{"gene":"TM9SF3","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2025,"finding":"TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy receptor (Golgiphagy receptor) essential for lysosomal degradation of Golgi fragments under nutrient stress and multiple Golgi-stress conditions. TM9SF3 binds all six mammalian ATG8 proteins through N-terminal LC3-interacting regions (LIRs). Knockout of TM9SF3 in U2OS cells blocks nutrient-stress-induced Golgi fragmentation, reduces targeting of Golgi fragments to autophagosomes, and results in decreased Golgi protein degradation.","method":"Knockout (CRISPR), overexpression, live-cell imaging, autophagosome targeting assays, co-immunoprecipitation with ATG8 family proteins, LIR mutation analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO, OE, LIR mutagenesis, imaging, co-IP) in single rigorous study","pmids":["40609542"],"is_preprint":false},{"year":2025,"finding":"TM9SF3 is required for Golgiphagy induced by monensin (pH disruptor), brefeldin A (ER-to-Golgi trafficking blocker), and perturbations in intra-Golgi protein glycosylation. Knockout or LIR mutation of TM9SF3 disrupts protein glycosylation, while overexpression promotes degradation of aberrantly glycosylated proteins, establishing TM9SF3 as a quality-control receptor for glycosylation fidelity.","method":"Knockout, overexpression, LIR mutagenesis, glycosylation assays, pharmacological stress (monensin, brefeldin A)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — multiple stress conditions and orthogonal functional assays in same study","pmids":["40609542"],"is_preprint":false},{"year":2025,"finding":"TM9SF3 mediates phosphatidylinositol 4,5-bisphosphate (PIP2) translocation from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification (PIP2 flop). Genome-wide screening identified TM9SF3 as a critical regulator of this pH-dependent PIP2 translocation. In zebrafish, loss of Tm9sf3 in anterior axial mesoderm causes disorganized collective cell migration due to impaired PIP2-dependent cytoskeletal organization during gastrulation.","method":"Genome-wide screening, zebrafish mutant analysis, live-cell imaging of PIP2 translocation, cytoskeletal organization assays, extracellular pH manipulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen combined with in vivo zebrafish loss-of-function and mechanistic PIP2 translocation assays","pmids":["41053185"],"is_preprint":false},{"year":2017,"finding":"TM9SF3 is a direct target of miR-1193; luciferase reporter assays confirmed miR-1193 binds the TM9SF3 3'UTR. Overexpression and knockdown experiments in Jurkat T-cell leukemia cells showed TM9SF3 positively regulates cell proliferation and invasion.","method":"Luciferase reporter assay, gene overexpression, siRNA knockdown, proliferation and invasion assays in Jurkat cells","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 3 — direct target validation by luciferase assay plus loss/gain-of-function phenotype, single lab","pmids":["28390114"],"is_preprint":false}],"current_model":"TM9SF3 is a Golgi-resident transmembrane protein that acts as a selective autophagy (Golgiphagy) receptor by binding all six mammalian ATG8 proteins via N-terminal LIR motifs to mediate lysosomal degradation of Golgi fragments under nutrient and Golgi stress, thereby maintaining Golgi integrity and glycosylation fidelity; it additionally mediates pH-dependent PIP2 translocation from the inner to outer plasma membrane leaflet, enabling cytoskeletal reorganization and collective cell migration in response to extracellular acidification."},"narrative":{"teleology":[{"year":2017,"claim":"The first functional characterization of TM9SF3 demonstrated it promotes cell proliferation and invasion, positioning it as a potential oncogenic effector, and identified miR-1193 as a direct upstream regulator targeting the TM9SF3 3′UTR.","evidence":"Luciferase reporter assays, siRNA knockdown, and overexpression in Jurkat T-cell leukemia cells","pmids":["28390114"],"confidence":"Medium","gaps":["Single cell-line system without in vivo validation","Molecular mechanism linking TM9SF3 to proliferation and invasion was not determined","No identification of downstream effectors or pathways"]},{"year":2025,"claim":"A genome-wide screen revealed that TM9SF3 mediates pH-dependent PIP2 flop across the plasma membrane, establishing its first defined lipid-handling activity and linking it to cytoskeletal reorganization and collective cell migration in vivo.","evidence":"Genome-wide screening, live-cell PIP2 translocation imaging, extracellular pH manipulation, and zebrafish loss-of-function analysis during gastrulation","pmids":["41053185"],"confidence":"High","gaps":["Whether TM9SF3 acts as a direct lipid flippase or recruits one is unresolved","Structural basis of pH-sensing by TM9SF3 is unknown","Relationship between PIP2 flop activity and the Golgiphagy receptor function has not been addressed"]},{"year":2025,"claim":"TM9SF3 was identified as a Golgiphagy receptor that binds all six mammalian ATG8 proteins via N-terminal LIR motifs, providing the first mechanistic explanation for how Golgi fragments are selectively targeted for autophagic degradation and how glycosylation quality control is maintained.","evidence":"CRISPR knockout, overexpression, LIR mutagenesis, co-immunoprecipitation with ATG8 proteins, autophagosome targeting assays, and glycosylation assays with monensin and brefeldin A stress in U2OS cells","pmids":["40609542"],"confidence":"High","gaps":["Whether TM9SF3 cooperates with other Golgi autophagy receptors or acts independently is unclear","Physiological consequences of TM9SF3 loss in whole organisms under Golgi-stress conditions have not been reported","How TM9SF3 senses glycosylation defects or Golgi damage to trigger its receptor activity is not defined"]},{"year":null,"claim":"It remains unknown how TM9SF3's two established activities — Golgiphagy receptor function and plasma membrane PIP2 translocation — are coordinated or whether they reflect distinct protein pools at different subcellular compartments, and the structural basis for ATG8 binding and pH-dependent lipid handling has not been determined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TM9SF3 exists","Whether post-translational modifications regulate the switch between Golgi and plasma membrane functions is unknown","In vivo mammalian loss-of-function phenotypes have not been characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["LC3A","LC3B","LC3C","GABARAP","GABARAPL1","GABARAPL2"],"other_free_text":[]},"mechanistic_narrative":"TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy (Golgiphagy) receptor, binding all six mammalian ATG8 family proteins through N-terminal LC3-interacting regions (LIR motifs) to target Golgi fragments for lysosomal degradation under nutrient stress and pharmacological Golgi stress, thereby maintaining Golgi integrity and protein glycosylation fidelity [PMID:40609542]. TM9SF3 additionally mediates pH-dependent translocation of phosphatidylinositol 4,5-bisphosphate (PIP2) from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification; in zebrafish, loss of Tm9sf3 disrupts PIP2-dependent cytoskeletal organization and collective cell migration during gastrulation [PMID:41053185]. TM9SF3 positively regulates cell proliferation and invasion in T-cell leukemia cells and is a direct target of miR-1193 [PMID:28390114]."},"prefetch_data":{"uniprot":{"accession":"Q9HD45","full_name":"Transmembrane 9 superfamily member 3","aliases":["EP70-P-iso","SM-11044-binding protein"],"length_aa":589,"mass_kda":67.9,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9HD45/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TM9SF3","classification":"Not 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TM9SF3"},"hgnc":{"alias_symbol":["SMBP"],"prev_symbol":[]},"alphafold":{"accession":"Q9HD45","domains":[{"cath_id":"-","chopping":"29-206","consensus_level":"high","plddt":88.3181,"start":29,"end":206},{"cath_id":"-","chopping":"223-247_286-429_442-584","consensus_level":"medium","plddt":91.3502,"start":223,"end":584}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD45","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD45-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HD45-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TM9SF3","jax_strain_url":"https://www.jax.org/strain/search?query=TM9SF3"},"sequence":{"accession":"Q9HD45","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HD45.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HD45/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HD45"}},"corpus_meta":[{"pmid":"28390114","id":"PMC_28390114","title":"miR-1193 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cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, LIR mutagenesis, Co-IP, imaging, degradation assays) in a single rigorous study with functional validation\",\n      \"pmids\": [\"40609542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM9SF3 knockout blocks nutrient-stress-induced Golgi fragmentation and reduces targeting of Golgi fragments to autophagosomes, resulting in decreased Golgi protein degradation; mutations in its LIR motifs compromise protein glycosylation, while TM9SF3 overexpression promotes degradation of incompletely glycosylated proteins, establishing TM9SF3 as essential for Golgi quality control and glycosylation fidelity.\",\n      \"method\": \"TM9SF3 knockout and LIR-mutant cell lines, glycosylation assays, Golgi protein degradation assays, overexpression experiments in U2OS and breast cancer cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated findings from same group in a companion/review paper, orthogonal methods including mutagenesis and functional glycosylation readouts\",\n      \"pmids\": [\"40709739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM9SF3 mediates the translocation (flop) of phosphatidylinositol 4,5-bisphosphate (PIP2) from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification, acting as a lipid translocase/scramblase; loss of Tm9sf3 in zebrafish anterior axial mesoderm causes disorganized collective cell migration due to impaired PIP2-dependent cytoskeletal organization.\",\n      \"method\": \"Genome-wide screening for PIP2 translocation regulators, TM9SF3 knockout/mutant zebrafish (Tm9sf3 mutant), live-cell PIP2 translocation assays, collective cell migration imaging during gastrulation, cytoskeletal organization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genome-wide unbiased screen identifying TM9SF3, functional validation in zebrafish in vivo model with specific lipid topology and cytoskeletal readouts\",\n      \"pmids\": [\"41053185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM9SF3 positively regulates proliferation and invasion of human T-cell leukemia (Jurkat) cells; it is a direct target of miR-1193, which suppresses these activities by repressing TM9SF3 expression.\",\n      \"method\": \"Luciferase reporter gene assay confirming miR-1193 targeting of TM9SF3 3'UTR, TM9SF3 overexpression and knockdown in Jurkat cells with proliferation and invasion readouts\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase assay plus KD/OE phenotype, but no pathway placement beyond miRNA targeting\",\n      \"pmids\": [\"28390114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TM9SF3 is a multifunctional Golgi-resident transmembrane protein that acts as a selective autophagy receptor (Golgiphagy receptor) by binding mammalian ATG8 proteins via N-terminal LIR motifs to deliver stressed Golgi fragments to lysosomes for degradation, thereby safeguarding Golgi integrity and protein glycosylation fidelity; additionally, TM9SF3 mediates pH-dependent PIP2 translocation from the inner to the outer leaflet of the plasma membrane to enable cytoskeletal adaptation to extracellular acidification.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy receptor (Golgiphagy receptor) essential for lysosomal degradation of Golgi fragments under nutrient stress and multiple Golgi-stress conditions. TM9SF3 binds all six mammalian ATG8 proteins through N-terminal LC3-interacting regions (LIRs). Knockout of TM9SF3 in U2OS cells blocks nutrient-stress-induced Golgi fragmentation, reduces targeting of Golgi fragments to autophagosomes, and results in decreased Golgi protein degradation.\",\n      \"method\": \"Knockout (CRISPR), overexpression, live-cell imaging, autophagosome targeting assays, co-immunoprecipitation with ATG8 family proteins, LIR mutation analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO, OE, LIR mutagenesis, imaging, co-IP) in single rigorous study\",\n      \"pmids\": [\"40609542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM9SF3 is required for Golgiphagy induced by monensin (pH disruptor), brefeldin A (ER-to-Golgi trafficking blocker), and perturbations in intra-Golgi protein glycosylation. Knockout or LIR mutation of TM9SF3 disrupts protein glycosylation, while overexpression promotes degradation of aberrantly glycosylated proteins, establishing TM9SF3 as a quality-control receptor for glycosylation fidelity.\",\n      \"method\": \"Knockout, overexpression, LIR mutagenesis, glycosylation assays, pharmacological stress (monensin, brefeldin A)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple stress conditions and orthogonal functional assays in same study\",\n      \"pmids\": [\"40609542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TM9SF3 mediates phosphatidylinositol 4,5-bisphosphate (PIP2) translocation from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification (PIP2 flop). Genome-wide screening identified TM9SF3 as a critical regulator of this pH-dependent PIP2 translocation. In zebrafish, loss of Tm9sf3 in anterior axial mesoderm causes disorganized collective cell migration due to impaired PIP2-dependent cytoskeletal organization during gastrulation.\",\n      \"method\": \"Genome-wide screening, zebrafish mutant analysis, live-cell imaging of PIP2 translocation, cytoskeletal organization assays, extracellular pH manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen combined with in vivo zebrafish loss-of-function and mechanistic PIP2 translocation assays\",\n      \"pmids\": [\"41053185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TM9SF3 is a direct target of miR-1193; luciferase reporter assays confirmed miR-1193 binds the TM9SF3 3'UTR. Overexpression and knockdown experiments in Jurkat T-cell leukemia cells showed TM9SF3 positively regulates cell proliferation and invasion.\",\n      \"method\": \"Luciferase reporter assay, gene overexpression, siRNA knockdown, proliferation and invasion assays in Jurkat cells\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct target validation by luciferase assay plus loss/gain-of-function phenotype, single lab\",\n      \"pmids\": [\"28390114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TM9SF3 is a Golgi-resident transmembrane protein that acts as a selective autophagy (Golgiphagy) receptor by binding all six mammalian ATG8 proteins via N-terminal LIR motifs to mediate lysosomal degradation of Golgi fragments under nutrient and Golgi stress, thereby maintaining Golgi integrity and glycosylation fidelity; it additionally mediates pH-dependent PIP2 translocation from the inner to outer plasma membrane leaflet, enabling cytoskeletal reorganization and collective cell migration in response to extracellular acidification.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy receptor (Golgiphagy receptor), binding all six mammalian ATG8 proteins through N-terminal LC3-interacting region (LIR) motifs to direct stressed Golgi fragments into phagophores for lysosomal degradation, thereby maintaining Golgi integrity and protein glycosylation fidelity [PMID:40609542, PMID:40709739]. Loss of TM9SF3 blocks nutrient-stress-induced Golgi fragmentation and autophagic targeting of Golgi components, while LIR-motif mutations compromise glycosylation quality control [PMID:40709739]. Independently of its Golgiphagy function, TM9SF3 acts as a pH-sensitive lipid translocase that mediates PIP2 translocation from the inner to the outer leaflet of the plasma membrane upon extracellular acidification, enabling cytoskeletal reorganization required for collective cell migration during zebrafish gastrulation [PMID:41053185].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"The first functional link for TM9SF3 in mammalian cells was established when it was identified as a positive regulator of proliferation and invasion in T-cell leukemia cells, though no molecular mechanism beyond miRNA-mediated regulation was defined.\",\n      \"evidence\": \"Luciferase reporter assay confirming miR-1193 targeting of TM9SF3 3′UTR, knockdown and overexpression in Jurkat cells with proliferation/invasion readouts\",\n      \"pmids\": [\"28390114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No downstream pathway or direct molecular mechanism was identified beyond the miRNA regulatory axis\",\n        \"Findings limited to a single leukemia cell line without in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The primary molecular function of TM9SF3 was resolved as a selective autophagy receptor for Golgi membranes (Golgiphagy receptor), revealing how cells clear damaged Golgi under nutrient stress and multiple Golgi-stress conditions, and establishing that this receptor activity depends on N-terminal LIR motifs that engage all six mammalian ATG8 proteins.\",\n      \"evidence\": \"TM9SF3 knockout in U2OS cells, LIR mutagenesis, co-immunoprecipitation with ATG8 family members, autophagosome targeting and Golgi fragmentation imaging, Golgi protein degradation assays, glycosylation readouts in knockout and LIR-mutant lines\",\n      \"pmids\": [\"40609542\", \"40709739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of LIR–ATG8 interactions for TM9SF3 is unknown\",\n        \"Whether TM9SF3-mediated Golgiphagy operates in vivo in mammalian tissues has not been tested\",\n        \"Upstream signals that activate or regulate TM9SF3 as a Golgiphagy receptor remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A second, mechanistically distinct function was uncovered: TM9SF3 acts as a pH-dependent lipid translocase/scramblase that flops PIP2 from the cytoplasmic to the exoplasmic leaflet of the plasma membrane upon extracellular acidification, coupling environmental pH sensing to cytoskeletal remodeling and collective cell migration.\",\n      \"evidence\": \"Genome-wide screen for PIP2 translocation regulators, Tm9sf3 mutant zebrafish with gastrulation migration defects, live-cell PIP2 topology assays, cytoskeletal organization imaging\",\n      \"pmids\": [\"41053185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TM9SF3 directly translocates PIP2 or acts indirectly through another scramblase has not been fully resolved\",\n        \"The relationship between the Golgi-resident Golgiphagy function and the plasma-membrane lipid translocase activity is unexplained\",\n        \"Whether pH-dependent PIP2 flop by TM9SF3 occurs in mammalian cells or is specific to zebrafish gastrulation is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how TM9SF3 coordinates its dual functions at the Golgi and the plasma membrane, whether these activities are mutually exclusive or regulated by trafficking, and what structural features enable pH-dependent lipid translocation versus ATG8 binding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of TM9SF3 exists to explain its dual activities\",\n        \"Tissue-specific and developmental roles of TM9SF3-mediated Golgiphagy are uncharacterized in mammals\",\n        \"Whether TM9SF3 lipid translocase activity extends to lipids other than PIP2 is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LC3A\",\n      \"LC3B\",\n      \"LC3C\",\n      \"GABARAP\",\n      \"GABARAPL1\",\n      \"GABARAPL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TM9SF3 is a Golgi-resident transmembrane protein that functions as a selective autophagy (Golgiphagy) receptor, binding all six mammalian ATG8 family proteins through N-terminal LC3-interacting regions (LIR motifs) to target Golgi fragments for lysosomal degradation under nutrient stress and pharmacological Golgi stress, thereby maintaining Golgi integrity and protein glycosylation fidelity [PMID:40609542]. TM9SF3 additionally mediates pH-dependent translocation of phosphatidylinositol 4,5-bisphosphate (PIP2) from the inner to the outer leaflet of the plasma membrane in response to extracellular acidification; in zebrafish, loss of Tm9sf3 disrupts PIP2-dependent cytoskeletal organization and collective cell migration during gastrulation [PMID:41053185]. TM9SF3 positively regulates cell proliferation and invasion in T-cell leukemia cells and is a direct target of miR-1193 [PMID:28390114].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"The first functional characterization of TM9SF3 demonstrated it promotes cell proliferation and invasion, positioning it as a potential oncogenic effector, and identified miR-1193 as a direct upstream regulator targeting the TM9SF3 3′UTR.\",\n      \"evidence\": \"Luciferase reporter assays, siRNA knockdown, and overexpression in Jurkat T-cell leukemia cells\",\n      \"pmids\": [\"28390114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell-line system without in vivo validation\",\n        \"Molecular mechanism linking TM9SF3 to proliferation and invasion was not determined\",\n        \"No identification of downstream effectors or pathways\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A genome-wide screen revealed that TM9SF3 mediates pH-dependent PIP2 flop across the plasma membrane, establishing its first defined lipid-handling activity and linking it to cytoskeletal reorganization and collective cell migration in vivo.\",\n      \"evidence\": \"Genome-wide screening, live-cell PIP2 translocation imaging, extracellular pH manipulation, and zebrafish loss-of-function analysis during gastrulation\",\n      \"pmids\": [\"41053185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TM9SF3 acts as a direct lipid flippase or recruits one is unresolved\",\n        \"Structural basis of pH-sensing by TM9SF3 is unknown\",\n        \"Relationship between PIP2 flop activity and the Golgiphagy receptor function has not been addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"TM9SF3 was identified as a Golgiphagy receptor that binds all six mammalian ATG8 proteins via N-terminal LIR motifs, providing the first mechanistic explanation for how Golgi fragments are selectively targeted for autophagic degradation and how glycosylation quality control is maintained.\",\n      \"evidence\": \"CRISPR knockout, overexpression, LIR mutagenesis, co-immunoprecipitation with ATG8 proteins, autophagosome targeting assays, and glycosylation assays with monensin and brefeldin A stress in U2OS cells\",\n      \"pmids\": [\"40609542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TM9SF3 cooperates with other Golgi autophagy receptors or acts independently is unclear\",\n        \"Physiological consequences of TM9SF3 loss in whole organisms under Golgi-stress conditions have not been reported\",\n        \"How TM9SF3 senses glycosylation defects or Golgi damage to trigger its receptor activity is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how TM9SF3's two established activities — Golgiphagy receptor function and plasma membrane PIP2 translocation — are coordinated or whether they reflect distinct protein pools at different subcellular compartments, and the structural basis for ATG8 binding and pH-dependent lipid handling has not been determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of TM9SF3 exists\",\n        \"Whether post-translational modifications regulate the switch between Golgi and plasma membrane functions is unknown\",\n        \"In vivo mammalian loss-of-function phenotypes have not been characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LC3A\",\n      \"LC3B\",\n      \"LC3C\",\n      \"GABARAP\",\n      \"GABARAPL1\",\n      \"GABARAPL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}