{"gene":"TMED1","run_date":"2026-06-11T17:50:40","timeline":{"discoveries":[{"year":2013,"finding":"TMED1 associates with the IL-1R family member ST2L (IL-33 receptor); this interaction is mediated by the GOLD domain of TMED1 and the TIR domain of ST2L. TMED1 is required for optimal IL-33-induced IL-8 and IL-6 production.","method":"Co-immunoprecipitation with deletion/mutation constructs; cytokine production assays (loss-of-function)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal domain-mapping with deletion/mutation constructs and functional cytokine readout, single lab","pmids":["23319592"],"is_preprint":false},{"year":2020,"finding":"TMED1 co-assembles with RNF26 (an ER-embedded ubiquitin ligase), TMEM43, ENDOD1, and TMEM33 to form a complex at the ER membrane that modulates innate immune signalling through the cGAS-STING pathway.","method":"Comparative proteomic workflow (interaction mapping of ER ubiquitin ligases); functional innate immune signalling assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interaction mapping with functional STING pathway readout, single study","pmids":["32614325"],"is_preprint":false},{"year":2021,"finding":"The GOLD domain of TMED1 forms homodimers in solution in a salt-dependent manner, independent of the coiled-coil region; the first high-resolution crystal structure of the TMED1 GOLD domain was determined, revealing residues important for oligomerization.","method":"X-ray crystallography; biophysical characterization in solution (SEC, analytical ultracentrifugation or similar); molecular dynamics simulation","journal":"Biochimie","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus biophysical solution-state characterization, single lab but multiple orthogonal methods","pmids":["34634369"],"is_preprint":false},{"year":2023,"finding":"In C. elegans, the γ-subfamily TMED genes tmed-1 and tmed-3 exhibit genetic redundancy: defects in movement and vulval morphology are only apparent in double mutants, not single mutants. TMED genes also function to facilitate basement membrane breakdown during vulval development.","method":"C. elegans genetic analysis (single and double mutants); phenotypic readouts of embryonic viability, movement, vulval morphology, and basement membrane dynamics","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double-mutant rescue/phenotype in C. elegans, single lab, defined developmental phenotype","pmids":["37204056"],"is_preprint":false}],"current_model":"TMED1 is an ER/Golgi-resident p24 family protein whose GOLD domain mediates homodimerization and interaction with the TIR domain of the IL-33 receptor ST2L to support optimal IL-33 signalling; it also participates in an ER-membrane complex with RNF26, TMEM43, ENDOD1, and TMEM33 that modulates cGAS-STING innate immune signalling, and in C. elegans its γ-subfamily paralogs display genetic redundancy required for basement membrane remodelling during development."},"narrative":{"mechanistic_narrative":"TMED1 is a p24-family secretory pathway protein that functions as an adaptor linking ER/Golgi membrane organization to innate immune signalling [PMID:23319592, PMID:32614325]. Its GOLD domain mediates self-association, forming salt-dependent homodimers independent of the coiled-coil region, and the crystal structure of this domain defines the residues required for oligomerization [PMID:34634369]. Through the same GOLD domain, TMED1 engages the TIR domain of the IL-33 receptor ST2L and is required for optimal IL-33-induced IL-8 and IL-6 production [PMID:23319592]. TMED1 also co-assembles with the ER-embedded ubiquitin ligase RNF26 together with TMEM43, ENDOD1, and TMEM33 in an ER-membrane complex that modulates cGAS-STING innate immune signalling [PMID:32614325]. Evolutionary conservation of function is indicated in C. elegans, where the γ-subfamily paralogs tmed-1 and tmed-3 are genetically redundant and facilitate basement membrane breakdown during vulval development [PMID:37204056]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established that TMED1 is not merely a housekeeping cargo receptor but a specific partner of an immune receptor, defining a role in cytokine signalling.","evidence":"Co-immunoprecipitation with domain deletion/mutation constructs mapping GOLD-TIR contacts, plus loss-of-function cytokine production assays","pmids":["23319592"],"confidence":"Medium","gaps":["Single lab without reciprocal in vivo validation","Stoichiometry and subcellular site of the TMED1-ST2L interaction not resolved","Whether TMED1 traffics ST2L or scaffolds downstream signalling is unaddressed"]},{"year":2020,"claim":"Placed TMED1 within a defined multiprotein ER-membrane complex, extending its immune role from IL-33 to the cGAS-STING axis.","evidence":"Comparative MS-based interaction mapping of ER ubiquitin ligases with functional innate immune signalling readouts","pmids":["32614325"],"confidence":"Medium","gaps":["Single study; direct binary contacts within the RNF26/TMEM43/ENDOD1/TMEM33 complex not dissected","Whether TMED1 is a ubiquitination substrate or a structural subunit is unclear","Mechanism by which the complex modulates STING is not defined"]},{"year":2021,"claim":"Provided the structural basis for TMED1 self-association, showing the GOLD domain alone drives salt-dependent homodimerization.","evidence":"X-ray crystallography of the GOLD domain with solution biophysics and molecular dynamics","pmids":["34634369"],"confidence":"High","gaps":["Functional consequence of homodimerization for ST2L binding or complex assembly not tested","No full-length structure including the coiled-coil or transmembrane regions"]},{"year":2023,"claim":"Demonstrated conserved developmental function via genetic redundancy, linking γ-subfamily TMEDs to basement membrane remodelling.","evidence":"C. elegans single and double mutant genetic analysis with phenotypic readouts of movement, vulval morphology, and basement membrane dynamics","pmids":["37204056"],"confidence":"Medium","gaps":["Redundancy masks single-gene contribution; molecular cargo or mechanism not identified","Relevance to mammalian TMED1 immune functions not established"]},{"year":null,"claim":"How TMED1's structurally defined homodimerization integrates with its two distinct immune complexes (ST2L and the RNF26 ER complex) and its developmental role remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting cargo trafficking, immune signalling, and basement membrane remodelling","No identified cargo substrate for mammalian TMED1","Subcellular dynamics during signalling not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]}],"complexes":["RNF26-TMEM43-ENDOD1-TMEM33 ER-membrane complex"],"partners":["ST2L","RNF26","TMEM43","ENDOD1","TMEM33"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13445","full_name":"Transmembrane emp24 domain-containing protein 1","aliases":["Interleukin-1 receptor-like 1 ligand","Putative T1/ST2 receptor-binding protein","p24 family protein gamma-1","Tp24","p24gamma1"],"length_aa":227,"mass_kda":25.2,"function":"Potential role in vesicular protein trafficking, mainly in the early secretory pathway. May act as a cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and may be involved in vesicle coat formation at the cytoplasmic side. Plays a positive role in IL-33-mediated IL-8 and IL-6 production by interacting with interleukin-33 receptor IL1RL1 (PubMed:23319592). Also plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26 (PubMed:32614325)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane; Golgi apparatus, cis-Golgi network membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane","url":"https://www.uniprot.org/uniprotkb/Q13445/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMED1","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":10.0},{"gene":"TMED2","stoichiometry":10.0},{"gene":"GORASP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMED1","total_profiled":1310},"omim":[{"mim_id":"605395","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 1; TMED1","url":"https://www.omim.org/entry/605395"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMED1"},"hgnc":{"alias_symbol":["ST2L","MGC1270","IL1RL1LG","Il1rl1l","p24gamma1","p24g1"],"prev_symbol":[]},"alphafold":{"accession":"Q13445","domains":[{"cath_id":"2.60.120.680","chopping":"31-179","consensus_level":"medium","plddt":85.25,"start":31,"end":179}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13445","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13445-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13445-F1-predicted_aligned_error_v6.png","plddt_mean":83.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMED1","jax_strain_url":"https://www.jax.org/strain/search?query=TMED1"},"sequence":{"accession":"Q13445","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13445.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13445/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13445"}},"corpus_meta":[{"pmid":"32614325","id":"PMC_32614325","title":"Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32614325","citation_count":71,"is_preprint":false},{"pmid":"23319592","id":"PMC_23319592","title":"The GOLD domain-containing protein TMED1 is involved in interleukin-33 signaling.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23319592","citation_count":40,"is_preprint":false},{"pmid":"24778190","id":"PMC_24778190","title":"The α-helical region in p24γ2 subunit of p24 protein cargo receptor is pivotal for the recognition and transport of glycosylphosphatidylinositol-anchored proteins.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24778190","citation_count":28,"is_preprint":false},{"pmid":"37928880","id":"PMC_37928880","title":"TMED family genes and their roles in human diseases.","date":"2023","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37928880","citation_count":24,"is_preprint":false},{"pmid":"20545785","id":"PMC_20545785","title":"Differential regulation of Toll-like receptor signalling in spleen and Peyer's patch dendritic cells.","date":"2010","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20545785","citation_count":23,"is_preprint":false},{"pmid":"34634369","id":"PMC_34634369","title":"Structural and thermodynamic analyses of human TMED1 (p24γ1) Golgi dynamics.","date":"2021","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/34634369","citation_count":13,"is_preprint":false},{"pmid":"33007975","id":"PMC_33007975","title":"p24G1 Encoded by Grapevine Leafroll-Associated Virus 1 Suppresses RNA Silencing and Elicits Hypersensitive Response-Like Necrosis in Nicotiana Species.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33007975","citation_count":8,"is_preprint":false},{"pmid":"35274021","id":"PMC_35274021","title":"Downregulation of Three Novel miRNAs in the Lymph Nodes of Sheep Immunized With the Brucella suis Strain 2 Vaccine.","date":"2022","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/35274021","citation_count":5,"is_preprint":false},{"pmid":"37204056","id":"PMC_37204056","title":"Genetic characterization of C. elegans TMED genes.","date":"2023","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/37204056","citation_count":3,"is_preprint":false},{"pmid":"35934202","id":"PMC_35934202","title":"Comparative proteomic analysis of PK15 swine kidney cells infected with a pseudorabies pathogenic variant and the Bartha-K/61 vaccine strain.","date":"2022","source":"Microbial pathogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/35934202","citation_count":3,"is_preprint":false},{"pmid":"38410689","id":"PMC_38410689","title":"Identification and Analysis of ZIC-Related Genes in Cerebellum of Autism Spectrum Disorders.","date":"2024","source":"Neuropsychiatric disease and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/38410689","citation_count":1,"is_preprint":false},{"pmid":"40602337","id":"PMC_40602337","title":"Moniezia benedeni infected Zaraibi (Egyptian Nubian) goats: Insights into serum biochemical changes, redox imbalance, and molecular mechanisms of oxidative-inflammatory cascades mediated intestinal injury.","date":"2025","source":"Research in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/40602337","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.09.627624","title":"A compact protein panel for organ-specific age and chronic disease prediction","date":"2024-12-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.09.627624","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8505,"output_tokens":985,"usd":0.020145,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7486,"output_tokens":1910,"usd":0.04259,"stage2_stop_reason":"end_turn"},"total_usd":0.062735,"stage1_batch_id":"msgbatch_01A16Jdp5GqAVCVpQZFEJ8ea","stage2_batch_id":"msgbatch_01U6kFCZ3it7YvGQU6uDxyp4","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TMED1 associates with the IL-1R family member ST2L (IL-33 receptor); this interaction is mediated by the GOLD domain of TMED1 and the TIR domain of ST2L. TMED1 is required for optimal IL-33-induced IL-8 and IL-6 production.\",\n      \"method\": \"Co-immunoprecipitation with deletion/mutation constructs; cytokine production assays (loss-of-function)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal domain-mapping with deletion/mutation constructs and functional cytokine readout, single lab\",\n      \"pmids\": [\"23319592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMED1 co-assembles with RNF26 (an ER-embedded ubiquitin ligase), TMEM43, ENDOD1, and TMEM33 to form a complex at the ER membrane that modulates innate immune signalling through the cGAS-STING pathway.\",\n      \"method\": \"Comparative proteomic workflow (interaction mapping of ER ubiquitin ligases); functional innate immune signalling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction mapping with functional STING pathway readout, single study\",\n      \"pmids\": [\"32614325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The GOLD domain of TMED1 forms homodimers in solution in a salt-dependent manner, independent of the coiled-coil region; the first high-resolution crystal structure of the TMED1 GOLD domain was determined, revealing residues important for oligomerization.\",\n      \"method\": \"X-ray crystallography; biophysical characterization in solution (SEC, analytical ultracentrifugation or similar); molecular dynamics simulation\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus biophysical solution-state characterization, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34634369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In C. elegans, the γ-subfamily TMED genes tmed-1 and tmed-3 exhibit genetic redundancy: defects in movement and vulval morphology are only apparent in double mutants, not single mutants. TMED genes also function to facilitate basement membrane breakdown during vulval development.\",\n      \"method\": \"C. elegans genetic analysis (single and double mutants); phenotypic readouts of embryonic viability, movement, vulval morphology, and basement membrane dynamics\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double-mutant rescue/phenotype in C. elegans, single lab, defined developmental phenotype\",\n      \"pmids\": [\"37204056\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMED1 is an ER/Golgi-resident p24 family protein whose GOLD domain mediates homodimerization and interaction with the TIR domain of the IL-33 receptor ST2L to support optimal IL-33 signalling; it also participates in an ER-membrane complex with RNF26, TMEM43, ENDOD1, and TMEM33 that modulates cGAS-STING innate immune signalling, and in C. elegans its γ-subfamily paralogs display genetic redundancy required for basement membrane remodelling during development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMED1 is a p24-family secretory pathway protein that functions as an adaptor linking ER/Golgi membrane organization to innate immune signalling [#0, #1]. Its GOLD domain mediates self-association, forming salt-dependent homodimers independent of the coiled-coil region, and the crystal structure of this domain defines the residues required for oligomerization [#2]. Through the same GOLD domain, TMED1 engages the TIR domain of the IL-33 receptor ST2L and is required for optimal IL-33-induced IL-8 and IL-6 production [#0]. TMED1 also co-assembles with the ER-embedded ubiquitin ligase RNF26 together with TMEM43, ENDOD1, and TMEM33 in an ER-membrane complex that modulates cGAS-STING innate immune signalling [#1]. Evolutionary conservation of function is indicated in C. elegans, where the γ-subfamily paralogs tmed-1 and tmed-3 are genetically redundant and facilitate basement membrane breakdown during vulval development [#3]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that TMED1 is not merely a housekeeping cargo receptor but a specific partner of an immune receptor, defining a role in cytokine signalling.\",\n      \"evidence\": \"Co-immunoprecipitation with domain deletion/mutation constructs mapping GOLD-TIR contacts, plus loss-of-function cytokine production assays\",\n      \"pmids\": [\"23319592\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single lab without reciprocal in vivo validation\",\n        \"Stoichiometry and subcellular site of the TMED1-ST2L interaction not resolved\",\n        \"Whether TMED1 traffics ST2L or scaffolds downstream signalling is unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed TMED1 within a defined multiprotein ER-membrane complex, extending its immune role from IL-33 to the cGAS-STING axis.\",\n      \"evidence\": \"Comparative MS-based interaction mapping of ER ubiquitin ligases with functional innate immune signalling readouts\",\n      \"pmids\": [\"32614325\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single study; direct binary contacts within the RNF26/TMEM43/ENDOD1/TMEM33 complex not dissected\",\n        \"Whether TMED1 is a ubiquitination substrate or a structural subunit is unclear\",\n        \"Mechanism by which the complex modulates STING is not defined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural basis for TMED1 self-association, showing the GOLD domain alone drives salt-dependent homodimerization.\",\n      \"evidence\": \"X-ray crystallography of the GOLD domain with solution biophysics and molecular dynamics\",\n      \"pmids\": [\"34634369\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional consequence of homodimerization for ST2L binding or complex assembly not tested\",\n        \"No full-length structure including the coiled-coil or transmembrane regions\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated conserved developmental function via genetic redundancy, linking γ-subfamily TMEDs to basement membrane remodelling.\",\n      \"evidence\": \"C. elegans single and double mutant genetic analysis with phenotypic readouts of movement, vulval morphology, and basement membrane dynamics\",\n      \"pmids\": [\"37204056\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Redundancy masks single-gene contribution; molecular cargo or mechanism not identified\",\n        \"Relevance to mammalian TMED1 immune functions not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMED1's structurally defined homodimerization integrates with its two distinct immune complexes (ST2L and the RNF26 ER complex) and its developmental role remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No unifying model connecting cargo trafficking, immune signalling, and basement membrane remodelling\",\n        \"No identified cargo substrate for mammalian TMED1\",\n        \"Subcellular dynamics during signalling not mapped\"\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:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"RNF26-TMEM43-ENDOD1-TMEM33 ER-membrane complex\"\n    ],\n    \"partners\": [\n      \"ST2L\",\n      \"RNF26\",\n      \"TMEM43\",\n      \"ENDOD1\",\n      \"TMEM33\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}