{"gene":"RABGAP1L","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2016,"finding":"AnkB (ankyrin-B) binds directly to RabGAP1L and recruits it to PI3P-positive early endosomes, where RabGAP1L inactivates Rab22A, promoting polarized trafficking of α5β1-integrin to the leading edge of migrating fibroblasts.","method":"Co-immunoprecipitation, live-cell imaging, subcellular fractionation, dominant-negative/overexpression rescue in mouse embryonic fibroblasts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, RabGAP activity linked to specific Rab (Rab22A), functional consequence (integrin recycling, directed migration) established with multiple orthogonal methods in a single rigorous study","pmids":["27718357"],"is_preprint":false},{"year":2022,"finding":"TBC1D18 (RABGAP1L) is a Rab5-GAP that inactivates Rab5 to promote endosome maturation; it associates with Mon1 and localizes near lysosomes in a Mon1-dependent manner. Rab5 hyperactivation (not solely Rab7 loss) underlies the endosome maturation defects in Mon1-KO cells, and TBC1D18 expression rescues these defects while its depletion attenuates endosome formation and endocytic cargo degradation.","method":"Comprehensive TBC-domain GAP screen, KO/KD cell lines, rescue experiments, live imaging, co-immunoprecipitation with Mon1","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic GAP activity identified by systematic screen with functional rescue, Mon1 interaction shown by Co-IP, multiple orthogonal loss-of-function and gain-of-function experiments","pmids":["36197338"],"is_preprint":false},{"year":2022,"finding":"RABGAP1L is an interferon-stimulated gene whose catalytically active TBC domain is required for antiviral activity; it associates with endosomal sorting/maturation/trafficking proteins and its overexpression disrupts endosomal function during influenza A virus (IAV) infection, blocking a post-attachment, pre-fusion step of IAV endocytic entry. Other endocytosis-dependent RNA viruses are also restricted, while SARS-CoV-2 (entry-promiscuous) is resistant.","method":"RNAi screen, overexpression with TBC-domain catalytic mutants, proximity interactome (BioID), endosome function assays, viral entry stage analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — catalytic-domain mutagenesis links TBC activity to function, multiple viral systems tested, interactome mapping, single lab but multiple orthogonal methods","pmids":["35320721"],"is_preprint":false},{"year":2025,"finding":"RabGAP1L modulates cell-autonomous immunity against Group A Streptococcus by inactivating two distinct Rab GTPases: it inactivates Rab7A (which positively regulates selective autophagy via endolysosomal trafficking) and Rab10 (which, together with Rab7A, negatively regulates bacterial expulsion by inhibiting Rab11A-positive recycling endosome formation). When autophagy is deficient (ATG7/ATG5 KO), RabGAP1L-dependent Rab10 inactivation promotes bacterial expulsion via the endocytic recycling pathway.","method":"Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model, overexpression and knockdown of RabGAP1L, Rab7A and Rab10 functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two distinct Rab substrates identified with loss-of-function and gain-of-function, functional consequences (autophagy vs. expulsion) dissected with genetic knockouts, multiple orthogonal approaches in single study","pmids":["40244851"],"is_preprint":false},{"year":2000,"finding":"The mouse ortholog Hhl (RABGAP1L) encodes a novel protein containing a putative phosphotyrosine-binding (PTB) domain and is expressed in a tissue-specific manner in hematopoietic cells (megakaryocytes, CFU-GEMM, BFU-E), as identified by expression gene trapping in ES cells differentiated on OP9 stromal cells.","method":"Expression gene trapping with lacZ reporter, in vitro hematopoietic differentiation on OP9, in vivo analysis of gene trap mice","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct experimental localization of expression to specific hematopoietic lineages with reporter gene in vivo; domain architecture identified computationally but in tissue-specific expression context validated experimentally","pmids":["10585558"],"is_preprint":false}],"current_model":"RABGAP1L (TBC1D18) is a TBC-domain Rab GTPase-activating protein that inactivates multiple Rab GTPases—including Rab5 (to drive endosome maturation in concert with Mon1), Rab22A (to promote polarized α5β1-integrin recycling downstream of ankyrin-B on PI3P endosomes), Rab7A and Rab10 (to balance selective autophagy against extracellular bacterial expulsion during cell-autonomous immunity)—and whose catalytic TBC activity is required for its function as an interferon-stimulated antiviral restriction factor that blocks endocytic virus entry."},"narrative":{"mechanistic_narrative":"RABGAP1L (TBC1D18) is a TBC-domain Rab GTPase-activating protein that governs endosomal maturation and trafficking by inactivating multiple Rab GTPases, thereby linking membrane traffic to cell migration and cell-autonomous immunity [PMID:36197338, PMID:27718357]. It is recruited to PI3P-positive early endosomes through direct binding to ankyrin-B, where it inactivates Rab22A to drive polarized recycling of α5β1-integrin to the leading edge of migrating fibroblasts [PMID:27718357]. Acting as a Rab5-GAP in association with Mon1, it inactivates Rab5 to promote endosome maturation and endocytic cargo degradation, rescuing the maturation defects of Mon1-deficient cells [PMID:36197338]. During defense against Group A Streptococcus it inactivates Rab7A and Rab10 to balance selective autophagy against Rab11A-dependent bacterial expulsion [PMID:40244851]. RABGAP1L is also an interferon-stimulated gene that acts as an antiviral restriction factor: its catalytically active TBC domain is required to disrupt endosomal function and block a post-attachment, pre-fusion step of influenza A virus and other endocytosis-dependent RNA virus entry, while entry-promiscuous SARS-CoV-2 escapes restriction [PMID:35320721].","teleology":[{"year":2000,"claim":"Established the gene's existence and an initial expression pattern, asking where an uncharacterized protein with a putative PTB domain operates.","evidence":"Expression gene trapping with lacZ reporter and in vitro hematopoietic differentiation on OP9 stroma, plus gene-trap mice","pmids":["10585558"],"confidence":"Medium","gaps":["No molecular function assigned","PTB domain identified computationally, not functionally tested","No Rab substrate or trafficking role established"]},{"year":2016,"claim":"Defined RABGAP1L as a Rab22A-inactivating GAP recruited by ankyrin-B to PI3P endosomes, connecting it for the first time to directed cell migration.","evidence":"Co-IP, live imaging, subcellular fractionation and dominant-negative/overexpression rescue in mouse embryonic fibroblasts","pmids":["27718357"],"confidence":"High","gaps":["Whether other Rabs are targeted in this context not resolved","Structural basis of AnkB recruitment unknown","Restricted to fibroblast migration system"]},{"year":2022,"claim":"Identified RABGAP1L (TBC1D18) as a Rab5-GAP acting with Mon1 to drive endosome maturation, showing Rab5 hyperactivation rather than Rab7 loss underlies the Mon1-KO defect.","evidence":"Systematic TBC-domain GAP screen, KO/KD and rescue cell lines, live imaging and Co-IP with Mon1","pmids":["36197338"],"confidence":"High","gaps":["Mechanism of Mon1-dependent recruitment not detailed","Relationship between Rab5 and Rab22A activities in the same cell unresolved"]},{"year":2022,"claim":"Established RABGAP1L as an interferon-stimulated antiviral restriction factor whose TBC catalytic activity blocks endocytic virus entry, linking its GAP function to innate antiviral defense.","evidence":"RNAi screen, TBC catalytic-mutant overexpression, BioID interactome, endosome function and viral entry-stage assays across multiple viruses","pmids":["35320721"],"confidence":"High","gaps":["Specific Rab substrate driving antiviral restriction not pinned down","Mechanism distinguishing endosome-dependent versus promiscuous viruses incomplete"]},{"year":2025,"claim":"Dissected dual Rab7A and Rab10 inactivation by RABGAP1L in anti-bacterial cell-autonomous immunity, explaining how it toggles between autophagy and bacterial expulsion.","evidence":"Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model with overexpression/knockdown and Rab7A/Rab10 functional assays","pmids":["40244851"],"confidence":"High","gaps":["How substrate Rab selection is regulated across contexts unknown","Direct GAP assays on Rab7A/Rab10 not shown","In vivo relevance to infection outcome untested"]},{"year":null,"claim":"How RABGAP1L selects among its multiple Rab substrates (Rab5, Rab22A, Rab7A, Rab10) in a context-specific manner, and the structural/regulatory basis of its recruitment, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of substrate engagement","Determinants of context-dependent Rab targeting unknown","Upstream regulation of GAP activity uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":["ANK2","MON1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"B7ZAP0","full_name":"Rab GTPase-activating protein 1-like, isoform 10","aliases":[],"length_aa":253,"mass_kda":29.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/B7ZAP0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RABGAP1L","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000152061","cell_line_id":"CID000448","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"centrosome","grade":2},{"compartment":"golgi","grade":2},{"compartment":"vesicles","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"RABGAP1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000448","total_profiled":1310},"omim":[{"mim_id":"609238","title":"RAB GTPase-ACTIVATING PROTEIN 1-LIKE; RABGAP1L","url":"https://www.omim.org/entry/609238"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"heart muscle","ntpm":114.9}],"url":"https://www.proteinatlas.org/search/RABGAP1L"},"hgnc":{"alias_symbol":["HHL","TBC1D18","KIAA0471","FLJ38519"],"prev_symbol":[]},"alphafold":{"accession":"B7ZAP0","domains":[{"cath_id":"1.20.5","chopping":"176-225","consensus_level":"medium","plddt":92.5126,"start":176,"end":225}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/B7ZAP0","model_url":"https://alphafold.ebi.ac.uk/files/AF-B7ZAP0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-B7ZAP0-F1-predicted_aligned_error_v6.png","plddt_mean":85.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RABGAP1L","jax_strain_url":"https://www.jax.org/strain/search?query=RABGAP1L"},"sequence":{"accession":"B7ZAP0","fasta_url":"https://rest.uniprot.org/uniprotkb/B7ZAP0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/B7ZAP0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/B7ZAP0"}},"corpus_meta":[{"pmid":"16476177","id":"PMC_16476177","title":"Performance 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Rab5 hyperactivation (not solely Rab7 loss) underlies the endosome maturation defects in Mon1-KO cells, and TBC1D18 expression rescues these defects while its depletion attenuates endosome formation and endocytic cargo degradation.\",\n      \"method\": \"Comprehensive TBC-domain GAP screen, KO/KD cell lines, rescue experiments, live imaging, co-immunoprecipitation with Mon1\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic GAP activity identified by systematic screen with functional rescue, Mon1 interaction shown by Co-IP, multiple orthogonal loss-of-function and gain-of-function experiments\",\n      \"pmids\": [\"36197338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RABGAP1L is an interferon-stimulated gene whose catalytically active TBC domain is required for antiviral activity; it associates with endosomal sorting/maturation/trafficking proteins and its overexpression disrupts endosomal function during influenza A virus (IAV) infection, blocking a post-attachment, pre-fusion step of IAV endocytic entry. Other endocytosis-dependent RNA viruses are also restricted, while SARS-CoV-2 (entry-promiscuous) is resistant.\",\n      \"method\": \"RNAi screen, overexpression with TBC-domain catalytic mutants, proximity interactome (BioID), endosome function assays, viral entry stage analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — catalytic-domain mutagenesis links TBC activity to function, multiple viral systems tested, interactome mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35320721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RabGAP1L modulates cell-autonomous immunity against Group A Streptococcus by inactivating two distinct Rab GTPases: it inactivates Rab7A (which positively regulates selective autophagy via endolysosomal trafficking) and Rab10 (which, together with Rab7A, negatively regulates bacterial expulsion by inhibiting Rab11A-positive recycling endosome formation). When autophagy is deficient (ATG7/ATG5 KO), RabGAP1L-dependent Rab10 inactivation promotes bacterial expulsion via the endocytic recycling pathway.\",\n      \"method\": \"Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model, overexpression and knockdown of RabGAP1L, Rab7A and Rab10 functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two distinct Rab substrates identified with loss-of-function and gain-of-function, functional consequences (autophagy vs. expulsion) dissected with genetic knockouts, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"40244851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The mouse ortholog Hhl (RABGAP1L) encodes a novel protein containing a putative phosphotyrosine-binding (PTB) domain and is expressed in a tissue-specific manner in hematopoietic cells (megakaryocytes, CFU-GEMM, BFU-E), as identified by expression gene trapping in ES cells differentiated on OP9 stromal cells.\",\n      \"method\": \"Expression gene trapping with lacZ reporter, in vitro hematopoietic differentiation on OP9, in vivo analysis of gene trap mice\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct experimental localization of expression to specific hematopoietic lineages with reporter gene in vivo; domain architecture identified computationally but in tissue-specific expression context validated experimentally\",\n      \"pmids\": [\"10585558\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RABGAP1L (TBC1D18) is a TBC-domain Rab GTPase-activating protein that inactivates multiple Rab GTPases—including Rab5 (to drive endosome maturation in concert with Mon1), Rab22A (to promote polarized α5β1-integrin recycling downstream of ankyrin-B on PI3P endosomes), Rab7A and Rab10 (to balance selective autophagy against extracellular bacterial expulsion during cell-autonomous immunity)—and whose catalytic TBC activity is required for its function as an interferon-stimulated antiviral restriction factor that blocks endocytic virus entry.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RABGAP1L (TBC1D18) is a TBC-domain Rab GTPase-activating protein that governs endosomal maturation and trafficking by inactivating multiple Rab GTPases, thereby linking membrane traffic to cell migration and cell-autonomous immunity [#1, #0]. It is recruited to PI3P-positive early endosomes through direct binding to ankyrin-B, where it inactivates Rab22A to drive polarized recycling of α5β1-integrin to the leading edge of migrating fibroblasts [#0]. Acting as a Rab5-GAP in association with Mon1, it inactivates Rab5 to promote endosome maturation and endocytic cargo degradation, rescuing the maturation defects of Mon1-deficient cells [#1]. During defense against Group A Streptococcus it inactivates Rab7A and Rab10 to balance selective autophagy against Rab11A-dependent bacterial expulsion [#3]. RABGAP1L is also an interferon-stimulated gene that acts as an antiviral restriction factor: its catalytically active TBC domain is required to disrupt endosomal function and block a post-attachment, pre-fusion step of influenza A virus and other endocytosis-dependent RNA virus entry, while entry-promiscuous SARS-CoV-2 escapes restriction [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the gene's existence and an initial expression pattern, asking where an uncharacterized protein with a putative PTB domain operates.\",\n      \"evidence\": \"Expression gene trapping with lacZ reporter and in vitro hematopoietic differentiation on OP9 stroma, plus gene-trap mice\",\n      \"pmids\": [\"10585558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"PTB domain identified computationally, not functionally tested\", \"No Rab substrate or trafficking role established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined RABGAP1L as a Rab22A-inactivating GAP recruited by ankyrin-B to PI3P endosomes, connecting it for the first time to directed cell migration.\",\n      \"evidence\": \"Co-IP, live imaging, subcellular fractionation and dominant-negative/overexpression rescue in mouse embryonic fibroblasts\",\n      \"pmids\": [\"27718357\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Rabs are targeted in this context not resolved\", \"Structural basis of AnkB recruitment unknown\", \"Restricted to fibroblast migration system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified RABGAP1L (TBC1D18) as a Rab5-GAP acting with Mon1 to drive endosome maturation, showing Rab5 hyperactivation rather than Rab7 loss underlies the Mon1-KO defect.\",\n      \"evidence\": \"Systematic TBC-domain GAP screen, KO/KD and rescue cell lines, live imaging and Co-IP with Mon1\",\n      \"pmids\": [\"36197338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Mon1-dependent recruitment not detailed\", \"Relationship between Rab5 and Rab22A activities in the same cell unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established RABGAP1L as an interferon-stimulated antiviral restriction factor whose TBC catalytic activity blocks endocytic virus entry, linking its GAP function to innate antiviral defense.\",\n      \"evidence\": \"RNAi screen, TBC catalytic-mutant overexpression, BioID interactome, endosome function and viral entry-stage assays across multiple viruses\",\n      \"pmids\": [\"35320721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Rab substrate driving antiviral restriction not pinned down\", \"Mechanism distinguishing endosome-dependent versus promiscuous viruses incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Dissected dual Rab7A and Rab10 inactivation by RABGAP1L in anti-bacterial cell-autonomous immunity, explaining how it toggles between autophagy and bacterial expulsion.\",\n      \"evidence\": \"Confocal microscopy, ATG7/ATG5 knockout cells, GAS infection model with overexpression/knockdown and Rab7A/Rab10 functional assays\",\n      \"pmids\": [\"40244851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate Rab selection is regulated across contexts unknown\", \"Direct GAP assays on Rab7A/Rab10 not shown\", \"In vivo relevance to infection outcome untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RABGAP1L selects among its multiple Rab substrates (Rab5, Rab22A, Rab7A, Rab10) in a context-specific manner, and the structural/regulatory basis of its recruitment, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of substrate engagement\", \"Determinants of context-dependent Rab targeting unknown\", \"Upstream regulation of GAP activity uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005096\" , \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ANK2\", \"MON1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}