{"gene":"RMC1","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2017,"finding":"C18orf8/RMC1 was identified as a new subunit of the CCZ1-MON1 RAB7 guanine exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes/autophagosomes, thereby promoting autophagic flux.","method":"Interaction proteomics (AP-MS) of proteins accumulating in GABARAP/L1/L2-deficient cells, combined with genetic loss-of-function and quantitative proteomics of autophagosome content","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — interaction proteomics with functional validation (RAB7 recruitment assay, flux measurements) in a single lab using multiple orthogonal methods","pmids":["29038162"],"is_preprint":false},{"year":2025,"finding":"RMC1/Bulli functions as a mediator of membrane recruitment for the metazoan Mon1-Ccz1-RMC1 trimeric complex; protein-lipid interaction studies showed the third subunit RMC1 enables membrane binding through electrostatic interactions via a distinct interface compared to the dimeric fungal Mon1-Ccz1 complex.","method":"Structural comparison (cryo-EM/structural biology implied), protein-lipid interaction studies, and reconstitution experiments comparing dimeric (fungal) vs. trimeric (metazoan) complexes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — reconstitution and protein-lipid interaction studies in a single preprint lab; not yet peer-reviewed","pmids":["bio_10.1101_2025.03.27.645700"],"is_preprint":true}],"current_model":"RMC1 (C18orf8/WDR98) is a subunit of the metazoan CCZ1-MON1 RAB7 guanine nucleotide exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes and autophagosomes to promote autophagic flux, and additionally serves as a membrane-recruitment mediator for the trimeric complex through electrostatic protein-lipid interactions."},"narrative":{"mechanistic_narrative":"RMC1 (C18orf8/WDR98) is a subunit of the metazoan CCZ1-MON1 RAB7 guanine nucleotide exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes and autophagosomes, thereby promoting autophagic flux [PMID:29038162]. Within this trimeric Mon1-Ccz1-RMC1 complex, RMC1 acts as a membrane-recruitment mediator, enabling complex association with membranes through electrostatic protein-lipid interactions via an interface distinct from that of the dimeric fungal Mon1-Ccz1 complex [PMID:bio_10.1101_2025.03.27.645700]. Beyond its role as a positive regulator of RAB7 GEF activity and membrane engagement of the GEF complex, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2017,"claim":"Before this work the metazoan RAB7 GEF was thought to be a Mon1-Ccz1 dimer; identifying RMC1 as a third subunit established a previously unrecognized component coupling RAB7 activation to autophagic flux.","evidence":"Interaction proteomics (AP-MS) in GABARAP-family-deficient cells with genetic loss-of-function and quantitative autophagosome proteomics","pmids":["29038162"],"confidence":"High","gaps":["Did not define the structural interface between RMC1 and Mon1-Ccz1","Mechanism by which RMC1 promotes RAB7 recruitment at the molecular level was not resolved","Did not establish how the complex is targeted to specific membranes"]},{"year":2025,"claim":"It was unknown why metazoans require a third subunit absent from fungal Mon1-Ccz1; reconstitution and protein-lipid studies showed RMC1 confers membrane binding through electrostatic interactions, defining its functional contribution to the trimer.","evidence":"Structural comparison, protein-lipid interaction assays, and reconstitution of dimeric (fungal) versus trimeric (metazoan) complexes (preprint)","pmids":["bio_10.1101_2025.03.27.645700"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Precise lipid specificity and residues mediating the electrostatic interface not fully defined","Whether membrane recruitment is regulated in cells is not addressed"]},{"year":null,"claim":"How RMC1-mediated membrane recruitment is spatially and temporally regulated to coordinate RAB7 activation at endosomes versus autophagosomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No regulatory inputs controlling RMC1 membrane engagement identified","No high-resolution structure of the membrane-bound trimer in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]}],"complexes":["MON1-CCZ1-RMC1 RAB7 GEF complex"],"partners":["MON1","CCZ1","RAB7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DM3","full_name":"Regulator of MON1-CCZ1 complex","aliases":["Colon cancer-associated protein Mic1","Mic-1","WD repeat-containing protein 98"],"length_aa":657,"mass_kda":75.0,"function":"Component of the CCZ1-MON1 RAB7A guanine exchange factor (GEF). Acts as a positive regulator of CCZ1-MON1A/B function necessary for endosomal/autophagic flux and efficient RAB7A localization (PubMed:29038162)","subcellular_location":"Lysosome membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96DM3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RMC1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCZ1B","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/RMC1","total_profiled":1310},"omim":[{"mim_id":"620267","title":"REGULATOR OF MON1-CCZ1; RMC1","url":"https://www.omim.org/entry/620267"},{"mim_id":"605237","title":"XENOTROPIC AND POLYTROPIC RETROVIRUS RECEPTOR; XPR1","url":"https://www.omim.org/entry/605237"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RMC1"},"hgnc":{"alias_symbol":["MIC1","HsT2591"],"prev_symbol":["C18orf8","WDR98"]},"alphafold":{"accession":"Q96DM3","domains":[{"cath_id":"-","chopping":"2-15_210-317_331-364","consensus_level":"medium","plddt":90.1058,"start":2,"end":364},{"cath_id":"2.130.10.10","chopping":"19-150","consensus_level":"medium","plddt":89.6399,"start":19,"end":150},{"cath_id":"1.25.40","chopping":"562-657","consensus_level":"medium","plddt":85.9728,"start":562,"end":657}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DM3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DM3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DM3-F1-predicted_aligned_error_v6.png","plddt_mean":88.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RMC1","jax_strain_url":"https://www.jax.org/strain/search?query=RMC1"},"sequence":{"accession":"Q96DM3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DM3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DM3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DM3"}},"corpus_meta":[{"pmid":"9988277","id":"PMC_9988277","title":"Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmc1.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9988277","citation_count":128,"is_preprint":false},{"pmid":"29038162","id":"PMC_29038162","title":"Systematic Analysis of Human Cells Lacking ATG8 Proteins Uncovers Roles for GABARAPs and the CCZ1/MON1 Regulator C18orf8/RMC1 in Macroautophagic and Selective Autophagic Flux.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29038162","citation_count":105,"is_preprint":false},{"pmid":"21832250","id":"PMC_21832250","title":"Purinergic regulation of high-glucose-induced caspase-1 activation in the rat retinal Müller cell line rMC-1.","date":"2011","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21832250","citation_count":47,"is_preprint":false},{"pmid":"2011795","id":"PMC_2011795","title":"Isolation and characterization of irradiation fusion hybrids from mouse chromosome 1 for mapping Rmc-1, a gene encoding a cellular receptor for MCF class murine retroviruses.","date":"1991","source":"Somatic cell and molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2011795","citation_count":19,"is_preprint":false},{"pmid":"25183762","id":"PMC_25183762","title":"Interphotoreceptor retinoid-binding protein (IRBP) promotes retinol uptake and release by rat Müller cells (rMC-1) in vitro: implications for the cone visual cycle.","date":"2014","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/25183762","citation_count":13,"is_preprint":false},{"pmid":"25352752","id":"PMC_25352752","title":"Serine 307 on insulin receptor substrate 1 is required for SOCS3 and TNF-α signaling in the rMC-1 cell line.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/25352752","citation_count":12,"is_preprint":false},{"pmid":"19890481","id":"PMC_19890481","title":"Characterization of Calcium-Mediated Intracellular and Intercellular Signaling in the rMC-1 Glial Cell Line.","date":"2009","source":"Cellular and molecular bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/19890481","citation_count":12,"is_preprint":false},{"pmid":"32485834","id":"PMC_32485834","title":"VEGF Upregulates EGFR Expression to Stimulate Chemotactic Behaviors in the rMC-1 Model of Müller Glia.","date":"2020","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32485834","citation_count":11,"is_preprint":false},{"pmid":"37511330","id":"PMC_37511330","title":"Construction, Expression, and Evaluation of the Naturally Acquired Humoral Immune Response against Plasmodium vivax RMC-1, a Multistage Chimeric Protein.","date":"2023","source":"International journal of molecular 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41024157","citation_count":0,"is_preprint":false},{"pmid":"31372389","id":"PMC_31372389","title":"RNA sequencing data of cultured primary rat Müller cells, the spontaneously immortalized rat Müller cell line, SIRMu-1, and the SV40-transformed rat Müller cell line, rMC-1.","date":"2019","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/31372389","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.27.645700","title":"Mechanistic Plasticity of the RabGEFs Mon1-Ccz1 and Fuzzy-Inturned","date":"2025-03-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.27.645700","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.24.25324577","title":"Investigating the shared genetic architecture between type 2 diabetes and stroke","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.25324577","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9617,"output_tokens":623,"usd":0.019098,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6969,"output_tokens":1342,"usd":0.034197,"stage2_stop_reason":"end_turn"},"total_usd":0.053295,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"C18orf8/RMC1 was identified as a new subunit of the CCZ1-MON1 RAB7 guanine exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes/autophagosomes, thereby promoting autophagic flux.\",\n      \"method\": \"Interaction proteomics (AP-MS) of proteins accumulating in GABARAP/L1/L2-deficient cells, combined with genetic loss-of-function and quantitative proteomics of autophagosome content\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction proteomics with functional validation (RAB7 recruitment assay, flux measurements) in a single lab using multiple orthogonal methods\",\n      \"pmids\": [\"29038162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RMC1/Bulli functions as a mediator of membrane recruitment for the metazoan Mon1-Ccz1-RMC1 trimeric complex; protein-lipid interaction studies showed the third subunit RMC1 enables membrane binding through electrostatic interactions via a distinct interface compared to the dimeric fungal Mon1-Ccz1 complex.\",\n      \"method\": \"Structural comparison (cryo-EM/structural biology implied), protein-lipid interaction studies, and reconstitution experiments comparing dimeric (fungal) vs. trimeric (metazoan) complexes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — reconstitution and protein-lipid interaction studies in a single preprint lab; not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.27.645700\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RMC1 (C18orf8/WDR98) is a subunit of the metazoan CCZ1-MON1 RAB7 guanine nucleotide exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes and autophagosomes to promote autophagic flux, and additionally serves as a membrane-recruitment mediator for the trimeric complex through electrostatic protein-lipid interactions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RMC1 (C18orf8/WDR98) is a subunit of the metazoan CCZ1-MON1 RAB7 guanine nucleotide exchange factor (GEF) complex that positively regulates RAB7 recruitment to late endosomes and autophagosomes, thereby promoting autophagic flux [#0]. Within this trimeric Mon1-Ccz1-RMC1 complex, RMC1 acts as a membrane-recruitment mediator, enabling complex association with membranes through electrostatic protein-lipid interactions via an interface distinct from that of the dimeric fungal Mon1-Ccz1 complex [#1]. Beyond its role as a positive regulator of RAB7 GEF activity and membrane engagement of the GEF complex, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Before this work the metazoan RAB7 GEF was thought to be a Mon1-Ccz1 dimer; identifying RMC1 as a third subunit established a previously unrecognized component coupling RAB7 activation to autophagic flux.\",\n      \"evidence\": \"Interaction proteomics (AP-MS) in GABARAP-family-deficient cells with genetic loss-of-function and quantitative autophagosome proteomics\",\n      \"pmids\": [\"29038162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not define the structural interface between RMC1 and Mon1-Ccz1\",\n        \"Mechanism by which RMC1 promotes RAB7 recruitment at the molecular level was not resolved\",\n        \"Did not establish how the complex is targeted to specific membranes\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unknown why metazoans require a third subunit absent from fungal Mon1-Ccz1; reconstitution and protein-lipid studies showed RMC1 confers membrane binding through electrostatic interactions, defining its functional contribution to the trimer.\",\n      \"evidence\": \"Structural comparison, protein-lipid interaction assays, and reconstitution of dimeric (fungal) versus trimeric (metazoan) complexes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.27.645700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Precise lipid specificity and residues mediating the electrostatic interface not fully defined\",\n        \"Whether membrane recruitment is regulated in cells is not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RMC1-mediated membrane recruitment is spatially and temporally regulated to coordinate RAB7 activation at endosomes versus autophagosomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No regulatory inputs controlling RMC1 membrane engagement identified\",\n        \"No high-resolution structure of the membrane-bound trimer in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"MON1-CCZ1-RMC1 RAB7 GEF complex\"],\n    \"partners\": [\"MON1\", \"CCZ1\", \"RAB7\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":1,"faith_total":1,"faith_pct":100.0}}