{"gene":"TMEM131","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TMEM131 amino termini contain bacterial PapD chaperone-like domains that recruit premature collagen monomers for proper assembly and secretion from the ER. Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. These roles were identified via RNAi screen in C. elegans and validated as evolutionarily conserved in C. elegans, Drosophila, and humans.","method":"RNA interference screen, domain analysis, Co-IP/pulldown with TRAPPC8, ER stress reporter assays, collagen secretion assays in C. elegans, Drosophila, and human cells","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi screen, domain characterization, protein interaction, functional secretion assays) replicated across three organisms in one rigorous study","pmids":["32095531"],"is_preprint":false},{"year":2024,"finding":"TMEM131 cooperates with TMEM39A to facilitate the formation of large COPII vesicles required for bulk secretion of extracellular matrix (ECM) proteins, including collagen. Knockdown of TMEM131 reduces TMEM39A-associated large vesicle (TMEM39A-LV) formation and collagen secretion in both C. elegans and human sarcoma cells. TMEM131 was identified as a TMEM39A-interacting protein by immunoprecipitation and proteomics.","method":"Immunoprecipitation with TMEM39A-FLAG followed by proteomics, RNAi/knockdown of TMEM131, collagen secretion assays, co-localization imaging in C. elegans and human sarcoma cells","journal":"Journal of genetics and genomics = Yi chuan xue bao","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP-proteomics plus functional knockdown with defined phenotype, single lab, two orthogonal methods","pmids":["39521045"],"is_preprint":false},{"year":2025,"finding":"ER-localized TMEM131 interacts with TRAIL and mediates its transportation from the ER to the Golgi through Sec23 homolog A of the COPII complex. Disruption of this transportation process leads to ER-associated degradation of TRAIL proteins via ubiquitylation.","method":"Immunoprecipitation mass spectrometry (IP-MS) to identify TMEM131-TRAIL interaction, AECII-specific TRAIL knockout mouse model, quantitative proteomics, single-cell RNA sequencing","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identification of interaction plus genetic knockout with defined cellular phenotype, single lab, two orthogonal methods","pmids":["41293955"],"is_preprint":false},{"year":2025,"finding":"TMEM131 derived CCL22+ dendritic cell generation via the TNF signaling pathway, as identified by single-cell RNA sequencing analysis and functional validation in colorectal tumorigenesis models.","method":"Single-cell RNA sequencing, multiplex immunohistochemistry, flow cytometry, bulk RNA sequencing, intraperitoneal injection of DCs","journal":"Acta pharmaceutica Sinica. B","confidence":"Low","confidence_rationale":"Tier 3 / Weak — primarily transcriptomic/scRNA-seq with limited direct mechanistic validation of TMEM131's role; single lab, single study","pmids":["40698132"],"is_preprint":false}],"current_model":"TMEM131 is an ER-localized transmembrane protein whose N-terminal PapD chaperone-like domains recruit premature collagen monomers for proper assembly, while its C-terminus interacts with the TRAPP tethering complex component TRAPPC8 to drive collagen cargo trafficking from the ER to the Golgi via large COPII vesicles; it also mediates secretory trafficking of TRAIL from ER to Golgi through the COPII component Sec23A, and cooperates with TMEM39A to facilitate bulk ECM protein secretion."},"narrative":{"mechanistic_narrative":"TMEM131 is an endoplasmic reticulum-localized transmembrane protein that couples the recruitment of secretory cargo to its export from the ER, functioning in collagen and broader extracellular matrix biogenesis [PMID:32095531, PMID:39521045]. Its amino-terminal bacterial PapD chaperone-like domains recruit premature collagen monomers for proper assembly, while its carboxy terminus binds TRAPPC8 of the TRAPP tethering complex to drive collagen trafficking from the ER to the Golgi; these activities are evolutionarily conserved across C. elegans, Drosophila, and human cells [PMID:32095531]. TMEM131 cooperates with TMEM39A to support formation of the large COPII vesicles required for bulk secretion of ECM proteins, with its knockdown reducing both large-vesicle formation and collagen secretion [PMID:39521045]. Beyond ECM cargo, ER-resident TMEM131 binds TRAIL and mediates its ER-to-Golgi transport via the COPII component Sec23A, with disruption diverting TRAIL toward ER-associated degradation through ubiquitylation [PMID:41293955].","teleology":[{"year":2020,"claim":"Establishing how nascent collagen is matched to ER export machinery, this work defined TMEM131 as a bifunctional protein whose N-terminal PapD-like domains recruit collagen monomers and whose C-terminus links cargo to the TRAPP tethering complex via TRAPPC8.","evidence":"RNAi screen, domain analysis, Co-IP/pulldown with TRAPPC8, ER stress reporters and collagen secretion assays across C. elegans, Drosophila and human cells","pmids":["32095531"],"confidence":"High","gaps":["Structural basis of PapD-like domain binding to collagen monomers not resolved","Whether TMEM131 acts catalytically or as a passive scaffold during cargo loading is unclear","Stoichiometry and regulation of the TMEM131–TRAPPC8 interaction not defined"]},{"year":2024,"claim":"Addressing how bulk ECM cargo is packaged into oversized carriers, this study placed TMEM131 in a complex with TMEM39A that is required for large COPII vesicle formation and collagen secretion.","evidence":"TMEM39A-FLAG immunoprecipitation with proteomics, TMEM131 knockdown, collagen secretion assays and co-localization imaging in C. elegans and human sarcoma cells","pmids":["39521045"],"confidence":"Medium","gaps":["Direct versus indirect nature of the TMEM131–TMEM39A interaction not established","Mechanism by which the pair enlarges COPII vesicles is unknown","Reciprocal validation in additional cell types is limited"]},{"year":2025,"claim":"Extending TMEM131 cargo beyond ECM, this work showed it binds TRAIL and routes it from ER to Golgi via Sec23A, with loss of transport shunting TRAIL into ubiquitin-dependent ER-associated degradation.","evidence":"IP-MS of the TMEM131–TRAIL interaction, AECII-specific TRAIL knockout mouse, quantitative proteomics and single-cell RNA sequencing","pmids":["41293955"],"confidence":"Medium","gaps":["Whether TRAIL trafficking uses the same domains/partners as collagen export is untested","Direct binding versus complex-mediated interaction not distinguished","Physiological breadth of TMEM131-dependent TRAIL secretion beyond the studied lung epithelial context unknown"]},{"year":2025,"claim":"A transcriptomic study associated TMEM131 with CCL22+ dendritic cell generation through TNF signaling in colorectal tumorigenesis, hinting at a role beyond secretory trafficking.","evidence":"Single-cell RNA sequencing, multiplex immunohistochemistry, flow cytometry and DC injection in colorectal models","pmids":["40698132"],"confidence":"Low","gaps":["Primarily correlative transcriptomics with limited direct mechanistic validation of TMEM131","Molecular link between TMEM131 secretory function and TNF/CCL22 axis not defined","Not independently replicated"]},{"year":null,"claim":"How TMEM131 selects among diverse cargoes (collagen, ECM proteins, TRAIL) and whether a single mechanism governs cargo recruitment and COPII-dependent export remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking cargo recognition to vesicle formation","No structural model of TMEM131 in any cargo-export complex","Regulation of TMEM131 activity across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2]},{"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":[0,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["TRAPPC8","TMEM39A","SEC23A","TNFSF10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92545","full_name":"Transmembrane protein 131","aliases":["Protein RW1"],"length_aa":1883,"mass_kda":205.1,"function":"Collagen binding transmembrane protein involved in collagen secretion by recruiting the ER-to-Golgi transport complex TRAPPIII (PubMed:32095531). May play a role in the immune response to viral infection","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q92545/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM131","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM131","total_profiled":1310},"omim":[{"mim_id":"621550","title":"TRANSMEMBRANE PROTEIN 39A; TMEM39A","url":"https://www.omim.org/entry/621550"},{"mim_id":"616243","title":"TRANSMEMBRANE PROTEIN 131-LIKE; TMEM131L","url":"https://www.omim.org/entry/616243"},{"mim_id":"615659","title":"TRANSMEMBRANE PROTEIN 131; TMEM131","url":"https://www.omim.org/entry/615659"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Intermediate filaments","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM131"},"hgnc":{"alias_symbol":["CC28","YR-23","RW1","KIAA0257","PRO1048"],"prev_symbol":[]},"alphafold":{"accession":"Q92545","domains":[{"cath_id":"2.60.40.10","chopping":"320-432","consensus_level":"medium","plddt":85.1235,"start":320,"end":432},{"cath_id":"2.60.40","chopping":"441-524","consensus_level":"high","plddt":80.3818,"start":441,"end":524},{"cath_id":"2.60.40.10","chopping":"539-669","consensus_level":"high","plddt":78.8262,"start":539,"end":669},{"cath_id":"2.60.40.10","chopping":"672-757_777-824","consensus_level":"medium","plddt":82.1107,"start":672,"end":824},{"cath_id":"2.60.40.10","chopping":"828-908_922-975","consensus_level":"medium","plddt":82.1828,"start":828,"end":975},{"cath_id":"2.60.40.10","chopping":"978-1113","consensus_level":"high","plddt":84.6468,"start":978,"end":1113}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92545","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92545-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92545-F1-predicted_aligned_error_v6.png","plddt_mean":59.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM131","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM131"},"sequence":{"accession":"Q92545","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92545.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92545/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92545"}},"corpus_meta":[{"pmid":"1575472","id":"PMC_1575472","title":"Metabolism of dibenzo-p-dioxin by Sphingomonas sp. strain RW1.","date":"1992","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1575472","citation_count":202,"is_preprint":false},{"pmid":"9683494","id":"PMC_9683494","title":"Genetic analysis of dioxin dioxygenase of Sphingomonas sp. 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Carboxy termini of TMEM131 interact with TRAPPC8, a component of the TRAPP tethering complex, to drive collagen cargo trafficking from ER to the Golgi. These roles were identified via RNAi screen in C. elegans and validated as evolutionarily conserved in C. elegans, Drosophila, and humans.\",\n      \"method\": \"RNA interference screen, domain analysis, Co-IP/pulldown with TRAPPC8, ER stress reporter assays, collagen secretion assays in C. elegans, Drosophila, and human cells\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi screen, domain characterization, protein interaction, functional secretion assays) replicated across three organisms in one rigorous study\",\n      \"pmids\": [\"32095531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM131 cooperates with TMEM39A to facilitate the formation of large COPII vesicles required for bulk secretion of extracellular matrix (ECM) proteins, including collagen. Knockdown of TMEM131 reduces TMEM39A-associated large vesicle (TMEM39A-LV) formation and collagen secretion in both C. elegans and human sarcoma cells. TMEM131 was identified as a TMEM39A-interacting protein by immunoprecipitation and proteomics.\",\n      \"method\": \"Immunoprecipitation with TMEM39A-FLAG followed by proteomics, RNAi/knockdown of TMEM131, collagen secretion assays, co-localization imaging in C. elegans and human sarcoma cells\",\n      \"journal\": \"Journal of genetics and genomics = Yi chuan xue bao\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP-proteomics plus functional knockdown with defined phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"39521045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ER-localized TMEM131 interacts with TRAIL and mediates its transportation from the ER to the Golgi through Sec23 homolog A of the COPII complex. Disruption of this transportation process leads to ER-associated degradation of TRAIL proteins via ubiquitylation.\",\n      \"method\": \"Immunoprecipitation mass spectrometry (IP-MS) to identify TMEM131-TRAIL interaction, AECII-specific TRAIL knockout mouse model, quantitative proteomics, single-cell RNA sequencing\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identification of interaction plus genetic knockout with defined cellular phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"41293955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM131 derived CCL22+ dendritic cell generation via the TNF signaling pathway, as identified by single-cell RNA sequencing analysis and functional validation in colorectal tumorigenesis models.\",\n      \"method\": \"Single-cell RNA sequencing, multiplex immunohistochemistry, flow cytometry, bulk RNA sequencing, intraperitoneal injection of DCs\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — primarily transcriptomic/scRNA-seq with limited direct mechanistic validation of TMEM131's role; single lab, single study\",\n      \"pmids\": [\"40698132\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM131 is an ER-localized transmembrane protein whose N-terminal PapD chaperone-like domains recruit premature collagen monomers for proper assembly, while its C-terminus interacts with the TRAPP tethering complex component TRAPPC8 to drive collagen cargo trafficking from the ER to the Golgi via large COPII vesicles; it also mediates secretory trafficking of TRAIL from ER to Golgi through the COPII component Sec23A, and cooperates with TMEM39A to facilitate bulk ECM protein secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM131 is an endoplasmic reticulum-localized transmembrane protein that couples the recruitment of secretory cargo to its export from the ER, functioning in collagen and broader extracellular matrix biogenesis [#0, #1]. Its amino-terminal bacterial PapD chaperone-like domains recruit premature collagen monomers for proper assembly, while its carboxy terminus binds TRAPPC8 of the TRAPP tethering complex to drive collagen trafficking from the ER to the Golgi; these activities are evolutionarily conserved across C. elegans, Drosophila, and human cells [#0]. TMEM131 cooperates with TMEM39A to support formation of the large COPII vesicles required for bulk secretion of ECM proteins, with its knockdown reducing both large-vesicle formation and collagen secretion [#1]. Beyond ECM cargo, ER-resident TMEM131 binds TRAIL and mediates its ER-to-Golgi transport via the COPII component Sec23A, with disruption diverting TRAIL toward ER-associated degradation through ubiquitylation [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing how nascent collagen is matched to ER export machinery, this work defined TMEM131 as a bifunctional protein whose N-terminal PapD-like domains recruit collagen monomers and whose C-terminus links cargo to the TRAPP tethering complex via TRAPPC8.\",\n      \"evidence\": \"RNAi screen, domain analysis, Co-IP/pulldown with TRAPPC8, ER stress reporters and collagen secretion assays across C. elegans, Drosophila and human cells\",\n      \"pmids\": [\"32095531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of PapD-like domain binding to collagen monomers not resolved\",\n        \"Whether TMEM131 acts catalytically or as a passive scaffold during cargo loading is unclear\",\n        \"Stoichiometry and regulation of the TMEM131–TRAPPC8 interaction not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Addressing how bulk ECM cargo is packaged into oversized carriers, this study placed TMEM131 in a complex with TMEM39A that is required for large COPII vesicle formation and collagen secretion.\",\n      \"evidence\": \"TMEM39A-FLAG immunoprecipitation with proteomics, TMEM131 knockdown, collagen secretion assays and co-localization imaging in C. elegans and human sarcoma cells\",\n      \"pmids\": [\"39521045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect nature of the TMEM131–TMEM39A interaction not established\",\n        \"Mechanism by which the pair enlarges COPII vesicles is unknown\",\n        \"Reciprocal validation in additional cell types is limited\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending TMEM131 cargo beyond ECM, this work showed it binds TRAIL and routes it from ER to Golgi via Sec23A, with loss of transport shunting TRAIL into ubiquitin-dependent ER-associated degradation.\",\n      \"evidence\": \"IP-MS of the TMEM131–TRAIL interaction, AECII-specific TRAIL knockout mouse, quantitative proteomics and single-cell RNA sequencing\",\n      \"pmids\": [\"41293955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether TRAIL trafficking uses the same domains/partners as collagen export is untested\",\n        \"Direct binding versus complex-mediated interaction not distinguished\",\n        \"Physiological breadth of TMEM131-dependent TRAIL secretion beyond the studied lung epithelial context unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A transcriptomic study associated TMEM131 with CCL22+ dendritic cell generation through TNF signaling in colorectal tumorigenesis, hinting at a role beyond secretory trafficking.\",\n      \"evidence\": \"Single-cell RNA sequencing, multiplex immunohistochemistry, flow cytometry and DC injection in colorectal models\",\n      \"pmids\": [\"40698132\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Primarily correlative transcriptomics with limited direct mechanistic validation of TMEM131\",\n        \"Molecular link between TMEM131 secretory function and TNF/CCL22 axis not defined\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM131 selects among diverse cargoes (collagen, ECM proteins, TRAIL) and whether a single mechanism governs cargo recruitment and COPII-dependent export remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unifying model linking cargo recognition to vesicle formation\",\n        \"No structural model of TMEM131 in any cargo-export complex\",\n        \"Regulation of TMEM131 activity across tissues unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAPPC8\", \"TMEM39A\", \"SEC23A\", \"TNFSF10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":4,"faith_pct":75.0}}