{"gene":"RINL","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2011,"finding":"RINL (Rin-like) functions as a guanine nucleotide exchange factor (GEF) for Rab5a and Rab22, preferentially binding nucleotide-free Rab5a and GDP-bound Rab22, with a higher catalytic rate for Rab22 than Rab5a. RINL is closely associated with the cytoskeleton and localizes to actin-positive compartments, contributing to spatial control of Rab5a and Rab22 signaling. Overexpression of RINL affects fluid-phase and EGFR endocytosis. RINL was also identified as a novel interaction partner of the receptor tyrosine kinase MuSK and localizes to neuromuscular synapses.","method":"Biochemical GEF assay (nucleotide exchange), protein-protein interaction (binding to nucleotide-free/GDP-bound Rab GTPases), overexpression functional assay (endocytosis), co-immunoprecipitation with MuSK, immunolocalization","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro GEF assay with kinetic measurements, functional overexpression readout, localization data, binding experiments; single lab but multiple orthogonal methods","pmids":["21419809"],"is_preprint":false},{"year":2012,"finding":"RINL has GEF activity for Rab5 subfamily proteins in cultured cells and interacts with odin (an Anks family protein). RINL, odin, and EphA8 form a ternary complex, and RINL expression reduces EphA8 protein levels in a manner dependent on both its GEF activity and interaction with odin. Conversely, RINL knockdown increases EphA8 levels, placing RINL in the EphA8-degradation pathway.","method":"GTP-bound Rab5 measurement in cultured cells, co-immunoprecipitation (RINL-odin-EphA8 ternary complex), GEF-activity mutant rescue, siRNA knockdown with protein level readout","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, catalytic mutant used to confirm GEF-dependence, knockdown phenotype; multiple orthogonal methods in single lab","pmids":["22291991"],"is_preprint":false},{"year":2023,"finding":"RINL acts as a negative regulator of T follicular helper (Tfh) cell differentiation in a GEF-dependent and T cell-intrinsic manner. RINL regulates CD28 internalization and downstream signaling, thereby shaping CD4+ T cell activation and differentiation. Loss of RINL increases Tfh cell numbers in aging, after immunization, and after LCMV infection in mice, and in human CD4+ T cell cultures.","method":"Rinl knockout mouse model, adoptive transfer experiments (WT vs. Rinl-KO naïve CD4+ T cells), in vivo immunization and LCMV infection, human in vitro CD4+ T cell cultures, CD28 internalization assay, GEF-mutant functional analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, adoptive transfer establishing T cell-intrinsic mechanism, GEF-dependence shown, replicated across mouse and human systems","pmids":["37703004"],"is_preprint":false}],"current_model":"RINL is a VPS9-domain-containing guanine nucleotide exchange factor (GEF) for Rab5a and Rab22 that, through Rab5-dependent endosomal trafficking, regulates receptor degradation (e.g., EphA8 via a ternary complex with odin) and receptor internalization (e.g., CD28 in T cells), thereby acting as a negative regulator of Tfh cell differentiation and a modulator of neuromuscular synapse signaling through interaction with MuSK."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing RINL as a Rab GEF resolved the enzymatic activity of this previously uncharacterized VPS9-domain protein and linked it to endocytic regulation and neuromuscular synapse biology via MuSK interaction.","evidence":"In vitro nucleotide exchange assays on Rab5a/Rab22, overexpression endocytosis assays, co-immunoprecipitation with MuSK, and immunolocalization at neuromuscular junctions","pmids":["21419809"],"confidence":"High","gaps":["Physiological role of the RINL–MuSK interaction at the neuromuscular synapse has not been functionally tested in vivo","The relative contribution of Rab5a versus Rab22 activation to RINL's endocytic effects is unresolved","No structural basis for RINL substrate preference has been determined"]},{"year":2012,"claim":"Demonstrating that RINL forms a ternary complex with odin and EphA8 and promotes GEF-dependent EphA8 degradation established a specific receptor-level trafficking function for RINL.","evidence":"Reciprocal co-immunoprecipitation of the RINL–odin–EphA8 complex, GEF-dead mutant rescue, and siRNA knockdown with EphA8 protein level readout in cultured cells","pmids":["22291991"],"confidence":"High","gaps":["In vivo relevance of RINL-dependent EphA8 degradation has not been tested","Whether RINL–odin interaction is direct or bridged through additional factors is not fully resolved","The endosomal compartment where EphA8 is sorted for degradation was not identified"]},{"year":2023,"claim":"Knockout studies revealed that RINL restrains Tfh cell differentiation by promoting CD28 internalization in a GEF-dependent, T cell-intrinsic manner, establishing a physiological immunological role.","evidence":"Rinl-KO mice, adoptive transfer of WT versus KO CD4+ T cells, in vivo immunization and LCMV infection, human CD4+ T cell cultures, CD28 internalization assays, and GEF-mutant functional analysis","pmids":["37703004"],"confidence":"High","gaps":["Which Rab substrate (Rab5a, Rab22, or both) mediates CD28 internalization downstream of RINL is unknown","The endosomal fate of internalized CD28 (recycling versus degradation) has not been defined","Whether RINL regulates other costimulatory or inhibitory receptors on T cells has not been explored"]},{"year":null,"claim":"The in vivo significance of RINL at the neuromuscular junction, the structural basis for its Rab substrate preference, and the full repertoire of receptors regulated by RINL-dependent endocytic trafficking remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo neuromuscular phenotype from RINL loss has been reported","No crystal or cryo-EM structure of RINL or its VPS9 domain bound to a Rab substrate exists","Systematic identification of RINL-regulated cargo beyond EphA8 and CD28 has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["RAB5A","RAB22A","MUSK","ANKS1A","EPHA8","CD28"],"other_free_text":[]},"mechanistic_narrative":"RINL is a VPS9-domain-containing guanine nucleotide exchange factor (GEF) that activates Rab5a and Rab22 GTPases, with higher catalytic efficiency toward Rab22, and associates with actin-positive cytoskeletal compartments to spatially control endosomal trafficking [PMID:21419809]. Through its GEF activity and interaction with the adaptor protein odin, RINL forms a ternary complex with the receptor tyrosine kinase EphA8 and promotes its degradation, while RINL knockdown increases EphA8 levels [PMID:22291991]. RINL also functions as a T cell-intrinsic negative regulator of T follicular helper (Tfh) cell differentiation by promoting GEF-dependent CD28 internalization, thereby attenuating costimulatory signaling during CD4+ T cell activation [PMID:37703004]."},"prefetch_data":{"uniprot":{"accession":"Q6ZS11","full_name":"Ras and Rab interactor-like protein","aliases":[],"length_aa":566,"mass_kda":62.5,"function":"Guanine nucleotide exchange factor (GEF) for RAB5A and RAB22A that activates RAB5A and RAB22A by exchanging bound GDP for free GTP. Plays a role in endocytosis via its role in activating Rab family members (By similarity)","subcellular_location":"Cell projection, ruffle; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/Q6ZS11/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RINL","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RINL","total_profiled":1310},"omim":[{"mim_id":"620678","title":"RAS AND RAB INTERACTOR-LIKE PROTEIN; RINL","url":"https://www.omim.org/entry/620678"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RINL"},"hgnc":{"alias_symbol":["FLJ45909"],"prev_symbol":[]},"alphafold":{"accession":"Q6ZS11","domains":[{"cath_id":"3.30.505.10","chopping":"38-128","consensus_level":"high","plddt":79.6951,"start":38,"end":128},{"cath_id":"-","chopping":"256-329_341-356","consensus_level":"high","plddt":85.9308,"start":256,"end":356},{"cath_id":"1.20.1050.80","chopping":"372-387_402-512_522-537","consensus_level":"high","plddt":85.0852,"start":372,"end":537}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZS11","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZS11-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZS11-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RINL","jax_strain_url":"https://www.jax.org/strain/search?query=RINL"},"sequence":{"accession":"Q6ZS11","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZS11.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZS11/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZS11"}},"corpus_meta":[{"pmid":"8035228","id":"PMC_8035228","title":"Effects of chronic spinalization on ankle extensor motoneurons. II. Motoneuron electrical properties.","date":"1994","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/8035228","citation_count":70,"is_preprint":false},{"pmid":"21419809","id":"PMC_21419809","title":"Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21419809","citation_count":14,"is_preprint":false},{"pmid":"22291991","id":"PMC_22291991","title":"RINL, guanine nucleotide exchange factor Rab5-subfamily, is involved in the EphA8-degradation pathway with odin.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22291991","citation_count":12,"is_preprint":false},{"pmid":"37703004","id":"PMC_37703004","title":"The guanine nucleotide exchange factor Rin-like controls Tfh cell differentiation via CD28 signaling.","date":"2023","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37703004","citation_count":4,"is_preprint":false},{"pmid":"38612491","id":"PMC_38612491","title":"Unveiling the Genetic Mechanism of Meat Color in Pigs through GWAS, Multi-Tissue, and Single-Cell Transcriptome Signatures Exploration.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38612491","citation_count":4,"is_preprint":false},{"pmid":"41098063","id":"PMC_41098063","title":"Molecular Atlas of PM2.5 Chemical Constituents on Cardiac Conduction: A Multiomics Landscape in Older Adults.","date":"2025","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/41098063","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4494,"output_tokens":1111,"usd":0.015074},"stage2":{"model":"claude-opus-4-6","input_tokens":4294,"output_tokens":1382,"usd":0.08403},"total_usd":0.099104,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"RINL (Rin-like) functions as a guanine nucleotide exchange factor (GEF) for Rab5a and Rab22, preferentially binding nucleotide-free Rab5a and GDP-bound Rab22, with a higher catalytic rate for Rab22 than Rab5a. RINL is closely associated with the cytoskeleton and localizes to actin-positive compartments, contributing to spatial control of Rab5a and Rab22 signaling. Overexpression of RINL affects fluid-phase and EGFR endocytosis. RINL was also identified as a novel interaction partner of the receptor tyrosine kinase MuSK and localizes to neuromuscular synapses.\",\n      \"method\": \"Biochemical GEF assay (nucleotide exchange), protein-protein interaction (binding to nucleotide-free/GDP-bound Rab GTPases), overexpression functional assay (endocytosis), co-immunoprecipitation with MuSK, immunolocalization\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro GEF assay with kinetic measurements, functional overexpression readout, localization data, binding experiments; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21419809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RINL has GEF activity for Rab5 subfamily proteins in cultured cells and interacts with odin (an Anks family protein). RINL, odin, and EphA8 form a ternary complex, and RINL expression reduces EphA8 protein levels in a manner dependent on both its GEF activity and interaction with odin. Conversely, RINL knockdown increases EphA8 levels, placing RINL in the EphA8-degradation pathway.\",\n      \"method\": \"GTP-bound Rab5 measurement in cultured cells, co-immunoprecipitation (RINL-odin-EphA8 ternary complex), GEF-activity mutant rescue, siRNA knockdown with protein level readout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, catalytic mutant used to confirm GEF-dependence, knockdown phenotype; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"22291991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RINL acts as a negative regulator of T follicular helper (Tfh) cell differentiation in a GEF-dependent and T cell-intrinsic manner. RINL regulates CD28 internalization and downstream signaling, thereby shaping CD4+ T cell activation and differentiation. Loss of RINL increases Tfh cell numbers in aging, after immunization, and after LCMV infection in mice, and in human CD4+ T cell cultures.\",\n      \"method\": \"Rinl knockout mouse model, adoptive transfer experiments (WT vs. Rinl-KO naïve CD4+ T cells), in vivo immunization and LCMV infection, human in vitro CD4+ T cell cultures, CD28 internalization assay, GEF-mutant functional analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, adoptive transfer establishing T cell-intrinsic mechanism, GEF-dependence shown, replicated across mouse and human systems\",\n      \"pmids\": [\"37703004\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RINL is a VPS9-domain-containing guanine nucleotide exchange factor (GEF) for Rab5a and Rab22 that, through Rab5-dependent endosomal trafficking, regulates receptor degradation (e.g., EphA8 via a ternary complex with odin) and receptor internalization (e.g., CD28 in T cells), thereby acting as a negative regulator of Tfh cell differentiation and a modulator of neuromuscular synapse signaling through interaction with MuSK.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RINL is a VPS9-domain-containing guanine nucleotide exchange factor (GEF) that activates Rab5a and Rab22 GTPases, with higher catalytic efficiency toward Rab22, and associates with actin-positive cytoskeletal compartments to spatially control endosomal trafficking [PMID:21419809]. Through its GEF activity and interaction with the adaptor protein odin, RINL forms a ternary complex with the receptor tyrosine kinase EphA8 and promotes its degradation, while RINL knockdown increases EphA8 levels [PMID:22291991]. RINL also functions as a T cell-intrinsic negative regulator of T follicular helper (Tfh) cell differentiation by promoting GEF-dependent CD28 internalization, thereby attenuating costimulatory signaling during CD4+ T cell activation [PMID:37703004].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing RINL as a Rab GEF resolved the enzymatic activity of this previously uncharacterized VPS9-domain protein and linked it to endocytic regulation and neuromuscular synapse biology via MuSK interaction.\",\n      \"evidence\": \"In vitro nucleotide exchange assays on Rab5a/Rab22, overexpression endocytosis assays, co-immunoprecipitation with MuSK, and immunolocalization at neuromuscular junctions\",\n      \"pmids\": [\"21419809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological role of the RINL–MuSK interaction at the neuromuscular synapse has not been functionally tested in vivo\",\n        \"The relative contribution of Rab5a versus Rab22 activation to RINL's endocytic effects is unresolved\",\n        \"No structural basis for RINL substrate preference has been determined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that RINL forms a ternary complex with odin and EphA8 and promotes GEF-dependent EphA8 degradation established a specific receptor-level trafficking function for RINL.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of the RINL–odin–EphA8 complex, GEF-dead mutant rescue, and siRNA knockdown with EphA8 protein level readout in cultured cells\",\n      \"pmids\": [\"22291991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of RINL-dependent EphA8 degradation has not been tested\",\n        \"Whether RINL–odin interaction is direct or bridged through additional factors is not fully resolved\",\n        \"The endosomal compartment where EphA8 is sorted for degradation was not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Knockout studies revealed that RINL restrains Tfh cell differentiation by promoting CD28 internalization in a GEF-dependent, T cell-intrinsic manner, establishing a physiological immunological role.\",\n      \"evidence\": \"Rinl-KO mice, adoptive transfer of WT versus KO CD4+ T cells, in vivo immunization and LCMV infection, human CD4+ T cell cultures, CD28 internalization assays, and GEF-mutant functional analysis\",\n      \"pmids\": [\"37703004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which Rab substrate (Rab5a, Rab22, or both) mediates CD28 internalization downstream of RINL is unknown\",\n        \"The endosomal fate of internalized CD28 (recycling versus degradation) has not been defined\",\n        \"Whether RINL regulates other costimulatory or inhibitory receptors on T cells has not been explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo significance of RINL at the neuromuscular junction, the structural basis for its Rab substrate preference, and the full repertoire of receptors regulated by RINL-dependent endocytic trafficking remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vivo neuromuscular phenotype from RINL loss has been reported\",\n        \"No crystal or cryo-EM structure of RINL or its VPS9 domain bound to a Rab substrate exists\",\n        \"Systematic identification of RINL-regulated cargo beyond EphA8 and CD28 has not been performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB5A\", \"RAB22A\", \"MUSK\", \"ANKS1A\", \"EPHA8\", \"CD28\"],\n    \"other_free_text\": []\n  }\n}\n```"}