibody and recombinant VEGF rescue, and in vivo tumor models","pmids":["38664392"],"confidence":"Medium","gaps":["How a lysosomal protein activates MEK/ERK/STAT3 not mechanistically connected","Whether this depends on v-ATPase or Wnt activity unknown"]},{"year":2025,"claim":"Structural work redefined TMEM9 as an accessory β-subunit of CLC antiporters, providing the first atomic mechanism: it seals the ClC-3 cytosolic Cl- entrance, lipid-stabilized by PtdIns(3,5)P2.","evidence":"Cryo-EM structures of the TMEM9–ClC-3 complex with biochemical interaction and PtdIns(3,5)P2 functional assays, plus ClC-4/ClC-5 interaction tests","pmids":["40670814"],"confidence":"High","gaps":["How CLC inhibition relates to the v-ATPase acidification role is unresolved","Physiological consequences of ClC regulation in tissues not defined"]},{"year":2025,"claim":"TMEM9 was tied to renal Cl-/H+ transport physiology through ClC-5 interaction, with knockdown phenocopying Dent's Disease type 1 features.","evidence":"Interactome (Co-IP/MS), knockdown in renal proximal tubule cells, endocytosis and pH measurements, and organelle morphology imaging (preprint)","pmids":["bio_10.1101_2025.11.03.686312"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Paradoxically enhanced acidification on TMEM9 loss is unexplained relative to the v-ATPase assembly model","No in vivo disease model"]},{"year":2025,"claim":"TMEM9 was implicated in neuroimmune function, promoting C1q complement activation and microglial synapse engulfment via ATP6V0D1, an exercise-sensitive pathway in Alzheimer's models.","evidence":"5xFAD exercise model, gain/loss-of-function in oAβ-treated BV2 cells, complement and synapse engulfment assays, and ATP6V0D1/V-ATPase westerns","pmids":["39871402"],"confidence":"Medium","gaps":["Direct TMEM9–ATP6V0D1 interaction not structurally defined","Single lab","Link to the CLC and Beclin1 functions not integrated"]},{"year":null,"claim":"It remains unresolved how TMEM9's apparently opposing molecular roles — promoting v-ATPase assembly/acidification versus inhibiting CLC antiporters and the paradoxically enhanced acidification on its loss — are reconciled into a single integrated endolysosomal function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking v-ATPase facilitation, CLC inhibition, and alternative autophagy","Stoichiometry and partner selection across these complexes undefined","Tissue-specific determinants of which function dominates unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":["v-ATPase","TMEM9–ClC-3 complex"],"partners":["ATP6V0D1","APC","BECLIN1","BCL-2","CLC-3","CLC-4","CLC-5","RAB9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P0T7","full_name":"Proton-transporting V-type ATPase complex assembly regulator TMEM9","aliases":["Dermal papilla-derived protein 4","Transmembrane protein 9","Protein TMEM9"],"length_aa":183,"mass_kda":20.6,"function":"Transmembrane protein that binds to and facilitates the assembly of lysosomal proton-transporting V-type ATPase (v-ATPase), resulting in enhanced lysosomal acidification and trafficking (PubMed:30374053). By bringing the v-ATPase accessory protein ATP6AP2 and the v-ATPase subunit ATP6V0D1 together, allows v-ATPase complex formation and activation (PubMed:30374053). TMEM9-controlled vesicular acidification induces hyperactivation of Wnt/beta-catenin signaling, involved in development, tissue homeostasis and tissue regeneration, through lysosomal degradation of adenomatous polyposis coli/APC (PubMed:30374053, PubMed:32380568). In the liver, involved in hepatic regeneration (PubMed:32380568)","subcellular_location":"Lysosome membrane; Late endosome membrane; Endosome, multivesicular body membrane","url":"https://www.uniprot.org/uniprotkb/Q9P0T7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM9","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM9","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":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM9"},"hgnc":{"alias_symbol":["TMEM9A"],"prev_symbol":[]},"alphafold":{"accession":"Q9P0T7","domains":[{"cath_id":"3.10.20","chopping":"25-83","consensus_level":"high","plddt":87.7517,"start":25,"end":83},{"cath_id":"1.20.5","chopping":"86-117","consensus_level":"medium","plddt":82.2738,"start":86,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0T7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0T7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P0T7-F1-predicted_aligned_error_v6.png","plddt_mean":72.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM9","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM9"},"sequence":{"accession":"Q9P0T7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P0T7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P0T7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P0T7"}},"corpus_meta":[{"pmid":"30374053","id":"PMC_30374053","title":"TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/β-catenin signalling.","date":"2018","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30374053","citation_count":81,"is_preprint":false},{"pmid":"32380568","id":"PMC_32380568","title":"TMEM9-v-ATPase Activates Wnt/β-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis.","date":"2020","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/32380568","citation_count":52,"is_preprint":false},{"pmid":"12359240","id":"PMC_12359240","title":"Characterization of the novel human transmembrane protein 9 (TMEM9) that localizes to lysosomes and late endosomes.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12359240","citation_count":21,"is_preprint":false},{"pmid":"30119033","id":"PMC_30119033","title":"TMEM9 mediates IL-6 and IL-1β secretion and is modulated by the Wnt pathway.","date":"2018","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30119033","citation_count":19,"is_preprint":false},{"pmid":"38664392","id":"PMC_38664392","title":"TMEM9 promotes lung adenocarcinoma progression via activating the MEK/ERK/STAT3 pathway to induce VEGF expression.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38664392","citation_count":15,"is_preprint":false},{"pmid":"27220462","id":"PMC_27220462","title":"Effects of TMEM9 gene on cell progression in hepatocellular carcinoma by RNA interference.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27220462","citation_count":15,"is_preprint":false},{"pmid":"39078420","id":"PMC_39078420","title":"TMEM9 activates Rab9-dependent alternative autophagy through interaction with Beclin1.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39078420","citation_count":10,"is_preprint":false},{"pmid":"39871402","id":"PMC_39871402","title":"Physical Exercise Decreases Complement-Mediated Synaptic Loss and Protects Against Cognitive Impairment by Inhibiting Microglial Tmem9-ATP6V0D1 in Alzheimer's Disease.","date":"2025","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/39871402","citation_count":8,"is_preprint":false},{"pmid":"36596527","id":"PMC_36596527","title":"Tumor-Promoting Properties of TMEM9A in Breast Cancer Progression via Activating the Wnt/β-Catenin Signaling Pathway.","date":"2023","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/36596527","citation_count":6,"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":"40053281","id":"PMC_40053281","title":"Comprehensive analysis of TMEM9 in human tumors.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40053281","citation_count":2,"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":null,"id":"bio_10.1101_2025.11.03.686312","title":"TMEM9 and SEC22B interact with ClC-5 to shape renal proximal tubule function and Dent’s Disease type I pathogenesis","date":"2025-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.03.686312","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},{"pmid":null,"id":"bio_10.1101_2025.02.07.636106","title":"EndoMAP.v1, a Structural Protein Complex Landscape of Human Endosomes","date":"2025-02-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.07.636106","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9291,"output_tokens":3080,"usd":0.037036,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10466,"output_tokens":4038,"usd":0.07664,"stage2_stop_reason":"end_turn"},"total_usd":0.113676,"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\": 2002,\n      \"finding\": \"TMEM9 localizes to late endosomes and lysosomes (co-localization with LAMP1) as well as ER when expressed in COS-1 cells. The protein has three N-glycosylation sites and is expressed as multiple glycosylated forms (~28, 31, 33 kDa) from a ~26 kDa backbone.\",\n      \"method\": \"Transfection of TMEM9-GFP in COS-1 cells, co-localization with LAMP1 by fluorescence microscopy; glycosylation assessment by SDS-PAGE\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization with co-expression marker, two orthogonal methods (GFP imaging + biochemical sizing), single lab\",\n      \"pmids\": [\"12359240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM9 binds to and facilitates assembly of vacuolar-ATPase (v-ATPase), enhancing vesicular acidification and trafficking. TMEM9-v-ATPase promotes lysosomal degradation of APC (adenomatous polyposis coli), which hyperactivates Wnt/β-catenin signaling. In addition, β-catenin transactivates TMEM9, creating a positive feedback loop in colorectal cancer.\",\n      \"method\": \"Proteomic and biochemical analyses (Co-IP, pulldown), vesicular acidification assays, lysosomal degradation assays, genetic ablation in vitro/ex vivo/in vivo, v-ATPase inhibitor experiments in APC mouse models and patient-derived xenografts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, biochemical v-ATPase assembly assay, genetic KO models, pharmacological rescue, multiple orthogonal methods across in vitro and in vivo systems\",\n      \"pmids\": [\"30374053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM9 overexpression increases IL-6 and IL-1β secretion in TNF-α-stimulated LX-2 cells, and this is associated with upregulation of canonical Wnt/β-catenin signaling components (wnt2b, wnt3a, β-catenin). TMEM9 knockdown decreases these cytokines.\",\n      \"method\": \"Transfection with pEGFP-C2-TMEM9 or TMEM9-siRNA in LX-2 cells; cytokine measurement (ELISA implied); western blotting for Wnt pathway components\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression/knockdown with western blot readout, no mechanistic dissection of pathway placement\",\n      \"pmids\": [\"30119033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal degradation of APC in hepatocytes. Tmem9 knockout in mice impairs hepatic regeneration with increased APC and reduced Wnt signaling. In HCC, TMEM9 maintains β-catenin hyperactivation by down-regulating APC via lysosomal degradation. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation stabilizes APC and retains β-catenin in the cytosol.\",\n      \"method\": \"Tmem9 knockout mouse model, pharmacological inhibition of v-ATPase and lysosomal degradation, western blot, Co-IP, hepatic regeneration assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo with defined phenotype, pharmacological rescue, biochemical pathway validation, replicates findings from earlier Nature Cell Biology paper in a different tissue context\",\n      \"pmids\": [\"32380568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM9 activates Rab9-dependent alternative autophagy (LC3-independent) through interaction with Beclin1. The cytosolic domain of TMEM9 binds Beclin1 via its Bcl-2-binding domain, displacing the autophagy-inhibitor Bcl-2 from Beclin1. TMEM9 colocalizes with Rab9 but not LC3 at late endosomes/lysosomes. N-glycosylation of TMEM9 is required for its lysosomal localization and, consequently, for its interaction with Beclin1 and activation of alternative autophagy.\",\n      \"method\": \"Co-IP demonstrating TMEM9–Beclin1 interaction and Bcl-2 displacement; colocalization studies (TMEM9 with Rab9 vs. LC3); glycosylation mutants; autophagy flux assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, glycosylation mutagenesis, colocalization, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"39078420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM9 upregulates VEGF expression by activating the MEK/ERK/STAT3 pathway in lung adenocarcinoma cells, promoting angiogenesis and tumor cell migration. VEGF-neutralizing antibodies reversed HUVEC angiogenesis caused by TMEM9 overexpression, and recombinant VEGF rescued the inhibitory effect of TMEM9 knockdown.\",\n      \"method\": \"TMEM9 knockdown/overexpression in LUAD cell lines; cancer cell/HUVEC co-culture model; VEGF neutralizing antibody rescue; western blotting for MEK/ERK/STAT3 pathway; in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway activation by western blot, rescue experiments with neutralizing antibody and recombinant VEGF, in vitro and in vivo models, single lab\",\n      \"pmids\": [\"38664392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM9 inhibits ClC-3 (a CLC-family Cl-/H+ antiporter) by sealing the cytosolic entrance to the Cl- ion pathway, acting as an accessory β-subunit. Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) stabilizes the TMEM9–ClC-3 interaction and is required for proper regulation of ClC-3 by TMEM9. TMEM9 and TMEM9B also directly interact with ClC-4 and ClC-5.\",\n      \"method\": \"Cryo-electron microscopy structures of TMEM9–ClC-3 complex; biochemical interaction assays; lipid (PtdIns(3,5)P2) binding and functional studies\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional validation, multiple CLC family members tested, published in peer-reviewed journal with preprint confirmation\",\n      \"pmids\": [\"40670814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM9 knockdown in renal proximal tubule epithelial cells recapitulates key Dent's Disease type 1 characteristics including defective endocytosis and epithelial dedifferentiation, but paradoxically enhanced endosomal acidification. TMEM9 interacts with all forms of ClC-5 (wild-type and pathogenic mutants I524K, E527D, V523Δ). Loss of TMEM9 also causes enlarged endosomes and fragmented Golgi apparatus.\",\n      \"method\": \"Interactome analysis (Co-IP/MS); TMEM9 knockdown in renal proximal tubule cell lines; endocytosis assays; pH measurement; immunofluorescence for organelle morphology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — interactome analysis plus KD with defined cellular phenotypes, preprint not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686312\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Physical exercise down-regulates microglial TMEM9 protein, which inhibits C1q activation and decreases C1q-dependent microglial synapse engulfment in Alzheimer's disease mouse models. Mechanistically, microglial TMEM9 contributes to complement activation by regulating ATP6V0D1, a V-ATPase subunit that controls V-ATPase assembly.\",\n      \"method\": \"5xFAD mouse model with exercise intervention; oAβ-treated BV2 cells with TMEM9 overexpression/knockdown; complement activation assays; synapse engulfment assays; western blot for ATP6V0D1 and V-ATPase components\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro plus in vivo exercise model, complement assay, two orthogonal systems, single lab\",\n      \"pmids\": [\"39871402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM9A (TMEM9) knockdown in breast cancer cells increases APC expression and decreases β-catenin, cyclin D1, and AXIN2, blocking Wnt/β-catenin signaling. Overexpression of constitutively active β-Catenin-S33Y rescues the proliferation/migration/invasion defects caused by TMEM9A knockdown, placing TMEM9A upstream of β-catenin in this pathway.\",\n      \"method\": \"Loss/gain-of-function experiments in BC cell lines; western blot for APC, β-catenin, cyclin D1, AXIN2; β-Catenin-S33Y rescue transfection; proliferation, migration, invasion, and apoptosis assays\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis by rescue experiment, multiple downstream markers assayed, single lab\",\n      \"pmids\": [\"36596527\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM9 is a lysosomal/late-endosomal transmembrane protein that acts on multiple fronts: it facilitates v-ATPase assembly to drive vesicular acidification, leading to lysosomal degradation of APC and consequent hyperactivation of Wnt/β-catenin signaling; it interacts with Beclin1 (displacing Bcl-2) to activate Rab9-dependent alternative autophagy; it functions as an accessory β-subunit that directly inhibits CLC-family Cl-/H+ antiporters (ClC-3/4/5) in a manner stabilized by PtdIns(3,5)P2; and in microglia it regulates complement activation via ATP6V0D1/V-ATPase to control synaptic pruning.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM9 is a multiply-glycosylated late-endosomal/lysosomal transmembrane protein that couples organellar acidification to cell signaling, autophagy, and ion transport [#0, #1]. Its central characterized activity is binding to and facilitating assembly of the vacuolar-ATPase (v-ATPase), enhancing vesicular acidification and driving lysosomal degradation of the Wnt antagonist APC; the resulting loss of APC hyperactivates Wnt/\\u03b2-catenin signaling, and \\u03b2-catenin in turn transactivates TMEM9 to form a positive feedback loop in colorectal cancer [#1]. This TMEM9\\u2013v-ATPase\\u2013APC axis operates across tissues, controlling hepatic regeneration and sustaining \\u03b2-catenin hyperactivation in hepatocellular carcinoma, where pharmacological blockade of TMEM9-v-ATPase stabilizes APC and retains \\u03b2-catenin in the cytosol [#3]; epistasis experiments place TMEM9 upstream of \\u03b2-catenin in cancer cells [#9]. Through its cytosolic domain TMEM9 also binds Beclin1 via the Bcl-2-binding region, displacing Bcl-2 to activate Rab9-dependent, LC3-independent alternative autophagy, a function that requires N-glycosylation-dependent lysosomal localization [#4]. Independently, TMEM9 acts as an accessory \\u03b2-subunit of CLC-family Cl-/H+ antiporters, inhibiting ClC-3 by sealing the cytosolic entrance to the Cl- pathway in a manner stabilized by PtdIns(3,5)P2, and also engaging ClC-4 and ClC-5 [#6]. In microglia TMEM9 promotes C1q-dependent complement activation and synaptic engulfment by regulating the V-ATPase subunit ATP6V0D1 [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing where TMEM9 resides was the first step toward any functional model; the protein was assigned to the endolysosomal system.\",\n      \"evidence\": \"TMEM9-GFP transfection in COS-1 cells with LAMP1 co-localization and glycosylation sizing by SDS-PAGE\",\n      \"pmids\": [\"12359240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"Overexpression in a single cell line may not reflect endogenous distribution\", \"ER signal may reflect biosynthetic transit rather than steady-state residence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The defining mechanistic advance: TMEM9 was shown to bind and assemble v-ATPase, driving lysosomal APC degradation and a \\u03b2-catenin feedback loop, linking an endolysosomal protein to Wnt-driven colorectal cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, v-ATPase assembly and acidification assays, genetic ablation, and v-ATPase inhibitor rescue in APC mouse models and patient-derived xenografts\",\n      \"pmids\": [\"30374053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of TMEM9 within the v-ATPase complex not defined\", \"Mechanism by which acidification selects APC for degradation not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An early correlative link tied TMEM9 to inflammatory cytokine output via Wnt components, hinting at a broader signaling role beyond cancer epithelium.\",\n      \"evidence\": \"Overexpression/knockdown in TNF-\\u03b1-stimulated LX-2 cells with cytokine and Wnt-component western blots\",\n      \"pmids\": [\"30119033\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement not dissected mechanistically\", \"Single lab, correlative readouts\", \"No demonstration that cytokine effect requires v-ATPase/APC axis\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Independent in vivo genetics confirmed the TMEM9-v-ATPase-APC-Wnt axis in a second tissue, showing it governs hepatic regeneration and HCC \\u03b2-catenin activation.\",\n      \"evidence\": \"Tmem9 knockout mouse, pharmacological v-ATPase/lysosomal inhibition, Co-IP, and regeneration assays\",\n      \"pmids\": [\"32380568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same mechanism operates in non-hepatic, non-colorectal contexts not addressed\", \"Direct biochemical link between TMEM9 and APC turnover not fully reconstituted\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Epistasis testing formally placed TMEM9 upstream of \\u03b2-catenin in another cancer type, reinforcing the APC/\\u03b2-catenin model.\",\n      \"evidence\": \"Loss/gain-of-function in breast cancer cells with constitutively active \\u03b2-catenin-S33Y rescue and downstream marker westerns\",\n      \"pmids\": [\"36596527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical interaction shown in this system\", \"Single lab\", \"Does not establish v-ATPase involvement in breast cancer context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A distinct function emerged: the TMEM9 cytosolic domain binds Beclin1 to displace Bcl-2 and trigger Rab9-dependent alternative autophagy, showing TMEM9 acts beyond v-ATPase assembly.\",\n      \"evidence\": \"Reciprocal Co-IP with Bcl-2 displacement, domain mapping, glycosylation mutants, and Rab9/LC3 colocalization with autophagy flux assays\",\n      \"pmids\": [\"39078420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between the autophagy role and the v-ATPase/Wnt role not integrated\", \"Physiological triggers of this pathway not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TMEM9 was linked to angiogenesis through MEK/ERK/STAT3-driven VEGF induction, expanding its pro-tumorigenic repertoire.\",\n      \"evidence\": \"Knockdown/overexpression in LUAD cells, HUVEC co-culture, VEGF neutralizing antibody and recombinant VEGF rescue, and in vivo tumor models\",\n      \"pmids\": [\"38664392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a lysosomal protein activates MEK/ERK/STAT3 not mechanistically connected\", \"Whether this depends on v-ATPase or Wnt activity unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural work redefined TMEM9 as an accessory \\u03b2-subunit of CLC antiporters, providing the first atomic mechanism: it seals the ClC-3 cytosolic Cl- entrance, lipid-stabilized by PtdIns(3,5)P2.\",\n      \"evidence\": \"Cryo-EM structures of the TMEM9\\u2013ClC-3 complex with biochemical interaction and PtdIns(3,5)P2 functional assays, plus ClC-4/ClC-5 interaction tests\",\n      \"pmids\": [\"40670814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CLC inhibition relates to the v-ATPase acidification role is unresolved\", \"Physiological consequences of ClC regulation in tissues not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TMEM9 was tied to renal Cl-/H+ transport physiology through ClC-5 interaction, with knockdown phenocopying Dent's Disease type 1 features.\",\n      \"evidence\": \"Interactome (Co-IP/MS), knockdown in renal proximal tubule cells, endocytosis and pH measurements, and organelle morphology imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.03.686312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Paradoxically enhanced acidification on TMEM9 loss is unexplained relative to the v-ATPase assembly model\", \"No in vivo disease model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TMEM9 was implicated in neuroimmune function, promoting C1q complement activation and microglial synapse engulfment via ATP6V0D1, an exercise-sensitive pathway in Alzheimer's models.\",\n      \"evidence\": \"5xFAD exercise model, gain/loss-of-function in oA\\u03b2-treated BV2 cells, complement and synapse engulfment assays, and ATP6V0D1/V-ATPase westerns\",\n      \"pmids\": [\"39871402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct TMEM9\\u2013ATP6V0D1 interaction not structurally defined\", \"Single lab\", \"Link to the CLC and Beclin1 functions not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how TMEM9's apparently opposing molecular roles \\u2014 promoting v-ATPase assembly/acidification versus inhibiting CLC antiporters and the paradoxically enhanced acidification on its loss \\u2014 are reconciled into a single integrated endolysosomal function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking v-ATPase facilitation, CLC inhibition, and alternative autophagy\", \"Stoichiometry and partner selection across these complexes undefined\", \"Tissue-specific determinants of which function dominates unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"v-ATPase\",\n      \"TMEM9\\u2013ClC-3 complex\"\n    ],\n    \"partners\": [\n      \"ATP6V0D1\",\n      \"APC\",\n      \"Beclin1\",\n      \"Bcl-2\",\n      \"ClC-3\",\n      \"ClC-4\",\n      \"ClC-5\",\n      \"Rab9\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}