{"gene":"TMEM150A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"TMEM150A was identified as a functional homologue of yeast Sfk1 in mammalian cells and shown to participate in the homeostatic regulation of PI(4,5)P2 at the plasma membrane. TMEM150A strongly reduces the association of TTC7 with the EFR3-PI4KIIIα complex without impairing PI4KIIIα localization at the plasma membrane, revealing plasticity in the molecular interactions controlling PI4KIIIα localization and function.","method":"Functional homology identification, co-immunoprecipitation to assess complex composition, plasma membrane localization assays, PI(4,5)P2 homeostasis readouts","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional rescue assay, and PI(4,5)P2 homeostasis readout in a single focused study on this protein","pmids":["25608530"],"is_preprint":false},{"year":2021,"finding":"Differential palmitoylation patterns within a tri-cysteine motif in EFR3B control its interaction with TMEM150A and the distribution of PI4KIIIα between two distinct complexes at the plasma membrane. TMEM150A governs formation of a PI4KIIIα complex that functions specifically in rapid PI(4,5)P2 resynthesis following phospholipase C signaling. Spacing of palmitoyl groups within doubly palmitoylated EFR3B lipoforms affects both EFR3B–TMEM150A interactions and EFR3B partitioning in liquid-ordered vs. liquid-disordered membrane regions.","method":"Palmitoylation mutagenesis of EFR3B cysteine motif, co-immunoprecipitation, PI(4,5)P2 resynthesis assay after phospholipase C stimulation, membrane domain fractionation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with Co-IP and functional phosphoinositide assay, single lab with multiple orthogonal methods","pmids":["34569608"],"is_preprint":false},{"year":2000,"finding":"Rat TM6P1 (ortholog of TMEM150A) encodes an integral membrane protein with six predicted transmembrane helices. A TM6P1-EGFP fusion protein was shown to localize to the plasma membrane, establishing plasma membrane localization for this protein family member.","method":"Hydrophobicity/topology prediction, fluorescence microscopy of EGFP fusion protein","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, single fluorescence localization experiment with no functional consequence tested","pmids":["10858565"],"is_preprint":false},{"year":2018,"finding":"In yeast, Sfk1p (the TMEM150A/TM6P1 family homologue) negatively regulates transbilayer movement of phospholipids (PS and PE) independently of the PI4-kinase Stt4p. Loss of Sfk1p in a lem3Δ background increased PS/PE exposure on the cell surface and dramatically elevated plasma membrane permeability, associated with decreased total ergosterol.","method":"Genetic epistasis (sfk1Δ lem3Δ double mutant), lipid exposure assays (PS/PE-binding peptide sensitivity), membrane permeability assay, ergosterol quantification","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple phenotypic readouts in yeast ortholog, single lab","pmids":["29540528"],"is_preprint":false},{"year":2022,"finding":"Knockdown of TMEM150A in TLR4-expressing epithelial cells led to increased LPS-induced cytokine secretion and transcript levels, indicating that TMEM150A, through its regulation of PI(4,5)P2 production at the plasma membrane, modulates TLR4 signaling. Knockdown in a lung epithelial cell line (H292) also increased cytokine levels under unstimulated conditions, suggesting a role in baseline cellular homeostasis.","method":"siRNA knockdown of TMEM150A, LPS stimulation, cytokine ELISA and transcript quantification","journal":"Journal of interferon & cytokine research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, phenotypic readout without direct pathway placement beyond PI(4,5)P2 connection inferred from prior work","pmids":["35834652"],"is_preprint":false},{"year":2022,"finding":"TMEM150A (designated DRAM5) was identified as a nutrient-responsive member of the DRAM autophagy modulator family that plays an interconnected role with TMEM150C/DRAM4 in modulating autophagic flux and cell survival under nutrient-deprived conditions.","method":"Characterization of DRAM family members under nutrient deprivation; autophagic flux assays (implied from context of review/commentary)","journal":"Autophagy reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — commentary/brief report summarizing findings; limited methodological detail in abstract; single lab","pmids":["40396042"],"is_preprint":false}],"current_model":"TMEM150A is a multi-pass plasma membrane protein that acts as a functional homologue of yeast Sfk1; it assembles into a PI4KIIIα complex (with EFR3 and TTC7) at the plasma membrane, where it displaces TTC7 from the core EFR3–PI4KIIIα interaction and directs the kinase specifically toward rapid PI(4,5)P2 resynthesis after phospholipase C signaling; complex formation is controlled by a palmitoylation code in EFR3B, and downstream consequences of TMEM150A activity include modulation of TLR4-driven cytokine production and, as a DRAM family member (DRAM5), regulation of autophagic flux under nutrient deprivation."},"narrative":{"mechanistic_narrative":"TMEM150A is a multi-pass plasma membrane protein that functions in the homeostatic control of phosphoinositide levels at the plasma membrane as a mammalian functional homologue of yeast Sfk1 [PMID:25608530]. It acts within the EFR3–PI4KIIIα machinery: TMEM150A strongly reduces the association of TTC7 with the EFR3–PI4KIIIα complex without disrupting PI4KIIIα localization, revealing plasticity in the interactions that govern this kinase complex [PMID:25608530]. This TMEM150A-dependent complex is dedicated to rapid PI(4,5)P2 resynthesis following phospholipase C signaling, and its assembly is controlled by differential palmitoylation of a tri-cysteine motif in EFR3B, with palmitoyl-group spacing dictating both EFR3B–TMEM150A interaction and EFR3B partitioning between liquid-ordered and liquid-disordered membrane regions [PMID:34569608]. Through this control of plasma membrane PI(4,5)P2, TMEM150A modulates TLR4-driven cytokine output [PMID:35834652], and it has additionally been characterized as a nutrient-responsive DRAM-family member (DRAM5) acting in autophagic flux under nutrient deprivation [PMID:40396042]. The yeast homologue Sfk1p further links this protein family to negative regulation of transbilayer phospholipid movement independent of PI4-kinase activity [PMID:29540528]; whether mammalian TMEM150A retains this lipid-scrambling-control function has not been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Established the basic membrane architecture and subcellular address of the protein family, framing it as an integral membrane protein rather than a soluble factor.","evidence":"Topology prediction and EGFP-fusion fluorescence microscopy of rat ortholog TM6P1","pmids":["10858565"],"confidence":"Medium","gaps":["No functional consequence of localization tested","Six-TM topology predicted, not experimentally resolved"]},{"year":2015,"claim":"Defined TMEM150A's molecular function by showing it is a functional Sfk1 homologue that remodels the EFR3–PI4KIIIα complex by displacing TTC7, placing it in phosphoinositide homeostasis at the plasma membrane.","evidence":"Functional homology rescue, reciprocal co-immunoprecipitation, and PI(4,5)P2 homeostasis readouts in mammalian cells","pmids":["25608530"],"confidence":"High","gaps":["Mechanism by which TMEM150A displaces TTC7 not resolved structurally","Stoichiometry of TMEM150A in the complex unknown"]},{"year":2018,"claim":"Revealed via the yeast ortholog a PI4-kinase-independent activity of the family — negative regulation of transbilayer phospholipid movement and membrane permeability — broadening its potential roles beyond phosphoinositide kinase scaffolding.","evidence":"Genetic epistasis (sfk1Δ lem3Δ), lipid exposure assays, permeability and ergosterol measurements in yeast","pmids":["29540528"],"confidence":"Medium","gaps":["Demonstrated only in yeast, not mammalian TMEM150A","Molecular basis of phospholipid movement control unidentified"]},{"year":2021,"claim":"Showed how complex assembly is regulated, establishing an EFR3B palmitoylation code that gates TMEM150A binding and directs a distinct PI4KIIIα complex toward rapid PI(4,5)P2 resynthesis after PLC signaling.","evidence":"EFR3B cysteine palmitoylation mutagenesis, co-immunoprecipitation, PI(4,5)P2 resynthesis assay, and membrane domain fractionation","pmids":["34569608"],"confidence":"High","gaps":["Enzymes setting the palmitoylation code not identified","How TMEM150A senses membrane domain partitioning unknown"]},{"year":2022,"claim":"Connected TMEM150A's phosphoinositide function to a physiological output by linking its loss to elevated TLR4-driven cytokine production.","evidence":"siRNA knockdown with LPS stimulation and cytokine ELISA/transcript quantification in epithelial cells","pmids":["35834652"],"confidence":"Low","gaps":["Single knockdown approach without rescue","Direct mechanistic placement relative to TLR4 inferred from prior PI(4,5)P2 work, not demonstrated"]},{"year":2022,"claim":"Assigned TMEM150A to the DRAM autophagy-modulator family (DRAM5) acting in autophagic flux under nutrient stress, implicating it in a second cellular program.","evidence":"Characterization of DRAM family members under nutrient deprivation with autophagic flux assays (commentary/brief report)","pmids":["40396042"],"confidence":"Low","gaps":["Limited methodological detail","Relationship between autophagy role and PI(4,5)P2 function not established"]},{"year":null,"claim":"Whether the mammalian TMEM150A protein directly regulates transbilayer phospholipid movement, and how its phosphoinositide, TLR4, and autophagy roles mechanistically interrelate, remains open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TMEM150A within the EFR3–PI4KIIIα complex","No mammalian demonstration of lipid-scrambling control","Unified mechanism linking distinct phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]}],"complexes":["EFR3-PI4KIIIα complex"],"partners":["EFR3B","TTC7","PI4KA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86TG1","full_name":"Transmembrane protein 150A","aliases":["Transmembrane protein 150"],"length_aa":271,"mass_kda":28.8,"function":"Regulates localization of phosphatidylinositol 4-kinase (PI4K) to the plasma membrane, possibly by reducing the association of TTC7 (TTC7A or TTC7B) with the PI4K complex (PubMed:25608530). Acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:25608530). May also play a role in fasting-induced catabolism (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q86TG1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM150A","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM150A","total_profiled":1310},"omim":[{"mim_id":"617292","title":"TRANSMEMBRANE PROTEIN 150C; TMEM150C","url":"https://www.omim.org/entry/617292"},{"mim_id":"616757","title":"TRANSMEMBRANE PROTEIN 150A; TMEM150A","url":"https://www.omim.org/entry/616757"},{"mim_id":"600286","title":"PHOSPHATIDYLINOSITOL 4-KINASE, ALPHA; PI4KA","url":"https://www.omim.org/entry/600286"}],"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/TMEM150A"},"hgnc":{"alias_symbol":["TM6P1","FLJ90024","TTN1"],"prev_symbol":["TMEM150"]},"alphafold":{"accession":"Q86TG1","domains":[{"cath_id":"-","chopping":"2-42_50-238","consensus_level":"high","plddt":96.4029,"start":2,"end":238}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TG1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TG1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86TG1-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM150A","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM150A"},"sequence":{"accession":"Q86TG1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86TG1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86TG1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86TG1"}},"corpus_meta":[{"pmid":"25608530","id":"PMC_25608530","title":"Plasticity of PI4KIIIα interactions at the plasma membrane.","date":"2015","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/25608530","citation_count":78,"is_preprint":false},{"pmid":"18337465","id":"PMC_18337465","title":"A novel protein phosphatase is a binding partner for the protein kinase domains of UNC-89 (Obscurin) in Caenorhabditis elegans.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18337465","citation_count":44,"is_preprint":false},{"pmid":"18390597","id":"PMC_18390597","title":"Single-molecule force spectroscopy reveals a stepwise unfolding of Caenorhabditis elegans giant protein kinase domains.","date":"2008","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18390597","citation_count":36,"is_preprint":false},{"pmid":"29540528","id":"PMC_29540528","title":"Phospholipid flippases and Sfk1p, a novel regulator of phospholipid asymmetry, contribute to low permeability of the plasma membrane.","date":"2018","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29540528","citation_count":29,"is_preprint":false},{"pmid":"17715366","id":"PMC_17715366","title":"Tudor nuclease genes and programmed DNA rearrangements in Tetrahymena thermophila.","date":"2007","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/17715366","citation_count":22,"is_preprint":false},{"pmid":"34569608","id":"PMC_34569608","title":"A palmitoylation code controls PI4KIIIα complex formation and PI(4,5)P2 homeostasis at the plasma membrane.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34569608","citation_count":21,"is_preprint":false},{"pmid":"20346955","id":"PMC_20346955","title":"Extensive and modular intrinsically disordered segments in C. elegans TTN-1 and implications in filament binding, elasticity and oblique striation.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20346955","citation_count":20,"is_preprint":false},{"pmid":"10858565","id":"PMC_10858565","title":"Identification of a new gene (rat TM6P1) encoding a fasting-inducible, integral membrane protein with six transmembrane domains.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10858565","citation_count":5,"is_preprint":false},{"pmid":"35834652","id":"PMC_35834652","title":"Knockdown of Transmembrane Protein 150A (TMEM150A) Results in Increased Production of Multiple Cytokines.","date":"2022","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/35834652","citation_count":2,"is_preprint":false},{"pmid":"39789885","id":"PMC_39789885","title":"Inflammation alters the expression and activity of the mechanosensitive ion channels in periodontal ligament cells.","date":"2024","source":"European journal of orthodontics","url":"https://pubmed.ncbi.nlm.nih.gov/39789885","citation_count":2,"is_preprint":false},{"pmid":"38055673","id":"PMC_38055673","title":"Overexpression of TMEM150A in glioblastoma multiforme patients correlated with dismal prognoses and compromised immune statuses.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38055673","citation_count":1,"is_preprint":false},{"pmid":"40396042","id":"PMC_40396042","title":"DRAMs and autophagy: a family affair.","date":"2022","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/40396042","citation_count":1,"is_preprint":false},{"pmid":"30708508","id":"PMC_30708508","title":"First Report of Bacterial Leaf Streak of Strelitzia reginae Caused by Burkholderia cepacia.","date":"2014","source":"Plant disease","url":"https://pubmed.ncbi.nlm.nih.gov/30708508","citation_count":1,"is_preprint":false},{"pmid":"38328600","id":"PMC_38328600","title":"A case report of isolated arrhythmogenic left ventricular cardiomyopathy: phenotypes, diagnosis, and treatment.","date":"2024","source":"European heart journal. Case reports","url":"https://pubmed.ncbi.nlm.nih.gov/38328600","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9727,"output_tokens":1734,"usd":0.027595,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8549,"output_tokens":2333,"usd":0.050535,"stage2_stop_reason":"end_turn"},"total_usd":0.07813,"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\": 2015,\n      \"finding\": \"TMEM150A was identified as a functional homologue of yeast Sfk1 in mammalian cells and shown to participate in the homeostatic regulation of PI(4,5)P2 at the plasma membrane. TMEM150A strongly reduces the association of TTC7 with the EFR3-PI4KIIIα complex without impairing PI4KIIIα localization at the plasma membrane, revealing plasticity in the molecular interactions controlling PI4KIIIα localization and function.\",\n      \"method\": \"Functional homology identification, co-immunoprecipitation to assess complex composition, plasma membrane localization assays, PI(4,5)P2 homeostasis readouts\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional rescue assay, and PI(4,5)P2 homeostasis readout in a single focused study on this protein\",\n      \"pmids\": [\"25608530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Differential palmitoylation patterns within a tri-cysteine motif in EFR3B control its interaction with TMEM150A and the distribution of PI4KIIIα between two distinct complexes at the plasma membrane. TMEM150A governs formation of a PI4KIIIα complex that functions specifically in rapid PI(4,5)P2 resynthesis following phospholipase C signaling. Spacing of palmitoyl groups within doubly palmitoylated EFR3B lipoforms affects both EFR3B–TMEM150A interactions and EFR3B partitioning in liquid-ordered vs. liquid-disordered membrane regions.\",\n      \"method\": \"Palmitoylation mutagenesis of EFR3B cysteine motif, co-immunoprecipitation, PI(4,5)P2 resynthesis assay after phospholipase C stimulation, membrane domain fractionation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with Co-IP and functional phosphoinositide assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34569608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Rat TM6P1 (ortholog of TMEM150A) encodes an integral membrane protein with six predicted transmembrane helices. A TM6P1-EGFP fusion protein was shown to localize to the plasma membrane, establishing plasma membrane localization for this protein family member.\",\n      \"method\": \"Hydrophobicity/topology prediction, fluorescence microscopy of EGFP fusion protein\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single fluorescence localization experiment with no functional consequence tested\",\n      \"pmids\": [\"10858565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In yeast, Sfk1p (the TMEM150A/TM6P1 family homologue) negatively regulates transbilayer movement of phospholipids (PS and PE) independently of the PI4-kinase Stt4p. Loss of Sfk1p in a lem3Δ background increased PS/PE exposure on the cell surface and dramatically elevated plasma membrane permeability, associated with decreased total ergosterol.\",\n      \"method\": \"Genetic epistasis (sfk1Δ lem3Δ double mutant), lipid exposure assays (PS/PE-binding peptide sensitivity), membrane permeability assay, ergosterol quantification\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple phenotypic readouts in yeast ortholog, single lab\",\n      \"pmids\": [\"29540528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of TMEM150A in TLR4-expressing epithelial cells led to increased LPS-induced cytokine secretion and transcript levels, indicating that TMEM150A, through its regulation of PI(4,5)P2 production at the plasma membrane, modulates TLR4 signaling. Knockdown in a lung epithelial cell line (H292) also increased cytokine levels under unstimulated conditions, suggesting a role in baseline cellular homeostasis.\",\n      \"method\": \"siRNA knockdown of TMEM150A, LPS stimulation, cytokine ELISA and transcript quantification\",\n      \"journal\": \"Journal of interferon & cytokine research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, phenotypic readout without direct pathway placement beyond PI(4,5)P2 connection inferred from prior work\",\n      \"pmids\": [\"35834652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM150A (designated DRAM5) was identified as a nutrient-responsive member of the DRAM autophagy modulator family that plays an interconnected role with TMEM150C/DRAM4 in modulating autophagic flux and cell survival under nutrient-deprived conditions.\",\n      \"method\": \"Characterization of DRAM family members under nutrient deprivation; autophagic flux assays (implied from context of review/commentary)\",\n      \"journal\": \"Autophagy reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — commentary/brief report summarizing findings; limited methodological detail in abstract; single lab\",\n      \"pmids\": [\"40396042\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM150A is a multi-pass plasma membrane protein that acts as a functional homologue of yeast Sfk1; it assembles into a PI4KIIIα complex (with EFR3 and TTC7) at the plasma membrane, where it displaces TTC7 from the core EFR3–PI4KIIIα interaction and directs the kinase specifically toward rapid PI(4,5)P2 resynthesis after phospholipase C signaling; complex formation is controlled by a palmitoylation code in EFR3B, and downstream consequences of TMEM150A activity include modulation of TLR4-driven cytokine production and, as a DRAM family member (DRAM5), regulation of autophagic flux under nutrient deprivation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM150A is a multi-pass plasma membrane protein that functions in the homeostatic control of phosphoinositide levels at the plasma membrane as a mammalian functional homologue of yeast Sfk1 [#0]. It acts within the EFR3–PI4KIIIα machinery: TMEM150A strongly reduces the association of TTC7 with the EFR3–PI4KIIIα complex without disrupting PI4KIIIα localization, revealing plasticity in the interactions that govern this kinase complex [#0]. This TMEM150A-dependent complex is dedicated to rapid PI(4,5)P2 resynthesis following phospholipase C signaling, and its assembly is controlled by differential palmitoylation of a tri-cysteine motif in EFR3B, with palmitoyl-group spacing dictating both EFR3B–TMEM150A interaction and EFR3B partitioning between liquid-ordered and liquid-disordered membrane regions [#1]. Through this control of plasma membrane PI(4,5)P2, TMEM150A modulates TLR4-driven cytokine output [#4], and it has additionally been characterized as a nutrient-responsive DRAM-family member (DRAM5) acting in autophagic flux under nutrient deprivation [#5]. The yeast homologue Sfk1p further links this protein family to negative regulation of transbilayer phospholipid movement independent of PI4-kinase activity [#3]; whether mammalian TMEM150A retains this lipid-scrambling-control function has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the basic membrane architecture and subcellular address of the protein family, framing it as an integral membrane protein rather than a soluble factor.\",\n      \"evidence\": \"Topology prediction and EGFP-fusion fluorescence microscopy of rat ortholog TM6P1\",\n      \"pmids\": [\"10858565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of localization tested\", \"Six-TM topology predicted, not experimentally resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined TMEM150A's molecular function by showing it is a functional Sfk1 homologue that remodels the EFR3–PI4KIIIα complex by displacing TTC7, placing it in phosphoinositide homeostasis at the plasma membrane.\",\n      \"evidence\": \"Functional homology rescue, reciprocal co-immunoprecipitation, and PI(4,5)P2 homeostasis readouts in mammalian cells\",\n      \"pmids\": [\"25608530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TMEM150A displaces TTC7 not resolved structurally\", \"Stoichiometry of TMEM150A in the complex unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed via the yeast ortholog a PI4-kinase-independent activity of the family — negative regulation of transbilayer phospholipid movement and membrane permeability — broadening its potential roles beyond phosphoinositide kinase scaffolding.\",\n      \"evidence\": \"Genetic epistasis (sfk1Δ lem3Δ), lipid exposure assays, permeability and ergosterol measurements in yeast\",\n      \"pmids\": [\"29540528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated only in yeast, not mammalian TMEM150A\", \"Molecular basis of phospholipid movement control unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed how complex assembly is regulated, establishing an EFR3B palmitoylation code that gates TMEM150A binding and directs a distinct PI4KIIIα complex toward rapid PI(4,5)P2 resynthesis after PLC signaling.\",\n      \"evidence\": \"EFR3B cysteine palmitoylation mutagenesis, co-immunoprecipitation, PI(4,5)P2 resynthesis assay, and membrane domain fractionation\",\n      \"pmids\": [\"34569608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes setting the palmitoylation code not identified\", \"How TMEM150A senses membrane domain partitioning unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected TMEM150A's phosphoinositide function to a physiological output by linking its loss to elevated TLR4-driven cytokine production.\",\n      \"evidence\": \"siRNA knockdown with LPS stimulation and cytokine ELISA/transcript quantification in epithelial cells\",\n      \"pmids\": [\"35834652\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single knockdown approach without rescue\", \"Direct mechanistic placement relative to TLR4 inferred from prior PI(4,5)P2 work, not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Assigned TMEM150A to the DRAM autophagy-modulator family (DRAM5) acting in autophagic flux under nutrient stress, implicating it in a second cellular program.\",\n      \"evidence\": \"Characterization of DRAM family members under nutrient deprivation with autophagic flux assays (commentary/brief report)\",\n      \"pmids\": [\"40396042\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited methodological detail\", \"Relationship between autophagy role and PI(4,5)P2 function not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the mammalian TMEM150A protein directly regulates transbilayer phospholipid movement, and how its phosphoinositide, TLR4, and autophagy roles mechanistically interrelate, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TMEM150A within the EFR3–PI4KIIIα complex\", \"No mammalian demonstration of lipid-scrambling control\", \"Unified mechanism linking distinct phenotypes not established\"]\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:0005886\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"EFR3-PI4KIIIα complex\"],\n    \"partners\": [\"EFR3B\", \"TTC7\", \"PI4KA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}