{"gene":"TMEM39A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2019,"finding":"TMEM39A/SUSR2 is an ER-localized transmembrane protein that acts as an adaptor protein promoting ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by interacting with both SAC1 and the COPII subunits SEC23/SEC24.","method":"Co-immunoprecipitation, knockdown experiments, subcellular fractionation/localization","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple binding partners (SAC1, SEC23/SEC24), KD phenotypes with defined molecular readouts, multiple orthogonal methods in one study","pmids":["31806350"],"is_preprint":false},{"year":2019,"finding":"Depletion of TMEM39A/SUSR2 retains SAC1 on the ER, leading to elevated PtdIns(3)P produced by the VPS34 complex, which promotes autophagosome formation.","method":"TMEM39A knockdown, phosphoinositide measurement, autophagy flux assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with defined molecular phenotype (elevated PtdIns(3)P, autophagosome formation), multiple orthogonal methods in a single rigorous study","pmids":["31806350"],"is_preprint":false},{"year":2019,"finding":"TMEM39A/SUSR2 depletion elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote SNARE complex assembly for autophagosome maturation, and also increases lysosomal degradative capability.","method":"TMEM39A knockdown, PtdIns(4)P lipid measurement, HOPS complex recruitment assays, SNARE assembly assays, lysosomal activity assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with multiple defined molecular readouts (PtdIns(4)P levels, HOPS recruitment, SNARE assembly, lysosomal activity), multiple orthogonal methods","pmids":["31806350"],"is_preprint":false},{"year":2021,"finding":"TMEM39A interacts with the dynein intermediate light chain DYNC1I2 to maintain proper perinuclear lysosome distribution; loss of TMEM39A causes redistribution of lysosomes from the perinuclear region to the cell periphery in mammalian cells.","method":"Co-immunoprecipitation (TMEM39A–DYNC1I2 interaction), loss-of-function experiments in C. elegans (tmem-39 mutants) and mammalian cells with lysosome localization readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interaction and KO phenotype in two model systems, single lab","pmids":["33531362"],"is_preprint":false},{"year":2021,"finding":"Loss of tmem-39 (C. elegans ortholog of TMEM39A) impairs mTOR signaling and activates the downstream TFEB-like transcription factor HLH-30, linking TMEM39A to lysosome-associated signaling.","method":"Genetic loss-of-function (tmem-39 mutants in C. elegans), mTOR pathway readouts, HLH-30/TFEB reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined pathway readouts in C. elegans, single lab","pmids":["33531362"],"is_preprint":false},{"year":2021,"finding":"Loss of tmem-39 in C. elegans leads to lysosome tubularization, reduced lysosome mobility, and accumulation of the lysosome-associated membrane protein LMP-1.","method":"Live imaging and genetic loss-of-function in C. elegans tmem-39 mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-imaging localization with functional phenotype, genetic KO, single lab","pmids":["33531362"],"is_preprint":false},{"year":2024,"finding":"TMEM39A co-localizes with the COPII coat complex in large vesicles (TMEM39A-LVs) and cooperates with TMEM131 to facilitate bulk secretion of extracellular matrix components (collagens, dual oxidase, carboxypeptidases) through large COPII vesicle formation.","method":"Immunoprecipitation of TMEM39A-FLAG followed by proteomics (identifying TMEM131 as interactor), TMEM131 knockdown with collagen secretion readout, co-localization imaging in C. elegans and human sarcoma cells","journal":"Journal of genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-proteomics interaction identification, KD phenotype in two systems (C. elegans and human cells), orthogonal methods, single lab","pmids":["39521045"],"is_preprint":false}],"current_model":"TMEM39A/SUSR2 is an ER-localized transmembrane protein that (1) acts as a COPII adaptor promoting ER-to-Golgi trafficking of the PtdIns(4)P phosphatase SAC1 by binding SAC1 and SEC23/SEC24, thereby controlling PtdIns(4)P and PtdIns(3)P levels to modulate autophagosome formation and maturation; (2) interacts with the dynein intermediate chain DYNC1I2 to maintain perinuclear lysosome distribution and support mTOR/TFEB signaling; and (3) cooperates with TMEM131 within large COPII vesicles to enable bulk secretion of extracellular matrix proteins."},"narrative":{"mechanistic_narrative":"TMEM39A/SUSR2 is an ER-localized transmembrane protein that coordinates COPII-dependent membrane trafficking to control phosphoinositide homeostasis, autophagy, and bulk secretion [PMID:31806350, PMID:39521045]. It functions as a COPII adaptor that promotes ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by simultaneously binding SAC1 and the COPII subunits SEC23/SEC24; loss of TMEM39A retains SAC1 on the ER, elevating VPS34-generated PtdIns(3)P to drive autophagosome formation while raising late endosomal/lysosomal PtdIns(4)P that recruits the HOPS complex, promotes SNARE assembly, and enhances lysosomal degradative capacity during autophagosome maturation [PMID:31806350]. Through interaction with the dynein intermediate chain DYNC1I2, TMEM39A maintains perinuclear lysosome positioning, and its loss disperses lysosomes to the cell periphery and impairs mTOR signaling with consequent activation of the TFEB-like factor HLH-30 [PMID:33531362]. TMEM39A also co-localizes with the COPII coat in large vesicles and cooperates with TMEM131 to enable bulk secretion of extracellular matrix proteins including collagens [PMID:39521045].","teleology":[{"year":2019,"claim":"Established TMEM39A as an ER COPII adaptor that links phosphoinositide metabolism to autophagy by escorting the phosphatase SAC1 out of the ER, answering how SAC1 reaches its site of action and how its mislocalization reshapes the lipid landscape.","evidence":"Reciprocal Co-IP with SAC1 and SEC23/SEC24, subcellular fractionation, and knockdown with phosphoinositide and autophagy-flux readouts in mammalian cells","pmids":["31806350"],"confidence":"High","gaps":["Structural basis of simultaneous SAC1 and SEC23/SEC24 binding not resolved","Whether TMEM39A is itself a COPII cargo or a coat-recruitment factor not distinguished","Stoichiometry and dynamics of adaptor-cargo assembly unknown"]},{"year":2019,"claim":"Demonstrated that TMEM39A loss couples elevated PtdIns(3)P (autophagosome formation) and elevated lysosomal PtdIns(4)P (HOPS recruitment, SNARE assembly, degradation) into a coordinated regulation of both autophagosome initiation and maturation.","evidence":"TMEM39A knockdown with lipid measurements, HOPS recruitment, SNARE assembly, and lysosomal activity assays","pmids":["31806350"],"confidence":"High","gaps":["Direct enzymatic link between SAC1 retention and lysosomal PtdIns(4)P increase not fully mapped","Physiological contexts where TMEM39A tunes autophagy not defined"]},{"year":2021,"claim":"Connected TMEM39A to lysosome positioning and nutrient signaling by identifying a dynein-intermediate-chain interaction, showing the protein has roles beyond ER trafficking.","evidence":"Co-IP of TMEM39A-DYNC1I2 and loss-of-function in C. elegans tmem-39 mutants and mammalian cells with lysosome localization, mTOR, and HLH-30/TFEB readouts; live imaging of lysosome morphology","pmids":["33531362"],"confidence":"Medium","gaps":["Single lab; DYNC1I2 interaction not reciprocally validated across systems","Mechanism linking lysosome dispersal to mTOR suppression unresolved","Whether positioning defect is a direct dynein-tethering role or a downstream consequence unclear"]},{"year":2024,"claim":"Extended TMEM39A function to bulk cargo export by showing it partners with TMEM131 in large COPII vesicles to secrete extracellular matrix proteins, broadening its trafficking role from a single phosphatase to oversized secretory cargo.","evidence":"TMEM39A-FLAG IP-proteomics identifying TMEM131, TMEM131 knockdown with collagen secretion readout, and co-localization imaging in C. elegans and human sarcoma cells","pmids":["39521045"],"confidence":"Medium","gaps":["Single lab; direct TMEM39A-TMEM131 binding interface not characterized","How large COPII vesicle formation is mechanistically driven not established","Relationship between the SAC1/autophagy role and the bulk-secretion role unintegrated"]},{"year":null,"claim":"How TMEM39A's distinct activities — SAC1 escort, dynein-dependent lysosome positioning, and TMEM131-dependent bulk secretion — are integrated or differentially regulated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TMEM39A","Domain assignments for its multiple interactions not defined","No mammalian disease or physiological phenotype directly linked in the available corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":["SAC1","SEC23","SEC24","DYNC1I2","TMEM131"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NV64","full_name":"Transmembrane protein 39A","aliases":[],"length_aa":488,"mass_kda":55.7,"function":"Regulates autophagy by controlling the spatial distribution and levels of the intracellular phosphatidylinositol 4-phosphate (PtdIns(4)P) pools (PubMed:31806350). Modulates (PtdIns(4)P) levels by regulating the ER-to-Golgi trafficking of the phosphatidylinositide phosphatase SACM1L (PubMed:31806350) (Microbial infection) Positively regulates the replication of encephalomyocarditis virus (EMCV) via autophagy-dependent pathway","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9NV64/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM39A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM39A","total_profiled":1310},"omim":[{"mim_id":"621551","title":"TRANSMEMBRANE PROTEIN 39B; TMEM39B","url":"https://www.omim.org/entry/621551"},{"mim_id":"621550","title":"TRANSMEMBRANE PROTEIN 39A; TMEM39A","url":"https://www.omim.org/entry/621550"},{"mim_id":"126200","title":"MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO; MS","url":"https://www.omim.org/entry/126200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM39A"},"hgnc":{"alias_symbol":["FLJ10902","SUSR2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NV64","domains":[{"cath_id":"-","chopping":"339-415","consensus_level":"medium","plddt":85.6764,"start":339,"end":415}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV64","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV64-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NV64-F1-predicted_aligned_error_v6.png","plddt_mean":73.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM39A","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM39A"},"sequence":{"accession":"Q9NV64","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NV64.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NV64/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NV64"}},"corpus_meta":[{"pmid":"22464253","id":"PMC_22464253","title":"Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22464253","citation_count":156,"is_preprint":false},{"pmid":"31806350","id":"PMC_31806350","title":"The ER-Localized Transmembrane Protein TMEM39A/SUSR2 Regulates Autophagy by Controlling the Trafficking of the PtdIns(4)P Phosphatase SAC1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31806350","citation_count":39,"is_preprint":false},{"pmid":"22194214","id":"PMC_22194214","title":"Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes.","date":"2011","source":"Multiple sclerosis (Houndmills, Basingstoke, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22194214","citation_count":25,"is_preprint":false},{"pmid":"28744351","id":"PMC_28744351","title":"TMEM39A and Human Diseases: A Brief Review.","date":"2017","source":"Toxicological research","url":"https://pubmed.ncbi.nlm.nih.gov/28744351","citation_count":22,"is_preprint":false},{"pmid":"33531362","id":"PMC_33531362","title":"The conserved autoimmune-disease risk gene TMEM39A regulates lysosome dynamics.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33531362","citation_count":8,"is_preprint":false},{"pmid":"31553233","id":"PMC_31553233","title":"Genetic Variants in TMEM39A Gene Are Associated with Autoimmune Thyroid Diseases.","date":"2019","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31553233","citation_count":8,"is_preprint":false},{"pmid":"28427360","id":"PMC_28427360","title":"Association of novel polymorphisms in TMEM39A gene with systemic lupus erythematosus in a Chinese Han population.","date":"2017","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28427360","citation_count":7,"is_preprint":false},{"pmid":"28444502","id":"PMC_28444502","title":"Preliminary Study on the Role of TMEM39A Gene in Multiple Sclerosis.","date":"2017","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/28444502","citation_count":6,"is_preprint":false},{"pmid":"39521045","id":"PMC_39521045","title":"TMEM39A and TMEM131 facilitate bulk transport of ECM proteins through large COPII vesicle formation.","date":"2024","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/39521045","citation_count":6,"is_preprint":false},{"pmid":"24752108","id":"PMC_24752108","title":"[Correlation between TMEM39A gene polymorphism and systemic lupus erythematosus in Chinese Han patients].","date":"2014","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/24752108","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7082,"output_tokens":1756,"usd":0.023793,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8540,"output_tokens":2235,"usd":0.049287,"stage2_stop_reason":"end_turn"},"total_usd":0.07308,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM39A/SUSR2 is an ER-localized transmembrane protein that acts as an adaptor protein promoting ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by interacting with both SAC1 and the COPII subunits SEC23/SEC24.\",\n      \"method\": \"Co-immunoprecipitation, knockdown experiments, subcellular fractionation/localization\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple binding partners (SAC1, SEC23/SEC24), KD phenotypes with defined molecular readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31806350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Depletion of TMEM39A/SUSR2 retains SAC1 on the ER, leading to elevated PtdIns(3)P produced by the VPS34 complex, which promotes autophagosome formation.\",\n      \"method\": \"TMEM39A knockdown, phosphoinositide measurement, autophagy flux assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with defined molecular phenotype (elevated PtdIns(3)P, autophagosome formation), multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31806350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMEM39A/SUSR2 depletion elevates late endosomal/lysosomal PtdIns(4)P levels, facilitating recruitment of the HOPS complex to promote SNARE complex assembly for autophagosome maturation, and also increases lysosomal degradative capability.\",\n      \"method\": \"TMEM39A knockdown, PtdIns(4)P lipid measurement, HOPS complex recruitment assays, SNARE assembly assays, lysosomal activity assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with multiple defined molecular readouts (PtdIns(4)P levels, HOPS recruitment, SNARE assembly, lysosomal activity), multiple orthogonal methods\",\n      \"pmids\": [\"31806350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM39A interacts with the dynein intermediate light chain DYNC1I2 to maintain proper perinuclear lysosome distribution; loss of TMEM39A causes redistribution of lysosomes from the perinuclear region to the cell periphery in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation (TMEM39A–DYNC1I2 interaction), loss-of-function experiments in C. elegans (tmem-39 mutants) and mammalian cells with lysosome localization readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interaction and KO phenotype in two model systems, single lab\",\n      \"pmids\": [\"33531362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of tmem-39 (C. elegans ortholog of TMEM39A) impairs mTOR signaling and activates the downstream TFEB-like transcription factor HLH-30, linking TMEM39A to lysosome-associated signaling.\",\n      \"method\": \"Genetic loss-of-function (tmem-39 mutants in C. elegans), mTOR pathway readouts, HLH-30/TFEB reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined pathway readouts in C. elegans, single lab\",\n      \"pmids\": [\"33531362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of tmem-39 in C. elegans leads to lysosome tubularization, reduced lysosome mobility, and accumulation of the lysosome-associated membrane protein LMP-1.\",\n      \"method\": \"Live imaging and genetic loss-of-function in C. elegans tmem-39 mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-imaging localization with functional phenotype, genetic KO, single lab\",\n      \"pmids\": [\"33531362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TMEM39A co-localizes with the COPII coat complex in large vesicles (TMEM39A-LVs) and cooperates with TMEM131 to facilitate bulk secretion of extracellular matrix components (collagens, dual oxidase, carboxypeptidases) through large COPII vesicle formation.\",\n      \"method\": \"Immunoprecipitation of TMEM39A-FLAG followed by proteomics (identifying TMEM131 as interactor), TMEM131 knockdown with collagen secretion readout, co-localization imaging in C. elegans and human sarcoma cells\",\n      \"journal\": \"Journal of genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-proteomics interaction identification, KD phenotype in two systems (C. elegans and human cells), orthogonal methods, single lab\",\n      \"pmids\": [\"39521045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM39A/SUSR2 is an ER-localized transmembrane protein that (1) acts as a COPII adaptor promoting ER-to-Golgi trafficking of the PtdIns(4)P phosphatase SAC1 by binding SAC1 and SEC23/SEC24, thereby controlling PtdIns(4)P and PtdIns(3)P levels to modulate autophagosome formation and maturation; (2) interacts with the dynein intermediate chain DYNC1I2 to maintain perinuclear lysosome distribution and support mTOR/TFEB signaling; and (3) cooperates with TMEM131 within large COPII vesicles to enable bulk secretion of extracellular matrix proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM39A/SUSR2 is an ER-localized transmembrane protein that coordinates COPII-dependent membrane trafficking to control phosphoinositide homeostasis, autophagy, and bulk secretion [#0, #6]. It functions as a COPII adaptor that promotes ER-to-Golgi transport of the PtdIns(4)P phosphatase SAC1 by simultaneously binding SAC1 and the COPII subunits SEC23/SEC24; loss of TMEM39A retains SAC1 on the ER, elevating VPS34-generated PtdIns(3)P to drive autophagosome formation while raising late endosomal/lysosomal PtdIns(4)P that recruits the HOPS complex, promotes SNARE assembly, and enhances lysosomal degradative capacity during autophagosome maturation [#0, #1, #2]. Through interaction with the dynein intermediate chain DYNC1I2, TMEM39A maintains perinuclear lysosome positioning, and its loss disperses lysosomes to the cell periphery and impairs mTOR signaling with consequent activation of the TFEB-like factor HLH-30 [#3, #4]. TMEM39A also co-localizes with the COPII coat in large vesicles and cooperates with TMEM131 to enable bulk secretion of extracellular matrix proteins including collagens [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established TMEM39A as an ER COPII adaptor that links phosphoinositide metabolism to autophagy by escorting the phosphatase SAC1 out of the ER, answering how SAC1 reaches its site of action and how its mislocalization reshapes the lipid landscape.\",\n      \"evidence\": \"Reciprocal Co-IP with SAC1 and SEC23/SEC24, subcellular fractionation, and knockdown with phosphoinositide and autophagy-flux readouts in mammalian cells\",\n      \"pmids\": [\"31806350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of simultaneous SAC1 and SEC23/SEC24 binding not resolved\", \"Whether TMEM39A is itself a COPII cargo or a coat-recruitment factor not distinguished\", \"Stoichiometry and dynamics of adaptor-cargo assembly unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that TMEM39A loss couples elevated PtdIns(3)P (autophagosome formation) and elevated lysosomal PtdIns(4)P (HOPS recruitment, SNARE assembly, degradation) into a coordinated regulation of both autophagosome initiation and maturation.\",\n      \"evidence\": \"TMEM39A knockdown with lipid measurements, HOPS recruitment, SNARE assembly, and lysosomal activity assays\",\n      \"pmids\": [\"31806350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic link between SAC1 retention and lysosomal PtdIns(4)P increase not fully mapped\", \"Physiological contexts where TMEM39A tunes autophagy not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TMEM39A to lysosome positioning and nutrient signaling by identifying a dynein-intermediate-chain interaction, showing the protein has roles beyond ER trafficking.\",\n      \"evidence\": \"Co-IP of TMEM39A-DYNC1I2 and loss-of-function in C. elegans tmem-39 mutants and mammalian cells with lysosome localization, mTOR, and HLH-30/TFEB readouts; live imaging of lysosome morphology\",\n      \"pmids\": [\"33531362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; DYNC1I2 interaction not reciprocally validated across systems\", \"Mechanism linking lysosome dispersal to mTOR suppression unresolved\", \"Whether positioning defect is a direct dynein-tethering role or a downstream consequence unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended TMEM39A function to bulk cargo export by showing it partners with TMEM131 in large COPII vesicles to secrete extracellular matrix proteins, broadening its trafficking role from a single phosphatase to oversized secretory cargo.\",\n      \"evidence\": \"TMEM39A-FLAG IP-proteomics identifying TMEM131, TMEM131 knockdown with collagen secretion readout, and co-localization imaging in C. elegans and human sarcoma cells\",\n      \"pmids\": [\"39521045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct TMEM39A-TMEM131 binding interface not characterized\", \"How large COPII vesicle formation is mechanistically driven not established\", \"Relationship between the SAC1/autophagy role and the bulk-secretion role unintegrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMEM39A's distinct activities — SAC1 escort, dynein-dependent lysosome positioning, and TMEM131-dependent bulk secretion — are integrated or differentially regulated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TMEM39A\", \"Domain assignments for its multiple interactions not defined\", \"No mammalian disease or physiological phenotype directly linked in the available corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SAC1\", \"SEC23\", \"SEC24\", \"DYNC1I2\", \"TMEM131\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}