{"gene":"TBC1D22A","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2013,"finding":"TBC1D22A and TBC1D22B were identified as ACBD3 (GCP60)-interacting factors by affinity purification-mass spectrometry. Fine-scale mapping revealed that the binding domains on ACBD3 for TBC1D22A/B and PI4KB are identical, and affinity purification confirmed that PI4KB and TBC1D22A/B interactions with ACBD3 are mutually exclusive, suggesting a competitive regulatory mechanism for PI4KB recruitment to the Golgi.","method":"Affinity purification-mass spectrometry, fine-scale domain mapping, affinity purification competition assay","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal affinity purification with domain mapping, single lab, two orthogonal methods (AP-MS and competition pulldown)","pmids":["23572552"],"is_preprint":false},{"year":2013,"finding":"TBC1D22A is annotated as a putative Rab33 GTPase-activating protein (RabGAP) based on its TBC domain, and its competition with PI4KB for ACBD3 binding is differentially affected by enteroviral versus kobuviral 3A replication proteins, indicating that distinct viral mechanisms modulate TBC1D22A displacement from ACBD3.","method":"Mammalian two-hybrid assay, affinity purification","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mammalian two-hybrid and affinity purification in single lab with two orthogonal methods","pmids":["23572552"],"is_preprint":false},{"year":2025,"finding":"In functional assays using the Retention Using Selective Hooks (RUSH) system, TBC1D22B (the paralog) inhibited ER-to-Golgi transport in a GAP-dependent manner, and this effect was NOT replicated by its paralog TBC1D22A, indicating TBC1D22A does not share this specific trafficking function with TBC1D22B.","method":"RUSH trafficking assay, overexpression of TBC1D22A vs TBC1D22B","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional RUSH assay with direct comparison, single lab, negative result for TBC1D22A","pmids":["40878439"],"is_preprint":false}],"current_model":"TBC1D22A is a putative Rab33 GTPase-activating protein (RabGAP) that binds ACBD3/GCP60 at the same site as PI4KB in a mutually exclusive manner, suggesting it competes with PI4KB for Golgi recruitment; this interaction is differentially disrupted by enteroviral versus kobuviral 3A replication proteins, and unlike its paralog TBC1D22B, TBC1D22A does not inhibit ER-to-Golgi trafficking."},"narrative":{"mechanistic_narrative":"TBC1D22A is a putative Rab33 GTPase-activating protein (RabGAP), annotated by virtue of its TBC domain, that functions at the Golgi through interaction with the scaffolding protein ACBD3 (GCP60) [PMID:23572552]. It binds ACBD3 at the same site used by the lipid kinase PI4KB, and these interactions are mutually exclusive, positioning TBC1D22A as a competitive regulator of PI4KB recruitment to the Golgi [PMID:23572552]. This competition is differentially modulated by viral 3A replication proteins, with enteroviral and kobuviral 3A proteins distinctly affecting TBC1D22A displacement from ACBD3, implicating it in the membrane remodeling co-opted during picornaviral replication [PMID:23572552]. Unlike its paralog TBC1D22B, which inhibits ER-to-Golgi transport in a GAP-dependent manner, TBC1D22A does not share this trafficking-inhibitory activity, indicating functional divergence between the paralogs [PMID:40878439]. Beyond these ACBD3-centered and paralog-comparison findings, the catalytic GAP activity of TBC1D22A on Rab substrates and its broader cellular roles have not been directly characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing what TBC1D22A physically associates with answered whether it operates at the Golgi: it was identified as an ACBD3-interacting factor that competes with PI4KB for the same binding site, defining a competitive recruitment mechanism.","evidence":"Affinity purification-mass spectrometry, fine-scale domain mapping, and competition pulldown in mammalian cells","pmids":["23572552"],"confidence":"Medium","gaps":["Functional consequence of PI4KB displacement on Golgi PI4P levels not demonstrated","Direct binding shown by AP-MS/pulldown but not by reconstitution with purified components","Rab GAP substrate not identified"]},{"year":2013,"claim":"Characterizing how the ACBD3 interaction is regulated answered whether viral factors hijack it: enteroviral versus kobuviral 3A proteins differentially displace TBC1D22A, linking the competition to virus-specific Golgi remodeling.","evidence":"Mammalian two-hybrid assay and affinity purification with viral 3A proteins","pmids":["23572552"],"confidence":"Medium","gaps":["RabGAP activity remains an annotation based on the TBC domain, not enzymatically demonstrated","Physiological role of TBC1D22A in uninfected cells not established","Whether displacement alters viral replication outcomes not tested directly"]},{"year":2025,"claim":"Comparing the paralogs answered whether TBC1D22A regulates secretory trafficking like TBC1D22B: it does not inhibit ER-to-Golgi transport, revealing functional divergence despite shared domain architecture.","evidence":"RUSH trafficking assay with overexpression of TBC1D22A versus TBC1D22B","pmids":["40878439"],"confidence":"Medium","gaps":["Negative result for TBC1D22A does not define its actual trafficking substrate or pathway","Whether endogenous TBC1D22A has any GAP-dependent transport role untested","Single-lab overexpression assay; loss-of-function consequences unknown"]},{"year":null,"claim":"The direct catalytic substrate and cellular function of TBC1D22A remain undefined: whether it acts as a bona fide Rab33 GAP and what process its ACBD3 competition with PI4KB ultimately controls is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No enzymatic demonstration of GAP activity on any Rab","No loss-of-function phenotype reported","No structural model of the TBC1D22A-ACBD3 interface"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":[],"partners":["ACBD3","PI4KB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUA7","full_name":"TBC1 domain family member 22A","aliases":[],"length_aa":517,"mass_kda":59.1,"function":"May act as a GTPase-activating protein for Rab family protein(s)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8WUA7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TBC1D22A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TBC1D22A","total_profiled":1310},"omim":[{"mim_id":"616880","title":"TBC1 DOMAIN FAMILY, MEMBER 22B; TBC1D22B","url":"https://www.omim.org/entry/616880"},{"mim_id":"616879","title":"TBC1 DOMAIN FAMILY, MEMBER 22A; TBC1D22A","url":"https://www.omim.org/entry/616879"},{"mim_id":"606809","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 3; ACBD3","url":"https://www.omim.org/entry/606809"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TBC1D22A"},"hgnc":{"alias_symbol":[],"prev_symbol":["C22orf4"]},"alphafold":{"accession":"Q8WUA7","domains":[{"cath_id":"-","chopping":"208-374","consensus_level":"high","plddt":95.8136,"start":208,"end":374},{"cath_id":"1.10.472.80","chopping":"381-510","consensus_level":"high","plddt":96.9453,"start":381,"end":510}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUA7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUA7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUA7-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TBC1D22A","jax_strain_url":"https://www.jax.org/strain/search?query=TBC1D22A"},"sequence":{"accession":"Q8WUA7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUA7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUA7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUA7"}},"corpus_meta":[{"pmid":"22326833","id":"PMC_22326833","title":"Gene deletions and amplifications in human hepatocellular carcinomas: correlation with hepatocyte growth regulation.","date":"2012","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22326833","citation_count":66,"is_preprint":false},{"pmid":"23572552","id":"PMC_23572552","title":"ACBD3 interaction with TBC1 domain 22 protein is differentially affected by enteroviral and kobuviral 3A protein binding.","date":"2013","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/23572552","citation_count":57,"is_preprint":false},{"pmid":"29430824","id":"PMC_29430824","title":"DNA methylation analyses of the candidate genes identified by a methylome-wide association study revealed common epigenetic alterations in schizophrenia and bipolar disorder.","date":"2018","source":"Psychiatry and clinical neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/29430824","citation_count":26,"is_preprint":false},{"pmid":"34855995","id":"PMC_34855995","title":"New insights into genetics underlying of plumage color.","date":"2021","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34855995","citation_count":19,"is_preprint":false},{"pmid":"34664257","id":"PMC_34664257","title":"Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures.","date":"2021","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34664257","citation_count":15,"is_preprint":false},{"pmid":"35167808","id":"PMC_35167808","title":"A functional genomics approach in Tanzanian population identifies distinct genetic regulators of cytokine production compared to European population.","date":"2022","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35167808","citation_count":15,"is_preprint":false},{"pmid":"30064533","id":"PMC_30064533","title":"Four-Generation Pedigree of Monozygotic Female Twins Reveals Genetic Factors in Twinning Process by Whole-Genome 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neurons (Preliminary analysis).","date":"2011","source":"Bioinformation","url":"https://pubmed.ncbi.nlm.nih.gov/21738310","citation_count":2,"is_preprint":false},{"pmid":"39449424","id":"PMC_39449424","title":"Network Pharmacology Approaches Used to Identify Therapeutic Molecules for Chronic Venous Disease Based on Potential miRNA Biomarkers.","date":"2024","source":"Journal of xenobiotics","url":"https://pubmed.ncbi.nlm.nih.gov/39449424","citation_count":1,"is_preprint":false},{"pmid":"41445639","id":"PMC_41445639","title":"Interactive Effects of Telomere Length and Genetic Variants on Alzheimer Disease Risk Across Multiple Ancestral Populations.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41445639","citation_count":0,"is_preprint":false},{"pmid":"42192297","id":"PMC_42192297","title":"Chromosome 22q13 terminal deletion size is associated with relevant clinical features in a sample of 63 Italian patients with Phelan-McDermid syndrome.","date":"2026","source":"Journal of neurodevelopmental disorders","url":"https://pubmed.ncbi.nlm.nih.gov/42192297","citation_count":0,"is_preprint":false},{"pmid":"41857676","id":"PMC_41857676","title":"Interactive effects of telomere length and genetic variants on Alzheimer disease risk across multiple ancestral populations.","date":"2026","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41857676","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12146,"output_tokens":847,"usd":0.024571,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7284,"output_tokens":1683,"usd":0.039247,"stage2_stop_reason":"end_turn"},"total_usd":0.063818,"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\": 2013,\n      \"finding\": \"TBC1D22A and TBC1D22B were identified as ACBD3 (GCP60)-interacting factors by affinity purification-mass spectrometry. Fine-scale mapping revealed that the binding domains on ACBD3 for TBC1D22A/B and PI4KB are identical, and affinity purification confirmed that PI4KB and TBC1D22A/B interactions with ACBD3 are mutually exclusive, suggesting a competitive regulatory mechanism for PI4KB recruitment to the Golgi.\",\n      \"method\": \"Affinity purification-mass spectrometry, fine-scale domain mapping, affinity purification competition assay\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal affinity purification with domain mapping, single lab, two orthogonal methods (AP-MS and competition pulldown)\",\n      \"pmids\": [\"23572552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TBC1D22A is annotated as a putative Rab33 GTPase-activating protein (RabGAP) based on its TBC domain, and its competition with PI4KB for ACBD3 binding is differentially affected by enteroviral versus kobuviral 3A replication proteins, indicating that distinct viral mechanisms modulate TBC1D22A displacement from ACBD3.\",\n      \"method\": \"Mammalian two-hybrid assay, affinity purification\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mammalian two-hybrid and affinity purification in single lab with two orthogonal methods\",\n      \"pmids\": [\"23572552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In functional assays using the Retention Using Selective Hooks (RUSH) system, TBC1D22B (the paralog) inhibited ER-to-Golgi transport in a GAP-dependent manner, and this effect was NOT replicated by its paralog TBC1D22A, indicating TBC1D22A does not share this specific trafficking function with TBC1D22B.\",\n      \"method\": \"RUSH trafficking assay, overexpression of TBC1D22A vs TBC1D22B\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional RUSH assay with direct comparison, single lab, negative result for TBC1D22A\",\n      \"pmids\": [\"40878439\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TBC1D22A is a putative Rab33 GTPase-activating protein (RabGAP) that binds ACBD3/GCP60 at the same site as PI4KB in a mutually exclusive manner, suggesting it competes with PI4KB for Golgi recruitment; this interaction is differentially disrupted by enteroviral versus kobuviral 3A replication proteins, and unlike its paralog TBC1D22B, TBC1D22A does not inhibit ER-to-Golgi trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TBC1D22A is a putative Rab33 GTPase-activating protein (RabGAP), annotated by virtue of its TBC domain, that functions at the Golgi through interaction with the scaffolding protein ACBD3 (GCP60) [#0, #1]. It binds ACBD3 at the same site used by the lipid kinase PI4KB, and these interactions are mutually exclusive, positioning TBC1D22A as a competitive regulator of PI4KB recruitment to the Golgi [#0]. This competition is differentially modulated by viral 3A replication proteins, with enteroviral and kobuviral 3A proteins distinctly affecting TBC1D22A displacement from ACBD3, implicating it in the membrane remodeling co-opted during picornaviral replication [#1]. Unlike its paralog TBC1D22B, which inhibits ER-to-Golgi transport in a GAP-dependent manner, TBC1D22A does not share this trafficking-inhibitory activity, indicating functional divergence between the paralogs [#2]. Beyond these ACBD3-centered and paralog-comparison findings, the catalytic GAP activity of TBC1D22A on Rab substrates and its broader cellular roles have not been directly characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing what TBC1D22A physically associates with answered whether it operates at the Golgi: it was identified as an ACBD3-interacting factor that competes with PI4KB for the same binding site, defining a competitive recruitment mechanism.\",\n      \"evidence\": \"Affinity purification-mass spectrometry, fine-scale domain mapping, and competition pulldown in mammalian cells\",\n      \"pmids\": [\n        \"23572552\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of PI4KB displacement on Golgi PI4P levels not demonstrated\",\n        \"Direct binding shown by AP-MS/pulldown but not by reconstitution with purified components\",\n        \"Rab GAP substrate not identified\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterizing how the ACBD3 interaction is regulated answered whether viral factors hijack it: enteroviral versus kobuviral 3A proteins differentially displace TBC1D22A, linking the competition to virus-specific Golgi remodeling.\",\n      \"evidence\": \"Mammalian two-hybrid assay and affinity purification with viral 3A proteins\",\n      \"pmids\": [\n        \"23572552\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RabGAP activity remains an annotation based on the TBC domain, not enzymatically demonstrated\",\n        \"Physiological role of TBC1D22A in uninfected cells not established\",\n        \"Whether displacement alters viral replication outcomes not tested directly\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comparing the paralogs answered whether TBC1D22A regulates secretory trafficking like TBC1D22B: it does not inhibit ER-to-Golgi transport, revealing functional divergence despite shared domain architecture.\",\n      \"evidence\": \"RUSH trafficking assay with overexpression of TBC1D22A versus TBC1D22B\",\n      \"pmids\": [\n        \"40878439\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result for TBC1D22A does not define its actual trafficking substrate or pathway\",\n        \"Whether endogenous TBC1D22A has any GAP-dependent transport role untested\",\n        \"Single-lab overexpression assay; loss-of-function consequences unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct catalytic substrate and cellular function of TBC1D22A remain undefined: whether it acts as a bona fide Rab33 GAP and what process its ACBD3 competition with PI4KB ultimately controls is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No enzymatic demonstration of GAP activity on any Rab\",\n        \"No loss-of-function phenotype reported\",\n        \"No structural model of the TBC1D22A-ACBD3 interface\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005794\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      }\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACBD3\",\n      \"PI4KB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}