{"gene":"RUNDC1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2023,"finding":"RUNDC1 was identified as a novel ATG14-interacting protein that negatively regulates autophagy by blocking autophagosome-lysosome fusion. Mechanistically, RUNDC1 clasps the ATG14-STX17-SNAP29 complex by stimulating ATG14 homo-oligomerization, which inhibits ATG14 dissociation and prevents VAMP8 from binding to the STX17-SNAP29 complex, thereby blocking assembly of the fusogenic STX17-SNAP29-VAMP8 SNARE complex.","method":"Co-immunoprecipitation, gain- and loss-of-function studies in human cells and zebrafish model, in vitro liposome fusion assay, in vitro autophagosome-lysosome fusion assay","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including in vitro reconstitution assays, reciprocal co-IP, mutagenesis (Ser379 phosphorylation), and in vivo zebrafish model; replicated/summarized in a follow-up Autophagy paper","pmids":["37684417","37876308"],"is_preprint":false},{"year":2023,"finding":"Phosphorylation of RUNDC1 at Ser379 is crucial for inhibiting the assembly of the STX17-SNAP29-VAMP8 SNARE complex by promoting ATG14 homo-oligomerization.","method":"Site-directed mutagenesis of Ser379, functional assays measuring SNARE complex assembly and autophagosome-lysosome fusion","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis with functional readout in a single lab; phosphorylation writer/eraser not identified","pmids":["37684417"],"is_preprint":false},{"year":2023,"finding":"RUNDC1 colocalizes with LC3 and associates with mature autophagosomes in cell lines and the zebrafish model, placing it at the autophagosome compartment prior to lysosome fusion.","method":"Fluorescence colocalization imaging (LC3 marker), subcellular fractionation/localization in cell lines and zebrafish","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiment with functional consequence (autophagy inhibition), single lab, confirmed in two model systems","pmids":["37876308"],"is_preprint":false},{"year":2006,"finding":"RNAi-mediated knockdown of RUNDC1 upregulated p53 transcriptional activity, while overexpression of RUNDC1 inhibited p53 target promoters and p53-mediated apoptosis, identifying RUNDC1 as a negative regulator of p53 transcriptional activity.","method":"High-throughput RNA interference screen, reporter assay for p53 transcriptional activity, overexpression with apoptosis readout","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RNAi screen with limited follow-up, no molecular mechanism identified for RUNDC1-p53 interaction","pmids":["16929179"],"is_preprint":false}],"current_model":"RUNDC1 (RUN domain containing 1) is a negative regulator of autophagy that localizes to mature autophagosomes and blocks autophagosome-lysosome fusion by interacting with ATG14 and clasping the ATG14-STX17-SNAP29 complex through stimulation of ATG14 homo-oligomerization, thereby preventing VAMP8 recruitment and SNARE complex assembly; phosphorylation of RUNDC1 at Ser379 is critical for this inhibitory mechanism, and RUNDC1 has additionally been identified as a negative regulator of p53 transcriptional activity in an RNAi screen."},"narrative":{"mechanistic_narrative":"RUNDC1 is a negative regulator of autophagy that acts at the terminal autophagosome-lysosome fusion step [PMID:37684417, PMID:37876308]. It localizes to mature autophagosomes, colocalizing with LC3 in both human cell lines and zebrafish, positioning it at the fusion-competent compartment prior to lysosome engagement [PMID:37876308]. Mechanistically, RUNDC1 interacts with ATG14 and stimulates ATG14 homo-oligomerization, clasping the ATG14-STX17-SNAP29 complex; this prevents ATG14 dissociation and blocks VAMP8 from binding the STX17-SNAP29 complex, thereby preventing assembly of the fusogenic STX17-SNAP29-VAMP8 SNARE complex [PMID:37684417, PMID:37876308]. Phosphorylation of RUNDC1 at Ser379 is required for this inhibitory activity [PMID:37684417]. An earlier RNAi screen additionally identified RUNDC1 as a negative regulator of p53 transcriptional activity and p53-mediated apoptosis, but no molecular mechanism for this link has been characterized in the available corpus [PMID:16929179].","teleology":[{"year":2006,"claim":"Before any mechanistic role was known, a functional screen asked whether RUNDC1 influences stress-response transcription, establishing it as a negative regulator of p53 transcriptional output.","evidence":"High-throughput RNAi screen with p53 reporter and overexpression apoptosis readout in human cells","pmids":["16929179"],"confidence":"Low","gaps":["Single lab RNAi screen with no molecular mechanism identified for the RUNDC1-p53 link","No direct physical interaction or pathway intermediate defined","Not connected to the later-defined autophagy function"]},{"year":2023,"claim":"The core question of RUNDC1's molecular function was answered by identifying it as an ATG14 interactor that blocks autophagosome-lysosome fusion, defining the SNARE-clasping mechanism.","evidence":"Reciprocal co-IP, gain/loss-of-function in human cells and zebrafish, in vitro liposome and autophagosome-lysosome fusion reconstitution assays","pmids":["37684417","37876308"],"confidence":"High","gaps":["Upstream signals controlling RUNDC1 engagement of ATG14 not defined","Structural basis of the ATG14 homo-oligomerization clasp unresolved"]},{"year":2023,"claim":"How RUNDC1 inhibitory activity is regulated was partially addressed by showing Ser379 phosphorylation is required to drive ATG14 homo-oligomerization and SNARE blockade.","evidence":"Site-directed mutagenesis of Ser379 with SNARE-assembly and fusion functional readouts","pmids":["37684417"],"confidence":"Medium","gaps":["The kinase (writer) and phosphatase (eraser) acting on Ser379 are not identified","Conditions triggering Ser379 phosphorylation are unknown"]},{"year":2023,"claim":"Where RUNDC1 acts within the autophagy pathway was established by localizing it to mature LC3-positive autophagosomes prior to lysosome fusion.","evidence":"LC3 colocalization imaging and subcellular localization in cell lines and zebrafish","pmids":["37876308"],"confidence":"Medium","gaps":["Mechanism of recruitment to the autophagosome membrane not defined","Whether localization depends on Ser379 phosphorylation or ATG14 binding untested"]},{"year":null,"claim":"Whether the autophagy regulatory function and the p53 regulatory function reflect a single unified mechanism or two independent activities remains unresolved.","evidence":"No timeline finding connects the SNARE-clasping autophagy role to the p53 transcriptional phenotype","pmids":[],"confidence":"Low","gaps":["No molecular bridge between RUNDC1 autophagy function and p53 regulation","Identity of the Ser379 kinase remains unknown","No structural model of the RUNDC1-ATG14 interaction"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["ATG14","STX17","SNAP29","VAMP8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96C34","full_name":"RUN domain-containing protein 1","aliases":[],"length_aa":613,"mass_kda":67.6,"function":"May play a role as p53/TP53 inhibitor and thus may have oncogenic activity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96C34/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RUNDC1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RUNDC1","total_profiled":1310},"omim":[{"mim_id":"619250","title":"RUN DOMAIN-CONTAINING PROTEIN 1; RUNDC1","url":"https://www.omim.org/entry/619250"},{"mim_id":"619249","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 186; CCDC186","url":"https://www.omim.org/entry/619249"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RUNDC1"},"hgnc":{"alias_symbol":["DKFZp761H0421"],"prev_symbol":[]},"alphafold":{"accession":"Q96C34","domains":[{"cath_id":"-","chopping":"100-132_179-208","consensus_level":"medium","plddt":82.5125,"start":100,"end":208},{"cath_id":"1.20.58.900","chopping":"382-400_417-447_456-613","consensus_level":"high","plddt":83.564,"start":382,"end":613}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96C34","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96C34-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96C34-F1-predicted_aligned_error_v6.png","plddt_mean":70.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RUNDC1","jax_strain_url":"https://www.jax.org/strain/search?query=RUNDC1"},"sequence":{"accession":"Q96C34","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96C34.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96C34/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96C34"}},"corpus_meta":[{"pmid":"16929179","id":"PMC_16929179","title":"A high-throughput loss-of-function screening identifies novel p53 regulators.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16929179","citation_count":54,"is_preprint":false},{"pmid":"25652157","id":"PMC_25652157","title":"Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25652157","citation_count":22,"is_preprint":false},{"pmid":"37684417","id":"PMC_37684417","title":"RUNDC1 inhibits autolysosome formation and survival of zebrafish via clasping ATG14-STX17-SNAP29 complex.","date":"2023","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/37684417","citation_count":19,"is_preprint":false},{"pmid":"38689208","id":"PMC_38689208","title":"Cis-eQTLs in seven duck tissues identify novel candidate genes for growth and carcass traits.","date":"2024","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38689208","citation_count":6,"is_preprint":false},{"pmid":"37876308","id":"PMC_37876308","title":"RUNDC1 negatively mediates the fusion of autophagosomes with lysosomes via regulating SNARE complex assembly.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37876308","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4259,"output_tokens":1118,"usd":0.014774,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7687,"output_tokens":1794,"usd":0.041642,"stage2_stop_reason":"end_turn"},"total_usd":0.056416,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"RUNDC1 was identified as a novel ATG14-interacting protein that negatively regulates autophagy by blocking autophagosome-lysosome fusion. Mechanistically, RUNDC1 clasps the ATG14-STX17-SNAP29 complex by stimulating ATG14 homo-oligomerization, which inhibits ATG14 dissociation and prevents VAMP8 from binding to the STX17-SNAP29 complex, thereby blocking assembly of the fusogenic STX17-SNAP29-VAMP8 SNARE complex.\",\n      \"method\": \"Co-immunoprecipitation, gain- and loss-of-function studies in human cells and zebrafish model, in vitro liposome fusion assay, in vitro autophagosome-lysosome fusion assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including in vitro reconstitution assays, reciprocal co-IP, mutagenesis (Ser379 phosphorylation), and in vivo zebrafish model; replicated/summarized in a follow-up Autophagy paper\",\n      \"pmids\": [\"37684417\", \"37876308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Phosphorylation of RUNDC1 at Ser379 is crucial for inhibiting the assembly of the STX17-SNAP29-VAMP8 SNARE complex by promoting ATG14 homo-oligomerization.\",\n      \"method\": \"Site-directed mutagenesis of Ser379, functional assays measuring SNARE complex assembly and autophagosome-lysosome fusion\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis with functional readout in a single lab; phosphorylation writer/eraser not identified\",\n      \"pmids\": [\"37684417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RUNDC1 colocalizes with LC3 and associates with mature autophagosomes in cell lines and the zebrafish model, placing it at the autophagosome compartment prior to lysosome fusion.\",\n      \"method\": \"Fluorescence colocalization imaging (LC3 marker), subcellular fractionation/localization in cell lines and zebrafish\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiment with functional consequence (autophagy inhibition), single lab, confirmed in two model systems\",\n      \"pmids\": [\"37876308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RNAi-mediated knockdown of RUNDC1 upregulated p53 transcriptional activity, while overexpression of RUNDC1 inhibited p53 target promoters and p53-mediated apoptosis, identifying RUNDC1 as a negative regulator of p53 transcriptional activity.\",\n      \"method\": \"High-throughput RNA interference screen, reporter assay for p53 transcriptional activity, overexpression with apoptosis readout\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RNAi screen with limited follow-up, no molecular mechanism identified for RUNDC1-p53 interaction\",\n      \"pmids\": [\"16929179\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RUNDC1 (RUN domain containing 1) is a negative regulator of autophagy that localizes to mature autophagosomes and blocks autophagosome-lysosome fusion by interacting with ATG14 and clasping the ATG14-STX17-SNAP29 complex through stimulation of ATG14 homo-oligomerization, thereby preventing VAMP8 recruitment and SNARE complex assembly; phosphorylation of RUNDC1 at Ser379 is critical for this inhibitory mechanism, and RUNDC1 has additionally been identified as a negative regulator of p53 transcriptional activity in an RNAi screen.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RUNDC1 is a negative regulator of autophagy that acts at the terminal autophagosome-lysosome fusion step [#0]. It localizes to mature autophagosomes, colocalizing with LC3 in both human cell lines and zebrafish, positioning it at the fusion-competent compartment prior to lysosome engagement [#2]. Mechanistically, RUNDC1 interacts with ATG14 and stimulates ATG14 homo-oligomerization, clasping the ATG14-STX17-SNAP29 complex; this prevents ATG14 dissociation and blocks VAMP8 from binding the STX17-SNAP29 complex, thereby preventing assembly of the fusogenic STX17-SNAP29-VAMP8 SNARE complex [#0]. Phosphorylation of RUNDC1 at Ser379 is required for this inhibitory activity [#1]. An earlier RNAi screen additionally identified RUNDC1 as a negative regulator of p53 transcriptional activity and p53-mediated apoptosis, but no molecular mechanism for this link has been characterized in the available corpus [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Before any mechanistic role was known, a functional screen asked whether RUNDC1 influences stress-response transcription, establishing it as a negative regulator of p53 transcriptional output.\",\n      \"evidence\": \"High-throughput RNAi screen with p53 reporter and overexpression apoptosis readout in human cells\",\n      \"pmids\": [\"16929179\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single lab RNAi screen with no molecular mechanism identified for the RUNDC1-p53 link\",\n        \"No direct physical interaction or pathway intermediate defined\",\n        \"Not connected to the later-defined autophagy function\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The core question of RUNDC1's molecular function was answered by identifying it as an ATG14 interactor that blocks autophagosome-lysosome fusion, defining the SNARE-clasping mechanism.\",\n      \"evidence\": \"Reciprocal co-IP, gain/loss-of-function in human cells and zebrafish, in vitro liposome and autophagosome-lysosome fusion reconstitution assays\",\n      \"pmids\": [\"37684417\", \"37876308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals controlling RUNDC1 engagement of ATG14 not defined\",\n        \"Structural basis of the ATG14 homo-oligomerization clasp unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How RUNDC1 inhibitory activity is regulated was partially addressed by showing Ser379 phosphorylation is required to drive ATG14 homo-oligomerization and SNARE blockade.\",\n      \"evidence\": \"Site-directed mutagenesis of Ser379 with SNARE-assembly and fusion functional readouts\",\n      \"pmids\": [\"37684417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The kinase (writer) and phosphatase (eraser) acting on Ser379 are not identified\",\n        \"Conditions triggering Ser379 phosphorylation are unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Where RUNDC1 acts within the autophagy pathway was established by localizing it to mature LC3-positive autophagosomes prior to lysosome fusion.\",\n      \"evidence\": \"LC3 colocalization imaging and subcellular localization in cell lines and zebrafish\",\n      \"pmids\": [\"37876308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of recruitment to the autophagosome membrane not defined\",\n        \"Whether localization depends on Ser379 phosphorylation or ATG14 binding untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the autophagy regulatory function and the p53 regulatory function reflect a single unified mechanism or two independent activities remains unresolved.\",\n      \"evidence\": \"No timeline finding connects the SNARE-clasping autophagy role to the p53 transcriptional phenotype\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No molecular bridge between RUNDC1 autophagy function and p53 regulation\",\n        \"Identity of the Ser379 kinase remains unknown\",\n        \"No structural model of the RUNDC1-ATG14 interaction\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ATG14\", \"STX17\", \"SNAP29\", \"VAMP8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}