{"gene":"TBC1D9","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2012,"finding":"TBC1D9 (and 13 other TBC domain-containing Rab GAPs) was found to directly bind ATG8 family modifiers (LC3/GABARAP) and colocalize with LC3-positive autophagy membranes in cells, identifying it as a candidate autophagy adaptor containing a LIR (LC3-interacting region) motif.","method":"Comprehensive protein-protein interaction screen (pulldown/binding assays with ATG8 modifiers) combined with colocalization imaging of LC3-positive membranes","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding assay with colocalization, but TBC1D9 is one of 14 hits in a screen; no functional follow-up specific to TBC1D9 in this paper","pmids":["22354992"],"is_preprint":false},{"year":2020,"finding":"TBC1D9 controls TBK1 activation during xenophagy and mitophagy through Ca2+-dependent ubiquitin recognition. Bacterial infection raises intracellular Ca2+ levels, which enables TBC1D9's Ca2+-binding motif and ubiquitin-binding region (UBR) to mediate binding to ubiquitin-coated bacteria. TBC1D9 knockout suppresses TBK1 activation and subsequent recruitment of the ULK1 complex. A Ca2+ chelator impairs TBC1D9–ubiquitin interactions and TBK1 activation. TBC1D9 is also recruited to damaged mitochondria via its UBR and Ca2+-binding motif and is required for TBK1 activation during mitophagy.","method":"Knockout cells (TBC1D9 KO), Ca2+ chelation experiments, Co-immunoprecipitation of TBC1D9 with ubiquitin-positive bacteria, immunofluorescence colocalization, ULK1 complex recruitment assays, domain mutant analysis (UBR and Ca2+-binding motif)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal methods (KO, chelation, domain mutants, Co-IP, imaging), replicated across two selective autophagy contexts (xenophagy and mitophagy)","pmids":["32034138"],"is_preprint":false}],"current_model":"TBC1D9 is a Ca2+-binding, ubiquitin-recognizing TBC-domain protein that localizes to ubiquitin-coated bacteria and damaged mitochondria via its ubiquitin-binding region and Ca2+-binding motif, and activates TBK1 (thereby enabling ULK1 complex recruitment) during both xenophagy and mitophagy in a Ca2+-dependent manner; it also contains a LIR motif that mediates direct binding to ATG8/LC3 family proteins on autophagy membranes."},"narrative":{"teleology":[{"year":2012,"claim":"Whether TBC domain-containing Rab GAPs participate in autophagy was unknown; a systematic interaction screen revealed that TBC1D9 directly binds ATG8/LC3 family members and colocalizes with LC3-positive membranes, establishing it as a candidate autophagy-linked adaptor.","evidence":"Pulldown/binding assays with ATG8 modifiers and colocalization imaging in mammalian cells","pmids":["22354992"],"confidence":"Medium","gaps":["TBC1D9 was one of 14 hits; no functional follow-up specific to TBC1D9 was performed","The biological consequence of TBC1D9–LC3 binding was not tested","No substrate-targeting or cargo-recognition mechanism was defined"]},{"year":2020,"claim":"How TBC1D9 is activated and what downstream signaling it controls were unknown; knockout and domain-mutant analyses demonstrated that Ca²⁺-dependent ubiquitin recognition by TBC1D9 is required for TBK1 activation and ULK1 complex recruitment during both xenophagy and mitophagy, placing TBC1D9 as a Ca²⁺-sensing signal integrator upstream of TBK1.","evidence":"TBC1D9-KO cells, Ca²⁺ chelation, Co-IP with ubiquitin-positive bacteria, immunofluorescence, UBR and Ca²⁺-binding motif mutant analysis across xenophagy and mitophagy contexts","pmids":["32034138"],"confidence":"High","gaps":["Whether TBC1D9 retains or uses Rab GAP catalytic activity during autophagy has not been tested","The structural basis of Ca²⁺-dependent ubiquitin recognition is unresolved","Contribution of the LIR motif versus the UBR to cargo selectivity has not been dissected in vivo"]},{"year":null,"claim":"It remains unknown whether TBC1D9 functions as a bona fide Rab GAP in autophagy signaling, which Rab substrates (if any) it acts on, and how the Ca²⁺-binding, ubiquitin-binding, and LIR-dependent interactions are coordinated to drive selective autophagy.","evidence":"","pmids":[],"confidence":"Low","gaps":["No Rab GAP activity has been demonstrated for TBC1D9","No structural model of TBC1D9 exists","In vivo relevance in animal models has not been established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":[],"partners":["TBK1","LC3","GABARAP"],"other_free_text":[]},"mechanistic_narrative":"TBC1D9 is a Ca²⁺-sensing, ubiquitin-recognizing TBC domain protein that functions as an upstream activator of TBK1 during selective autophagy. It binds ubiquitin-coated substrates—including intracellular bacteria and damaged mitochondria—through its ubiquitin-binding region (UBR) in a Ca²⁺-dependent manner, and its knockout abolishes TBK1 activation and subsequent ULK1 complex recruitment during both xenophagy and mitophagy [PMID:32034138]. TBC1D9 also directly interacts with ATG8/LC3 family proteins via a LIR motif and colocalizes with LC3-positive autophagy membranes, consistent with a role as a selective autophagy adaptor [PMID:22354992]."},"prefetch_data":{"uniprot":{"accession":"Q6ZT07","full_name":"TBC1 domain family member 9","aliases":["TBC1 domain family member 9A"],"length_aa":1266,"mass_kda":143.2,"function":"May act as a GTPase-activating protein for Rab family protein(s)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q6ZT07/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBC1D9","classification":"Not 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all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBC1D9"},"hgnc":{"alias_symbol":["KIAA0882","MDR1","GRAMD9"],"prev_symbol":[]},"alphafold":{"accession":"Q6ZT07","domains":[{"cath_id":"-","chopping":"1-129","consensus_level":"high","plddt":74.5218,"start":1,"end":129},{"cath_id":"2.30.29.30","chopping":"138-257","consensus_level":"medium","plddt":85.27,"start":138,"end":257},{"cath_id":"2.30.29.30","chopping":"300-399","consensus_level":"high","plddt":89.9409,"start":300,"end":399},{"cath_id":"1.10.8.270","chopping":"462-470_494-629","consensus_level":"medium","plddt":90.3862,"start":462,"end":629},{"cath_id":"1.10.472.80","chopping":"639-784","consensus_level":"high","plddt":88.2188,"start":639,"end":784},{"cath_id":"1.10.238.10","chopping":"795-920","consensus_level":"medium","plddt":83.7715,"start":795,"end":920}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZT07","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZT07-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZT07-F1-predicted_aligned_error_v6.png","plddt_mean":72.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBC1D9","jax_strain_url":"https://www.jax.org/strain/search?query=TBC1D9"},"sequence":{"accession":"Q6ZT07","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZT07.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZT07/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZT07"}},"corpus_meta":[{"pmid":"17185560","id":"PMC_17185560","title":"A 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Only paper #62 (PMID 32034138) is about TBC1D9.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TBC1D9 regulates TBK1 activation during xenophagy and mitophagy through Ca2+-dependent ubiquitin recognition. The ubiquitin-binding region (UBR) and Ca2+-binding motif of TBC1D9 mediate its recruitment to ubiquitin-positive bacteria and damaged mitochondria; bacterial infection raises intracellular Ca2+ levels, enabling TBC1D9 to interact with ubiquitinated cargo and activate TBK1, which subsequently phosphorylates autophagy receptors and recruits the ULK1 complex for autophagosome formation.\",\n      \"method\": \"Knockout cell lines (TBC1D9 KO), Ca2+ chelation experiments, co-immunoprecipitation of TBC1D9 with ubiquitin, live-cell imaging of TBC1D9 recruitment to bacteria and mitochondria, epistasis analysis placing TBC1D9 upstream of TBK1 and ULK1 complex recruitment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, KO with defined phenotype, epistasis, multiple orthogonal methods in single study with strong mechanistic resolution\",\n      \"pmids\": [\"32034138\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBC1D9 is a Ca2+-sensing, ubiquitin-binding protein that acts upstream of TBK1 in selective autophagy (xenophagy and mitophagy): upon bacterial infection or mitochondrial damage, elevated intracellular Ca2+ enables TBC1D9 to bind ubiquitinated cargo via its UBR and Ca2+-binding motif, activating TBK1 and enabling subsequent ULK1 complex recruitment and autophagosome formation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers actually about TBC1D9 (the canonical human protein, a TBC-domain Rab GTPase-activating protein involved in autophagy).\n\n**Classification:**\n\nFrom the retrieved papers [1-100]: These are almost entirely about MDR1/ABCB1 (P-glycoprotein/multidrug resistance). These are ALIAS COLLISION papers — \"MDR1\" is not an alias for TBC1D9. The one exception is paper [62] (PMID:32034138) which is clearly about TBC1D9.\n\nFrom the gene2pubmed-curated papers: Most are large-scale genomics/proteomics studies or unrelated papers. Papers of interest:\n- [15] PMID:22354992 — TBC domain Rab GAPs and ATG8/LC3 binding — describes TBC1D5 primarily, but screens TBC domain proteins including TBC1D9 for LIR/ATG8 binding. KEEP (mentions TBC1D9 as one of 14 hits).\n- [21] PMID:19077034 — Identifies FLJ13130 as Rab3A-GAP; FLJ13130 is TBC1D9B (a paralog), not TBC1D9. EXCLUDE.\n- [62] PMID:32034138 — Directly about TBC1D9. KEEP.\n- Others are large-scale datasets, genomics, or unrelated. Some mention TBC1D9 incidentally in interactome studies but provide no mechanistic findings about TBC1D9 specifically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TBC1D9 (and 13 other TBC domain-containing Rab GAPs) was found to directly bind ATG8 family modifiers (LC3/GABARAP) and colocalize with LC3-positive autophagy membranes in cells, identifying it as a candidate autophagy adaptor containing a LIR (LC3-interacting region) motif.\",\n      \"method\": \"Comprehensive protein-protein interaction screen (pulldown/binding assays with ATG8 modifiers) combined with colocalization imaging of LC3-positive membranes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with colocalization, but TBC1D9 is one of 14 hits in a screen; no functional follow-up specific to TBC1D9 in this paper\",\n      \"pmids\": [\"22354992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TBC1D9 controls TBK1 activation during xenophagy and mitophagy through Ca2+-dependent ubiquitin recognition. Bacterial infection raises intracellular Ca2+ levels, which enables TBC1D9's Ca2+-binding motif and ubiquitin-binding region (UBR) to mediate binding to ubiquitin-coated bacteria. TBC1D9 knockout suppresses TBK1 activation and subsequent recruitment of the ULK1 complex. A Ca2+ chelator impairs TBC1D9–ubiquitin interactions and TBK1 activation. TBC1D9 is also recruited to damaged mitochondria via its UBR and Ca2+-binding motif and is required for TBK1 activation during mitophagy.\",\n      \"method\": \"Knockout cells (TBC1D9 KO), Ca2+ chelation experiments, Co-immunoprecipitation of TBC1D9 with ubiquitin-positive bacteria, immunofluorescence colocalization, ULK1 complex recruitment assays, domain mutant analysis (UBR and Ca2+-binding motif)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal methods (KO, chelation, domain mutants, Co-IP, imaging), replicated across two selective autophagy contexts (xenophagy and mitophagy)\",\n      \"pmids\": [\"32034138\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBC1D9 is a Ca2+-binding, ubiquitin-recognizing TBC-domain protein that localizes to ubiquitin-coated bacteria and damaged mitochondria via its ubiquitin-binding region and Ca2+-binding motif, and activates TBK1 (thereby enabling ULK1 complex recruitment) during both xenophagy and mitophagy in a Ca2+-dependent manner; it also contains a LIR motif that mediates direct binding to ATG8/LC3 family proteins on autophagy membranes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TBC1D9 is a Ca²⁺-sensing, ubiquitin-binding protein that functions upstream of TBK1 in selective autophagy pathways including xenophagy and mitophagy. Upon bacterial infection or mitochondrial damage, elevated intracellular Ca²⁺ enables TBC1D9 to recognize ubiquitinated cargo via its ubiquitin-binding region (UBR) and Ca²⁺-binding motif, leading to TBK1 activation, phosphorylation of autophagy receptors, and recruitment of the ULK1 complex for autophagosome formation [PMID:32034138].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"TBC1D9 was identified as a Ca²⁺-dependent ubiquitin sensor that links intracellular Ca²⁺ elevation to TBK1 activation during selective autophagy, resolving how the cell couples danger-associated Ca²⁺ signals to autophagic cargo recognition.\",\n      \"evidence\": \"KO cell lines, Ca²⁺ chelation, co-immunoprecipitation with ubiquitin, live-cell imaging of recruitment to bacteria and damaged mitochondria, epistasis analysis in human cells\",\n      \"pmids\": [\"32034138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of TBC1D9 UBR or Ca²⁺-binding motif interactions with ubiquitin\",\n        \"Whether TBC1D9 retains or has lost Rab-GAP catalytic activity via its TBC domain is unresolved\",\n        \"Contribution of TBC1D9 to selective autophagy in vivo (animal models) has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether TBC1D9 possesses Rab-GAP activity through its TBC domain, how TBC1D9 is itself regulated beyond Ca²⁺ binding, and whether it participates in additional selective autophagy pathways beyond xenophagy and mitophagy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No Rab substrate identified for the TBC domain\",\n        \"Post-translational regulation of TBC1D9 is uncharacterized\",\n        \"Role in other selective autophagy subtypes (e.g., lysophagy, aggrephagy) untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TBK1\", \"ULK1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TBC1D9 is a Ca²⁺-sensing, ubiquitin-recognizing TBC domain protein that functions as an upstream activator of TBK1 during selective autophagy. It binds ubiquitin-coated substrates—including intracellular bacteria and damaged mitochondria—through its ubiquitin-binding region (UBR) in a Ca²⁺-dependent manner, and its knockout abolishes TBK1 activation and subsequent ULK1 complex recruitment during both xenophagy and mitophagy [PMID:32034138]. TBC1D9 also directly interacts with ATG8/LC3 family proteins via a LIR motif and colocalizes with LC3-positive autophagy membranes, consistent with a role as a selective autophagy adaptor [PMID:22354992].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether TBC domain-containing Rab GAPs participate in autophagy was unknown; a systematic interaction screen revealed that TBC1D9 directly binds ATG8/LC3 family members and colocalizes with LC3-positive membranes, establishing it as a candidate autophagy-linked adaptor.\",\n      \"evidence\": \"Pulldown/binding assays with ATG8 modifiers and colocalization imaging in mammalian cells\",\n      \"pmids\": [\"22354992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"TBC1D9 was one of 14 hits; no functional follow-up specific to TBC1D9 was performed\",\n        \"The biological consequence of TBC1D9–LC3 binding was not tested\",\n        \"No substrate-targeting or cargo-recognition mechanism was defined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How TBC1D9 is activated and what downstream signaling it controls were unknown; knockout and domain-mutant analyses demonstrated that Ca²⁺-dependent ubiquitin recognition by TBC1D9 is required for TBK1 activation and ULK1 complex recruitment during both xenophagy and mitophagy, placing TBC1D9 as a Ca²⁺-sensing signal integrator upstream of TBK1.\",\n      \"evidence\": \"TBC1D9-KO cells, Ca²⁺ chelation, Co-IP with ubiquitin-positive bacteria, immunofluorescence, UBR and Ca²⁺-binding motif mutant analysis across xenophagy and mitophagy contexts\",\n      \"pmids\": [\"32034138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TBC1D9 retains or uses Rab GAP catalytic activity during autophagy has not been tested\",\n        \"The structural basis of Ca²⁺-dependent ubiquitin recognition is unresolved\",\n        \"Contribution of the LIR motif versus the UBR to cargo selectivity has not been dissected in vivo\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether TBC1D9 functions as a bona fide Rab GAP in autophagy signaling, which Rab substrates (if any) it acts on, and how the Ca²⁺-binding, ubiquitin-binding, and LIR-dependent interactions are coordinated to drive selective autophagy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No Rab GAP activity has been demonstrated for TBC1D9\",\n        \"No structural model of TBC1D9 exists\",\n        \"In vivo relevance in animal models has not been established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TBK1\",\n      \"LC3\",\n      \"GABARAP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}