{"gene":"VPS26C","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2022,"finding":"VPS26C (DSCR3) directly binds internalized SLC38A1 and mediates its sorting into the recycling pathway, maintaining SLC38A1 abundance on the plasma membrane and enhancing glutamine uptake in glioblastoma cells; this recycling activity promotes acquired temozolomide resistance.","method":"Co-immunoprecipitation, label-free quantitative proteomics of plasma membrane fractions, immunofluorescence, and in vitro silencing/rescue experiments in MGMT-deficient GBM cells and orthotopic mouse model","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed by proteomics and in vitro experiments with functional readout, single lab","pmids":["35187626"],"is_preprint":false},{"year":2022,"finding":"VPS26C, as a subunit of the Retriever complex (with VPS35L and VPS29), selectively mediates endosomal recycling of LRP1 (but not LDLR) to the hepatocyte cell surface; liver-specific VPS26C ablation in mice delayed postprandial triglyceride clearance and increased plasma triglycerides, while VPS35L (shared between Retriever and CCC) is required for both LDLR and LRP1 surface expression.","method":"Somatic CRISPR/Cas9 liver-specific knockout in mice, surface protein quantification, plasma lipid measurements, Western blotting of CCC and Retriever subunit composition, VPS26C-deficient hepatoma cell experiments","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR KO with defined metabolic phenotype, complemented by cell-based mechanistic experiments, multiple orthogonal readouts in a single rigorous study","pmids":["36353989"],"is_preprint":false},{"year":2019,"finding":"A homozygous loss-of-function nonsense variant (p.Glu60*) in VPS26C, a member of the Retriever endosomal recycling complex, causes significantly reduced transcript levels and is associated with a syndrome of neurodevelopmental deficits, growth failure, and skeletal abnormalities in humans, supporting an essential biological role for VPS26C.","method":"Genome sequencing, expression studies (transcript quantification), co-segregation analysis in two affected cousins","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — human genetic variant with expression data, no direct mechanistic reconstitution; single family, no functional rescue","pmids":["31845315"],"is_preprint":false}],"current_model":"VPS26C (also known as DSCR3) is a subunit of the Retriever endosomal recycling complex that selectively recycles cargo proteins—such as LRP1 in hepatocytes and SLC38A1 in glioblastoma cells—from endosomes back to the plasma membrane, and loss of VPS26C impairs lipoprotein clearance and alters cellular metabolite uptake."},"narrative":{"mechanistic_narrative":"VPS26C is a subunit of the Retriever endosomal recycling complex that, together with VPS35L and VPS29, selectively returns internalized transmembrane cargo from endosomes to the plasma membrane [PMID:36353989]. In hepatocytes, VPS26C-dependent Retriever activity specifically recycles LRP1—but not LDLR—to the cell surface, and liver-specific VPS26C ablation in mice delays postprandial triglyceride clearance and raises plasma triglycerides, defining a role in lipoprotein metabolism [PMID:36353989]. The complex acts with cargo selectivity that distinguishes it from the shared CCC-associated subunit VPS35L, which is required for surface expression of both LRP1 and LDLR [PMID:36353989]. VPS26C extends this recycling function to other cargo: it directly binds internalized SLC38A1 and sorts it into the recycling pathway, sustaining surface SLC38A1 levels, enhancing glutamine uptake, and promoting temozolomide resistance in glioblastoma cells [PMID:35187626].","teleology":[{"year":2019,"claim":"Establishing whether VPS26C is biologically essential in humans, a homozygous loss-of-function variant was linked to a multisystem developmental disorder, implicating Retriever-mediated recycling in normal growth and neurodevelopment.","evidence":"Genome sequencing, transcript quantification, and co-segregation in two affected cousins","pmids":["31845315"],"confidence":"Low","gaps":["Single family with no functional rescue; causation not mechanistically demonstrated","No molecular cargo or pathway connected to the clinical phenotype","Tissue-level mechanism underlying skeletal and neurodevelopmental defects unknown"]},{"year":2022,"claim":"Identifying a specific cargo of VPS26C, the protein was shown to directly bind internalized SLC38A1 and route it back to the surface, defining VPS26C as a determinant of nutrient transporter abundance and a driver of glutamine-fueled drug resistance.","evidence":"Co-IP, plasma-membrane proteomics, immunofluorescence, and silencing/rescue in MGMT-deficient GBM cells plus orthotopic mouse model","pmids":["35187626"],"confidence":"Medium","gaps":["Single lab; binding interface and sorting signal on SLC38A1 not mapped","Whether recycling requires the full Retriever complex in this context not tested","Generality beyond glioblastoma not established"]},{"year":2022,"claim":"Placing VPS26C within the Retriever complex in vivo, liver-specific knockout demonstrated cargo-selective recycling of LRP1 and a defined metabolic phenotype, distinguishing Retriever-specific from CCC-shared subunit functions.","evidence":"Somatic CRISPR/Cas9 liver-specific KO in mice, surface protein quantification, plasma lipid measurements, and VPS26C-deficient hepatoma cell experiments","pmids":["36353989"],"confidence":"High","gaps":["Structural basis for LRP1 versus LDLR cargo selectivity not resolved","Recognition motif on LRP1 that VPS26C reads not identified","Full spectrum of VPS26C-dependent cargo across tissues unknown"]},{"year":null,"claim":"How VPS26C selects its diverse cargo (LRP1, SLC38A1) and the structural rules governing Retriever cargo specificity remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of VPS26C cargo recognition","Mechanism of endosomal recruitment of the Retriever complex via VPS26C unresolved","Link between molecular cargo handling and the human disease phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1]}],"complexes":["Retriever"],"partners":["VPS35L","VPS29","LRP1","SLC38A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14972","full_name":"Vacuolar protein sorting-associated protein 26C","aliases":["Down syndrome critical region protein 3","Down syndrome critical region protein A"],"length_aa":297,"mass_kda":33.0,"function":"Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the commander complex is composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:39587083, PubMed:38062209, PubMed:38459129). Component of the retriever complex, which is a heterotrimeric complex related to retromer cargo-selective complex (CSC) and essential for retromer-independent retrieval and recycling of numerous cargos such as integrin alpha-5/beta-1 (ITGA5:ITGB1) (PubMed:28892079, PubMed:37172566, PubMed:39587083, PubMed:38062209, PubMed:38459129). The recruitment of the retriever complex to the endosomal membrane involves CCC and WASH complexes (PubMed:28892079). In the endosomes, drives the retriever and recycling of NxxY-motif-containing cargo proteins by coupling to SNX17, a cargo essential for the homeostatic maintenance of numerous cell surface proteins associated with processes that include cell migration, cell adhesion, nutrient supply and cell signaling (PubMed:28892079, PubMed:39587083) (Microbial infection) The heterotrimeric retriever complex, in collaboration with the CCC complex, mediates the exit of human papillomavirus to the cell surface","subcellular_location":"Endosome","url":"https://www.uniprot.org/uniprotkb/O14972/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS26C","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC22","stoichiometry":10.0},{"gene":"CCDC93","stoichiometry":10.0},{"gene":"COMMD1","stoichiometry":10.0},{"gene":"COMMD2","stoichiometry":10.0},{"gene":"COMMD4","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/VPS26C","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"607238","title":"COMM DOMAIN-CONTAINING PROTEIN 1; COMMD1","url":"https://www.omim.org/entry/607238"},{"mim_id":"606932","title":"VPS29 RETROMER COMPLEX COMPONENT; VPS29","url":"https://www.omim.org/entry/606932"},{"mim_id":"605963","title":"SORTING NEXIN 17; SNX17","url":"https://www.omim.org/entry/605963"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS26C"},"hgnc":{"alias_symbol":["DCRA"],"prev_symbol":["DSCR3"]},"alphafold":{"accession":"O14972","domains":[{"cath_id":"2.60.40.640","chopping":"5-142","consensus_level":"high","plddt":91.9983,"start":5,"end":142},{"cath_id":"2.60.40.640","chopping":"154-296","consensus_level":"high","plddt":94.7905,"start":154,"end":296}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14972","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14972-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14972-F1-predicted_aligned_error_v6.png","plddt_mean":92.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS26C","jax_strain_url":"https://www.jax.org/strain/search?query=VPS26C"},"sequence":{"accession":"O14972","fasta_url":"https://rest.uniprot.org/uniprotkb/O14972.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14972/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14972"}},"corpus_meta":[{"pmid":"8288528","id":"PMC_8288528","title":"DcrA, a c-type heme-containing methyl-accepting protein from Desulfovibrio vulgaris Hildenborough, senses the oxygen concentration or redox potential of the environment.","date":"1994","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8288528","citation_count":65,"is_preprint":false},{"pmid":"9202456","id":"PMC_9202456","title":"Targeted gene-replacement mutagenesis of dcrA, encoding an oxygen sensor of the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough.","date":"1997","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9202456","citation_count":43,"is_preprint":false},{"pmid":"1548224","id":"PMC_1548224","title":"Nucleotide sequence of dcrA, a Desulfovibrio vulgaris Hildenborough chemoreceptor gene, and its expression in Escherichia coli.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1548224","citation_count":24,"is_preprint":false},{"pmid":"16285745","id":"PMC_16285745","title":"Biophysical properties of a c-type heme in chemotaxis signal transducer protein DcrA.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16285745","citation_count":20,"is_preprint":false},{"pmid":"12558182","id":"PMC_12558182","title":"DcrA and dcrB Escherichia coli genes can control DNA injection by phages specific for BtuB and FhuA receptors.","date":"2002","source":"Research in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12558182","citation_count":19,"is_preprint":false},{"pmid":"15629915","id":"PMC_15629915","title":"Identification of Chlamydia trachomatis genomic sequences recognized by chlamydial divalent cation-dependent regulator A (DcrA).","date":"2005","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/15629915","citation_count":17,"is_preprint":false},{"pmid":"36353989","id":"PMC_36353989","title":"Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.","date":"2022","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36353989","citation_count":14,"is_preprint":false},{"pmid":"8060126","id":"PMC_8060126","title":"Membrane topology of the methyl-accepting chemotaxis protein DcrA from Desulfovibrio vulgaris Hildenborough.","date":"1994","source":"Antonie van Leeuwenhoek","url":"https://pubmed.ncbi.nlm.nih.gov/8060126","citation_count":8,"is_preprint":false},{"pmid":"35187626","id":"PMC_35187626","title":"Recycling of SLC38A1 to the plasma membrane by DSCR3 promotes acquired temozolomide resistance in glioblastoma.","date":"2022","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35187626","citation_count":7,"is_preprint":false},{"pmid":"31845315","id":"PMC_31845315","title":"VPS26C homozygous nonsense variant in two cousins with neurodevelopmental deficits, growth failure, skeletal abnormalities, and distinctive facial features.","date":"2019","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31845315","citation_count":5,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.29.605694","title":"Deciphering Reductive Dehalogenase Specificity Through Targeted Mutagenesis of Chloroalkane Reductases","date":"2024-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.29.605694","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7369,"output_tokens":881,"usd":0.017661,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7352,"output_tokens":1734,"usd":0.040055,"stage2_stop_reason":"end_turn"},"total_usd":0.057716,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS26C (DSCR3) directly binds internalized SLC38A1 and mediates its sorting into the recycling pathway, maintaining SLC38A1 abundance on the plasma membrane and enhancing glutamine uptake in glioblastoma cells; this recycling activity promotes acquired temozolomide resistance.\",\n      \"method\": \"Co-immunoprecipitation, label-free quantitative proteomics of plasma membrane fractions, immunofluorescence, and in vitro silencing/rescue experiments in MGMT-deficient GBM cells and orthotopic mouse model\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed by proteomics and in vitro experiments with functional readout, single lab\",\n      \"pmids\": [\"35187626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VPS26C, as a subunit of the Retriever complex (with VPS35L and VPS29), selectively mediates endosomal recycling of LRP1 (but not LDLR) to the hepatocyte cell surface; liver-specific VPS26C ablation in mice delayed postprandial triglyceride clearance and increased plasma triglycerides, while VPS35L (shared between Retriever and CCC) is required for both LDLR and LRP1 surface expression.\",\n      \"method\": \"Somatic CRISPR/Cas9 liver-specific knockout in mice, surface protein quantification, plasma lipid measurements, Western blotting of CCC and Retriever subunit composition, VPS26C-deficient hepatoma cell experiments\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR KO with defined metabolic phenotype, complemented by cell-based mechanistic experiments, multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"36353989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous loss-of-function nonsense variant (p.Glu60*) in VPS26C, a member of the Retriever endosomal recycling complex, causes significantly reduced transcript levels and is associated with a syndrome of neurodevelopmental deficits, growth failure, and skeletal abnormalities in humans, supporting an essential biological role for VPS26C.\",\n      \"method\": \"Genome sequencing, expression studies (transcript quantification), co-segregation analysis in two affected cousins\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — human genetic variant with expression data, no direct mechanistic reconstitution; single family, no functional rescue\",\n      \"pmids\": [\"31845315\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS26C (also known as DSCR3) is a subunit of the Retriever endosomal recycling complex that selectively recycles cargo proteins—such as LRP1 in hepatocytes and SLC38A1 in glioblastoma cells—from endosomes back to the plasma membrane, and loss of VPS26C impairs lipoprotein clearance and alters cellular metabolite uptake.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS26C is a subunit of the Retriever endosomal recycling complex that, together with VPS35L and VPS29, selectively returns internalized transmembrane cargo from endosomes to the plasma membrane [#1]. In hepatocytes, VPS26C-dependent Retriever activity specifically recycles LRP1—but not LDLR—to the cell surface, and liver-specific VPS26C ablation in mice delays postprandial triglyceride clearance and raises plasma triglycerides, defining a role in lipoprotein metabolism [#1]. The complex acts with cargo selectivity that distinguishes it from the shared CCC-associated subunit VPS35L, which is required for surface expression of both LRP1 and LDLR [#1]. VPS26C extends this recycling function to other cargo: it directly binds internalized SLC38A1 and sorts it into the recycling pathway, sustaining surface SLC38A1 levels, enhancing glutamine uptake, and promoting temozolomide resistance in glioblastoma cells [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing whether VPS26C is biologically essential in humans, a homozygous loss-of-function variant was linked to a multisystem developmental disorder, implicating Retriever-mediated recycling in normal growth and neurodevelopment.\",\n      \"evidence\": \"Genome sequencing, transcript quantification, and co-segregation in two affected cousins\",\n      \"pmids\": [\"31845315\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single family with no functional rescue; causation not mechanistically demonstrated\",\n        \"No molecular cargo or pathway connected to the clinical phenotype\",\n        \"Tissue-level mechanism underlying skeletal and neurodevelopmental defects unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a specific cargo of VPS26C, the protein was shown to directly bind internalized SLC38A1 and route it back to the surface, defining VPS26C as a determinant of nutrient transporter abundance and a driver of glutamine-fueled drug resistance.\",\n      \"evidence\": \"Co-IP, plasma-membrane proteomics, immunofluorescence, and silencing/rescue in MGMT-deficient GBM cells plus orthotopic mouse model\",\n      \"pmids\": [\"35187626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; binding interface and sorting signal on SLC38A1 not mapped\",\n        \"Whether recycling requires the full Retriever complex in this context not tested\",\n        \"Generality beyond glioblastoma not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placing VPS26C within the Retriever complex in vivo, liver-specific knockout demonstrated cargo-selective recycling of LRP1 and a defined metabolic phenotype, distinguishing Retriever-specific from CCC-shared subunit functions.\",\n      \"evidence\": \"Somatic CRISPR/Cas9 liver-specific KO in mice, surface protein quantification, plasma lipid measurements, and VPS26C-deficient hepatoma cell experiments\",\n      \"pmids\": [\"36353989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for LRP1 versus LDLR cargo selectivity not resolved\",\n        \"Recognition motif on LRP1 that VPS26C reads not identified\",\n        \"Full spectrum of VPS26C-dependent cargo across tissues unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS26C selects its diverse cargo (LRP1, SLC38A1) and the structural rules governing Retriever cargo specificity remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of VPS26C cargo recognition\",\n        \"Mechanism of endosomal recruitment of the Retriever complex via VPS26C unresolved\",\n        \"Link between molecular cargo handling and the human disease phenotype not 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:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"Retriever\"],\n    \"partners\": [\"VPS35L\", \"VPS29\", \"LRP1\", \"SLC38A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}