{"gene":"TMED7","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2014,"finding":"TMED7 is required for trafficking of TLR4 from the endoplasmic reticulum to the cell surface through the Golgi. TMED7 forms a stable complex with the ectodomain of TLR4, an interaction requiring the coiled-coil and GOLD domains but not the cytosolic COPII sorting motif of TMED7. Depletion of TMED7 reduces MyD88-dependent TLR4 signaling but not TRIF/TRAM-mediated signaling. Truncated TMED7 lacking the COPII sorting motif or transmembrane domain is mislocalized and causes ligand-independent signaling from intracellularly accumulated receptors.","method":"Co-immunoprecipitation, domain deletion/truncation analysis, siRNA knockdown, reporter assays for MyD88- and TRIF-dependent signaling, confocal microscopy","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction studies with domain mapping, loss-of-function with specific pathway readouts, and localization experiments in a single focused study","pmids":["25074978"],"is_preprint":false},{"year":2012,"finding":"TMED7 inhibits MyD88-independent TLR4 signaling from endosomes. Upon LPS stimulation, TMED7 co-localizes with TRAM and TLR4 in late endosomes. TMED7 is essential for TAG-mediated disruption of the TRAM/TRIF complex and subsequent degradation of TLR4. TMED7 overexpression inhibits TRAM- or LPS-induced IRF3-signaling pathway activation, while TMED7 knockdown enhances RANTES production after LPS stimulation.","method":"Overexpression and knockdown studies, co-immunoprecipitation, co-localization by confocal microscopy, cytokine ELISA, reporter assays for IRF3 pathway","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, localization, knockdown/OE with specific pathway readouts), single rigorous study","pmids":["22426228"],"is_preprint":false},{"year":2024,"finding":"The intramembrane protease RHBDL4 negatively regulates TLR4 signaling by triggering degradation of TMED7, thereby counteracting TLR4 transport to the cell surface. TLR4 activation transcriptionally upregulates RHBDL4, creating a negative feedback loop that reduces TLR4 plasma membrane trafficking. This mechanism prevents over-activation of TLR4-dependent signaling during Mycobacterium tuberculosis macrophage infection and alleviates septic shock in a mouse model.","method":"RHBDL4 gain/loss-of-function, western blotting for TMED7 protein levels, flow cytometry for TLR4 surface expression, cytokine assays, in vitro macrophage infection model, mouse septic shock model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vitro and in vivo models, clear mechanism (RHBDL4 degrades TMED7 to limit TLR4 trafficking), replicated across model systems","pmids":["38453906"],"is_preprint":false},{"year":2016,"finding":"GAPR-1 (phosphorylated at Ser58 by IRAK1 downstream of MyD88 signaling) interacts with TMED7, and this phosphorylation-dependent interaction impairs TMED7-mediated disruption of the TRAM-TRIF complex, thereby promoting IFN-β and IL-10 secretion downstream of TLR4.","method":"Co-immunoprecipitation, phosphorylation assay, overexpression/knockdown, ELISA for IFN-β and IL-10","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and functional assays from a single lab with no independent replication reported","pmids":["26678074"],"is_preprint":false},{"year":2023,"finding":"TMED7 interacts with TLR2, TLR4, and TLR5 but not with TLR3 or TLR9 in protein interaction studies. Dominant-negative forms of TMED7 suppress the export of cell-surface TLRs from the ER to the Golgi, establishing TMED7 as a cargo sorting adaptor specifically required for anterograde trafficking of plasma membrane-destined TLRs.","method":"Protein interaction studies (co-immunoprecipitation/pulldown), dominant-negative TMED7 expression, confocal microscopy for TLR trafficking","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction studies with multiple TLR family members and dominant-negative functional validation, single lab","pmids":["37491993"],"is_preprint":false},{"year":2010,"finding":"TMED2/p24beta(1) loss in the 99J mouse mutant results in absence of its oligomerization partners TMED7/p24gamma(3) and TMED10/p24delta(1) from affected tissues, demonstrating that TMED7 protein stability/localization depends on TMED2 within hetero-oligomeric p24 complexes.","method":"ENU mutagenesis mouse model, immunohistochemistry and western blotting for TMED7 and TMED10 protein levels in mutant vs wild-type tissues","journal":"Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with direct protein detection of TMED7 complex partners, single study","pmids":["20178780"],"is_preprint":false},{"year":2009,"finding":"In Xenopus melanotrope cells, transgenic overexpression of p24gamma(3) (TMED7 ortholog) affects endogenous p24gamma(3) levels, reduces cargo (POMC) cleavage rate (suggesting reduced ER-to-Golgi transport), and affects POMC glycosylation, demonstrating a non-redundant role for this p24 subfamily member in early secretory pathway cargo processing distinct from other p24 members.","method":"Melanotrope cell-specific transgene expression in Xenopus laevis, pulse-chase radiolabeling, glycosylation and sulfation assays, western blotting","journal":"Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts, ortholog study in Xenopus","pmids":["18699773"],"is_preprint":false},{"year":2010,"finding":"In Xenopus melanotrope cells, p24gamma(3) (TMED7 ortholog) has a distinct function from its subfamily relative p24gamma(2) in secretory cargo transport, glycosylation, sulfation, and cleavage of POMC, demonstrating functional non-redundancy even among same-subfamily p24 proteins.","method":"Melanotrope-specific transgene expression in Xenopus, POMC processing assays (glycosylation, sulfation, cleavage)","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic Xenopus model with multiple biochemical readouts, single lab","pmids":["21118709"],"is_preprint":false},{"year":2015,"finding":"TMED7/p27 localizes specifically to unstacked flattened Golgi cisternae of the Hermes body (cytoplasmic droplet) of epididymal sperm, as determined by quantitative electron microscope gold antibody labeling, and is segregated from the acrosome during spermiogenesis. TMED7-positive vesicles (~50 nm) emanate from these Golgi cisternae, proposed to transport GLUT-3 to the plasma membrane.","method":"Quantitative electron microscopy immunogold labeling, tandem mass spectrometry, light microscopy immunolocalization","journal":"Open Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electron microscopy localization with gold labeling, quantitative mass spectrometry, single study","pmids":["26311421"],"is_preprint":false},{"year":2015,"finding":"During acrosome formation in spermiogenesis, TMED7/p27 is segregated from the acrosome and continues to mark Golgi identity as the Golgi migrates away from the acrosome in later steps of spermatid differentiation.","method":"Immunofluorescence microscopy, subcellular fractionation, mass spectrometry of germ cell Golgi fractions","journal":"Molecular Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence and fractionation, single study","pmids":["25808494"],"is_preprint":false},{"year":2020,"finding":"In early mouse embryos, AGS3 knockout causes dispersal of TMED7-positive vesicles (tracked by fluorescent protein tagging) and impairs their polarization toward the membrane, with concomitant reduction of E-cadherin (Cdh1) at cell-contact surfaces. This establishes TMED7-positive vesicles as carriers of Cdh1 cargo to the plasma membrane in a process regulated by AGS3/Gαi signaling.","method":"CRISPR/Cas9 knockout of AGS3, fluorescent protein tagging of TMED7 and TGN46 in mouse embryos, live imaging, immunofluorescence","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live fluorescent imaging of TMED7-tagged vesicles in a genetic loss-of-function model with specific cargo (Cdh1) readout, single study","pmids":["33148610"],"is_preprint":false},{"year":2010,"finding":"Knockdown of p24gamma(3)/TMED7 did not alter Aβ secretion or APP processing in cell-based and cell-free assays, indicating TMED7 does not modulate gamma-secretase cleavage of APP (negative result).","method":"siRNA knockdown, cell-based and cell-free Aβ secretion assays","journal":"Journal of Neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with loss-of-function, single lab, explicitly negative result","pmids":["20807314"],"is_preprint":false}],"current_model":"TMED7 is a p24 family cargo sorting adaptor that forms hetero-oligomeric complexes with TMED2 and TMED10, functions at the ER-Golgi interface to facilitate anterograde trafficking of specific transmembrane cargoes (including TLR4, TLR2, and TLR5) to the plasma membrane via its GOLD/coiled-coil ectodomain interactions, and also acts as a negative regulator of endosomal TLR4/TRAM-TRIF signaling; TMED7 abundance is itself controlled post-translationally by the intramembrane protease RHBDL4, which degrades TMED7 to limit TLR4 surface delivery in a TLR4-activated negative feedback loop."},"narrative":{"mechanistic_narrative":"TMED7 is a p24-family cargo sorting adaptor of the early secretory pathway that selects specific transmembrane cargoes for anterograde ER-to-Golgi-to-plasma membrane transport [PMID:25074978, PMID:37491993]. Its best-defined cargo class is the cell-surface Toll-like receptors: TMED7 binds the ectodomains of TLR2, TLR4, and TLR5 but not endosomal TLR3 or TLR9, and dominant-negative TMED7 blocks export of these receptors from the ER, identifying it as a sorting adaptor dedicated to plasma-membrane-destined TLRs [PMID:25074978, PMID:37491993]. Productive trafficking of TLR4 requires the TMED7 coiled-coil and GOLD ectodomain for cargo binding and its cytosolic COPII sorting motif and transmembrane anchor for correct localization; loss of TMED7 reduces MyD88-dependent TLR4 signaling, whereas truncated TMED7 mislocalizes receptors and drives ligand-independent signaling [PMID:25074978]. Beyond receptor delivery, TMED7 acts as a negative regulator of endosomal TLR4 signaling, where it co-localizes with TRAM and TLR4 in late endosomes and is required for TAG-mediated disruption of the TRAM/TRIF complex and TLR4 degradation, restraining IRF3-dependent output [PMID:22426228]; this brake is relieved when IRAK1-phosphorylated GAPR-1 binds TMED7 and impairs its disruption of the TRAM-TRIF complex [PMID:26678074]. TMED7 abundance is set post-translationally: the intramembrane protease RHBDL4, transcriptionally induced upon TLR4 activation, degrades TMED7 to limit TLR4 surface delivery in a negative feedback loop that constrains inflammatory output in macrophage infection and septic shock [PMID:38453906]. As a hetero-oligomeric p24 subunit, TMED7 stability depends on its partner TMED2, whose loss eliminates TMED7 and TMED10 from tissues [PMID:20178780], and the protein marks Golgi-derived transport vesicles that carry other cargoes such as E-cadherin to the cell surface under AGS3/Gαi control [PMID:33148610].","teleology":[{"year":2009,"claim":"Established that this p24 subfamily member has a non-redundant role in early secretory cargo handling, ruling out simple functional interchangeability among p24 proteins.","evidence":"Melanotrope-specific transgenic overexpression of the p24gamma(3)/TMED7 ortholog in Xenopus with POMC pulse-chase, glycosylation and sulfation assays","pmids":["18699773"],"confidence":"Medium","gaps":["Specific cargo selectivity in mammalian cells not addressed","Ortholog overexpression in a single cell type; physiological substrates undefined"]},{"year":2010,"claim":"Showed that TMED7 protein stability within the secretory pathway is enforced by hetero-oligomerization, defining it as an obligate complex subunit rather than a standalone factor.","evidence":"ENU-mutant 99J mouse lacking TMED2 with immunohistochemistry and western blotting of TMED7 and TMED10 in tissues; parallel Xenopus transgenic studies of subfamily non-redundancy and a negative APP/Abeta result","pmids":["20178780","21118709","20807314"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the TMED2/7/10 complex not resolved","Whether TMED7 has activity outside the complex untested"]},{"year":2012,"claim":"Defined a signaling-regulatory role distinct from trafficking by showing TMED7 restrains endosomal TLR4-TRAM-TRIF output.","evidence":"Overexpression/knockdown, co-IP, confocal co-localization with TRAM/TLR4 in late endosomes, IRF3 reporter and RANTES ELISA","pmids":["22426228"],"confidence":"High","gaps":["Molecular mechanism by which TMED7 enables TAG-mediated TRAM/TRIF disruption unresolved","Direct binding interface with TRAM not mapped"]},{"year":2014,"claim":"Mapped the cargo-adaptor mechanism, demonstrating TMED7 binds the TLR4 ectodomain via its coiled-coil/GOLD domains and uses its COPII motif for forward transport.","evidence":"Co-IP with domain deletion/truncation mapping, siRNA knockdown with MyD88- vs TRIF-specific reporters, confocal microscopy","pmids":["25074978"],"confidence":"High","gaps":["Structural basis of ectodomain recognition not determined","How a single adaptor reconciles trafficking versus endosomal signaling-inhibition roles unclear"]},{"year":2016,"claim":"Identified a signal-dependent switch that disables the TMED7 brake, linking MyD88/IRAK1 activity to enhanced TRIF-branch cytokine output.","evidence":"Co-IP, Ser58 phosphorylation assay, overexpression/knockdown, IFN-beta and IL-10 ELISA","pmids":["26678074"],"confidence":"Medium","gaps":["Single lab without independent replication","Direct effect of GAPR-1 binding on the TMED7-TRAM-TRIF interaction not structurally defined"]},{"year":2023,"claim":"Generalized TMED7's adaptor function across the surface-TLR family, showing selective binding and export control for TLR2/4/5 but not endosomal TLR3/9.","evidence":"Protein interaction studies, dominant-negative TMED7 expression, confocal microscopy of TLR ER-to-Golgi export","pmids":["37491993"],"confidence":"Medium","gaps":["Determinants distinguishing surface- from endosome-TLRs as cargo not defined","Single-lab interaction data"]},{"year":2024,"claim":"Closed the regulatory loop by identifying RHBDL4 as the protease that degrades TMED7 to dampen TLR4 surface delivery, providing in vivo relevance to infection and sepsis.","evidence":"RHBDL4 gain/loss-of-function, western blot of TMED7, flow cytometry of surface TLR4, cytokine assays, macrophage M. tuberculosis infection and mouse septic shock models","pmids":["38453906"],"confidence":"High","gaps":["Cleavage site and processing intermediates of TMED7 by RHBDL4 not mapped","Whether RHBDL4 also regulates TMED7-dependent non-TLR cargo unknown"]},{"year":null,"claim":"How TMED7 mechanistically partitions between forward cargo transport (TLR2/4/5, E-cadherin, GLUT-3) and its endosomal signaling-inhibitory function, and the structural basis of its cargo selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TMED7-cargo recognition","Full set of physiological cargoes undefined","Coordination between trafficking and signaling roles unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,8,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]}],"complexes":["TMED2/TMED7/TMED10 p24 hetero-oligomer"],"partners":["TLR4","TLR2","TLR5","TMED2","TMED10","TRAM","GAPR-1","RHBDL4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y3B3","full_name":"Transmembrane emp24 domain-containing protein 7","aliases":["p24 family protein gamma-3","p24gamma3","p27"],"length_aa":224,"mass_kda":25.2,"function":"Potential role in vesicular protein trafficking, mainly in the early secretory pathway. Appears to play a role in the biosynthesis of secreted cargo including processing and post-translational modifications","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus, cis-Golgi network membrane; Endoplasmic reticulum-Golgi intermediate compartment membrane; Cytoplasmic vesicle, COPI-coated vesicle membrane; Cytoplasmic vesicle, COPII-coated vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y3B3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMED7","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMED7","total_profiled":1310},"omim":[{"mim_id":"620436","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 9; TMED9","url":"https://www.omim.org/entry/620436"},{"mim_id":"619990","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 7; TMED7","url":"https://www.omim.org/entry/619990"},{"mim_id":"619642","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 2; TMED2","url":"https://www.omim.org/entry/619642"},{"mim_id":"608321","title":"TIR DOMAIN-CONTAINING ADAPTOR MOLECULE 2; TICAM2","url":"https://www.omim.org/entry/608321"}],"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/TMED7"},"hgnc":{"alias_symbol":["CGI-109","FLJ90481","p24gamma3","p24g3"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y3B3","domains":[{"cath_id":"2.60.120.380","chopping":"29-131","consensus_level":"medium","plddt":92.6747,"start":29,"end":131},{"cath_id":"1.20.5","chopping":"144-210","consensus_level":"medium","plddt":93.4045,"start":144,"end":210}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3B3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3B3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y3B3-F1-predicted_aligned_error_v6.png","plddt_mean":84.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMED7","jax_strain_url":"https://www.jax.org/strain/search?query=TMED7"},"sequence":{"accession":"Q9Y3B3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y3B3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y3B3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y3B3"}},"corpus_meta":[{"pmid":"16308470","id":"PMC_16308470","title":"Identification of differentially expressed genes in metastatic and non-metastatic nasopharyngeal carcinoma cells by suppression subtractive hybridization.","date":"2005","source":"Cellular oncology : the official journal of the International Society for Cellular Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16308470","citation_count":66,"is_preprint":false},{"pmid":"20178780","id":"PMC_20178780","title":"The trafficking protein Tmed2/p24beta(1) is required for morphogenesis of the mouse embryo and placenta.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20178780","citation_count":57,"is_preprint":false},{"pmid":"25074978","id":"PMC_25074978","title":"The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25074978","citation_count":52,"is_preprint":false},{"pmid":"22426228","id":"PMC_22426228","title":"The GOLD domain-containing protein TMED7 inhibits TLR4 signalling from the endosome upon LPS stimulation.","date":"2012","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/22426228","citation_count":48,"is_preprint":false},{"pmid":"24357726","id":"PMC_24357726","title":"Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24357726","citation_count":47,"is_preprint":false},{"pmid":"31102346","id":"PMC_31102346","title":"Dark side of the epididymis: tails of sperm maturation.","date":"2019","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/31102346","citation_count":34,"is_preprint":false},{"pmid":"18699773","id":"PMC_18699773","title":"Functional diversity among p24 subfamily members.","date":"2009","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18699773","citation_count":30,"is_preprint":false},{"pmid":"26311421","id":"PMC_26311421","title":"Compartmentalization of membrane trafficking, glucose transport, glycolysis, actin, tubulin and the proteasome in the cytoplasmic droplet/Hermes body of epididymal sperm.","date":"2015","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/26311421","citation_count":24,"is_preprint":false},{"pmid":"25808494","id":"PMC_25808494","title":"Expression, sorting, and segregation of Golgi proteins during germ cell differentiation in the testis.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/25808494","citation_count":23,"is_preprint":false},{"pmid":"26881866","id":"PMC_26881866","title":"Classification of Cholestatic and Necrotic Hepatotoxicants Using Transcriptomics on Human Precision-Cut Liver Slices.","date":"2016","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/26881866","citation_count":21,"is_preprint":false},{"pmid":"38453906","id":"PMC_38453906","title":"RHBDL4-triggered downregulation of COPII adaptor protein TMED7 suppresses TLR4-mediated inflammatory signaling.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38453906","citation_count":19,"is_preprint":false},{"pmid":"26678074","id":"PMC_26678074","title":"The Golgi-Associated Plant Pathogenesis-Related Protein GAPR-1 Enhances Type I Interferon Signaling Pathway in Response to Toll-Like Receptor 4.","date":"2016","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26678074","citation_count":16,"is_preprint":false},{"pmid":"20807314","id":"PMC_20807314","title":"Dilysine retrieval signal-containing p24 proteins collaborate in inhibiting γ-cleavage of amyloid precursor protein.","date":"2010","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20807314","citation_count":11,"is_preprint":false},{"pmid":"33911883","id":"PMC_33911883","title":"Overexpression of microRNA-340-5p Ameliorates Inflammatory Response and Intracellular Survival of Mycobacterium Tuberculosis in Alveolar Type II Cells.","date":"2021","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/33911883","citation_count":5,"is_preprint":false},{"pmid":"39844587","id":"PMC_39844587","title":"Several variants on chromosome 10 are associated with coarse hair diameter in Dazu black goats (Capra hircus).","date":"2025","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39844587","citation_count":5,"is_preprint":false},{"pmid":"21118709","id":"PMC_21118709","title":"p24 Proteins from the same subfamily are functionally nonredundant.","date":"2010","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/21118709","citation_count":5,"is_preprint":false},{"pmid":"32435407","id":"PMC_32435407","title":"Predictive Gene Signature for Pyrazolopyrimidine Derivative c-Src Inhibitor 10a Sensitivity in Melanoma Cells.","date":"2020","source":"ACS medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/32435407","citation_count":4,"is_preprint":false},{"pmid":"33148610","id":"PMC_33148610","title":"AGS3-dependent trans-Golgi network membrane trafficking is essential for compaction in mouse embryos.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33148610","citation_count":3,"is_preprint":false},{"pmid":"37491993","id":"PMC_37491993","title":"Anterograde trafficking of Toll-like receptors requires the cargo sorting adaptors TMED-2 and 7.","date":"2023","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/37491993","citation_count":2,"is_preprint":false},{"pmid":"40874303","id":"PMC_40874303","title":"Transcriptomic and Proteomic Insights Into Buffalo Milk Fat Synthesis and the Role of IGFBP4 in BMECs.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40874303","citation_count":2,"is_preprint":false},{"pmid":"41877912","id":"PMC_41877912","title":"Proteomic Analysis of Cerebrospinal Fluid: Toward the Identification of Biomarkers for Early Central Nervous System Infection.","date":"2026","source":"Infection and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/41877912","citation_count":0,"is_preprint":false},{"pmid":"42205681","id":"PMC_42205681","title":"Evolocumab Alters Transcriptomic Signatures and Identifies Inflammatory Biomarkers in Brain-Heart Syndrome with Coronary Heart Disease History.","date":"2026","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42205681","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12896,"output_tokens":3223,"usd":0.043516,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10599,"output_tokens":3278,"usd":0.067473,"stage2_stop_reason":"end_turn"},"total_usd":0.110989,"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\": 2014,\n      \"finding\": \"TMED7 is required for trafficking of TLR4 from the endoplasmic reticulum to the cell surface through the Golgi. TMED7 forms a stable complex with the ectodomain of TLR4, an interaction requiring the coiled-coil and GOLD domains but not the cytosolic COPII sorting motif of TMED7. Depletion of TMED7 reduces MyD88-dependent TLR4 signaling but not TRIF/TRAM-mediated signaling. Truncated TMED7 lacking the COPII sorting motif or transmembrane domain is mislocalized and causes ligand-independent signaling from intracellularly accumulated receptors.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/truncation analysis, siRNA knockdown, reporter assays for MyD88- and TRIF-dependent signaling, confocal microscopy\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction studies with domain mapping, loss-of-function with specific pathway readouts, and localization experiments in a single focused study\",\n      \"pmids\": [\"25074978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TMED7 inhibits MyD88-independent TLR4 signaling from endosomes. Upon LPS stimulation, TMED7 co-localizes with TRAM and TLR4 in late endosomes. TMED7 is essential for TAG-mediated disruption of the TRAM/TRIF complex and subsequent degradation of TLR4. TMED7 overexpression inhibits TRAM- or LPS-induced IRF3-signaling pathway activation, while TMED7 knockdown enhances RANTES production after LPS stimulation.\",\n      \"method\": \"Overexpression and knockdown studies, co-immunoprecipitation, co-localization by confocal microscopy, cytokine ELISA, reporter assays for IRF3 pathway\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, localization, knockdown/OE with specific pathway readouts), single rigorous study\",\n      \"pmids\": [\"22426228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The intramembrane protease RHBDL4 negatively regulates TLR4 signaling by triggering degradation of TMED7, thereby counteracting TLR4 transport to the cell surface. TLR4 activation transcriptionally upregulates RHBDL4, creating a negative feedback loop that reduces TLR4 plasma membrane trafficking. This mechanism prevents over-activation of TLR4-dependent signaling during Mycobacterium tuberculosis macrophage infection and alleviates septic shock in a mouse model.\",\n      \"method\": \"RHBDL4 gain/loss-of-function, western blotting for TMED7 protein levels, flow cytometry for TLR4 surface expression, cytokine assays, in vitro macrophage infection model, mouse septic shock model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vitro and in vivo models, clear mechanism (RHBDL4 degrades TMED7 to limit TLR4 trafficking), replicated across model systems\",\n      \"pmids\": [\"38453906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GAPR-1 (phosphorylated at Ser58 by IRAK1 downstream of MyD88 signaling) interacts with TMED7, and this phosphorylation-dependent interaction impairs TMED7-mediated disruption of the TRAM-TRIF complex, thereby promoting IFN-β and IL-10 secretion downstream of TLR4.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, overexpression/knockdown, ELISA for IFN-β and IL-10\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and functional assays from a single lab with no independent replication reported\",\n      \"pmids\": [\"26678074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMED7 interacts with TLR2, TLR4, and TLR5 but not with TLR3 or TLR9 in protein interaction studies. Dominant-negative forms of TMED7 suppress the export of cell-surface TLRs from the ER to the Golgi, establishing TMED7 as a cargo sorting adaptor specifically required for anterograde trafficking of plasma membrane-destined TLRs.\",\n      \"method\": \"Protein interaction studies (co-immunoprecipitation/pulldown), dominant-negative TMED7 expression, confocal microscopy for TLR trafficking\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction studies with multiple TLR family members and dominant-negative functional validation, single lab\",\n      \"pmids\": [\"37491993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TMED2/p24beta(1) loss in the 99J mouse mutant results in absence of its oligomerization partners TMED7/p24gamma(3) and TMED10/p24delta(1) from affected tissues, demonstrating that TMED7 protein stability/localization depends on TMED2 within hetero-oligomeric p24 complexes.\",\n      \"method\": \"ENU mutagenesis mouse model, immunohistochemistry and western blotting for TMED7 and TMED10 protein levels in mutant vs wild-type tissues\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with direct protein detection of TMED7 complex partners, single study\",\n      \"pmids\": [\"20178780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Xenopus melanotrope cells, transgenic overexpression of p24gamma(3) (TMED7 ortholog) affects endogenous p24gamma(3) levels, reduces cargo (POMC) cleavage rate (suggesting reduced ER-to-Golgi transport), and affects POMC glycosylation, demonstrating a non-redundant role for this p24 subfamily member in early secretory pathway cargo processing distinct from other p24 members.\",\n      \"method\": \"Melanotrope cell-specific transgene expression in Xenopus laevis, pulse-chase radiolabeling, glycosylation and sulfation assays, western blotting\",\n      \"journal\": \"Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts, ortholog study in Xenopus\",\n      \"pmids\": [\"18699773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Xenopus melanotrope cells, p24gamma(3) (TMED7 ortholog) has a distinct function from its subfamily relative p24gamma(2) in secretory cargo transport, glycosylation, sulfation, and cleavage of POMC, demonstrating functional non-redundancy even among same-subfamily p24 proteins.\",\n      \"method\": \"Melanotrope-specific transgene expression in Xenopus, POMC processing assays (glycosylation, sulfation, cleavage)\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic Xenopus model with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"21118709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMED7/p27 localizes specifically to unstacked flattened Golgi cisternae of the Hermes body (cytoplasmic droplet) of epididymal sperm, as determined by quantitative electron microscope gold antibody labeling, and is segregated from the acrosome during spermiogenesis. TMED7-positive vesicles (~50 nm) emanate from these Golgi cisternae, proposed to transport GLUT-3 to the plasma membrane.\",\n      \"method\": \"Quantitative electron microscopy immunogold labeling, tandem mass spectrometry, light microscopy immunolocalization\",\n      \"journal\": \"Open Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electron microscopy localization with gold labeling, quantitative mass spectrometry, single study\",\n      \"pmids\": [\"26311421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"During acrosome formation in spermiogenesis, TMED7/p27 is segregated from the acrosome and continues to mark Golgi identity as the Golgi migrates away from the acrosome in later steps of spermatid differentiation.\",\n      \"method\": \"Immunofluorescence microscopy, subcellular fractionation, mass spectrometry of germ cell Golgi fractions\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence and fractionation, single study\",\n      \"pmids\": [\"25808494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In early mouse embryos, AGS3 knockout causes dispersal of TMED7-positive vesicles (tracked by fluorescent protein tagging) and impairs their polarization toward the membrane, with concomitant reduction of E-cadherin (Cdh1) at cell-contact surfaces. This establishes TMED7-positive vesicles as carriers of Cdh1 cargo to the plasma membrane in a process regulated by AGS3/Gαi signaling.\",\n      \"method\": \"CRISPR/Cas9 knockout of AGS3, fluorescent protein tagging of TMED7 and TGN46 in mouse embryos, live imaging, immunofluorescence\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live fluorescent imaging of TMED7-tagged vesicles in a genetic loss-of-function model with specific cargo (Cdh1) readout, single study\",\n      \"pmids\": [\"33148610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of p24gamma(3)/TMED7 did not alter Aβ secretion or APP processing in cell-based and cell-free assays, indicating TMED7 does not modulate gamma-secretase cleavage of APP (negative result).\",\n      \"method\": \"siRNA knockdown, cell-based and cell-free Aβ secretion assays\",\n      \"journal\": \"Journal of Neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with loss-of-function, single lab, explicitly negative result\",\n      \"pmids\": [\"20807314\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMED7 is a p24 family cargo sorting adaptor that forms hetero-oligomeric complexes with TMED2 and TMED10, functions at the ER-Golgi interface to facilitate anterograde trafficking of specific transmembrane cargoes (including TLR4, TLR2, and TLR5) to the plasma membrane via its GOLD/coiled-coil ectodomain interactions, and also acts as a negative regulator of endosomal TLR4/TRAM-TRIF signaling; TMED7 abundance is itself controlled post-translationally by the intramembrane protease RHBDL4, which degrades TMED7 to limit TLR4 surface delivery in a TLR4-activated negative feedback loop.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMED7 is a p24-family cargo sorting adaptor of the early secretory pathway that selects specific transmembrane cargoes for anterograde ER-to-Golgi-to-plasma membrane transport [#0, #4]. Its best-defined cargo class is the cell-surface Toll-like receptors: TMED7 binds the ectodomains of TLR2, TLR4, and TLR5 but not endosomal TLR3 or TLR9, and dominant-negative TMED7 blocks export of these receptors from the ER, identifying it as a sorting adaptor dedicated to plasma-membrane-destined TLRs [#0, #4]. Productive trafficking of TLR4 requires the TMED7 coiled-coil and GOLD ectodomain for cargo binding and its cytosolic COPII sorting motif and transmembrane anchor for correct localization; loss of TMED7 reduces MyD88-dependent TLR4 signaling, whereas truncated TMED7 mislocalizes receptors and drives ligand-independent signaling [#0]. Beyond receptor delivery, TMED7 acts as a negative regulator of endosomal TLR4 signaling, where it co-localizes with TRAM and TLR4 in late endosomes and is required for TAG-mediated disruption of the TRAM/TRIF complex and TLR4 degradation, restraining IRF3-dependent output [#1]; this brake is relieved when IRAK1-phosphorylated GAPR-1 binds TMED7 and impairs its disruption of the TRAM-TRIF complex [#3]. TMED7 abundance is set post-translationally: the intramembrane protease RHBDL4, transcriptionally induced upon TLR4 activation, degrades TMED7 to limit TLR4 surface delivery in a negative feedback loop that constrains inflammatory output in macrophage infection and septic shock [#2]. As a hetero-oligomeric p24 subunit, TMED7 stability depends on its partner TMED2, whose loss eliminates TMED7 and TMED10 from tissues [#5], and the protein marks Golgi-derived transport vesicles that carry other cargoes such as E-cadherin to the cell surface under AGS3/Gαi control [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that this p24 subfamily member has a non-redundant role in early secretory cargo handling, ruling out simple functional interchangeability among p24 proteins.\",\n      \"evidence\": \"Melanotrope-specific transgenic overexpression of the p24gamma(3)/TMED7 ortholog in Xenopus with POMC pulse-chase, glycosylation and sulfation assays\",\n      \"pmids\": [\"18699773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific cargo selectivity in mammalian cells not addressed\", \"Ortholog overexpression in a single cell type; physiological substrates undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that TMED7 protein stability within the secretory pathway is enforced by hetero-oligomerization, defining it as an obligate complex subunit rather than a standalone factor.\",\n      \"evidence\": \"ENU-mutant 99J mouse lacking TMED2 with immunohistochemistry and western blotting of TMED7 and TMED10 in tissues; parallel Xenopus transgenic studies of subfamily non-redundancy and a negative APP/Abeta result\",\n      \"pmids\": [\"20178780\", \"21118709\", \"20807314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the TMED2/7/10 complex not resolved\", \"Whether TMED7 has activity outside the complex untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a signaling-regulatory role distinct from trafficking by showing TMED7 restrains endosomal TLR4-TRAM-TRIF output.\",\n      \"evidence\": \"Overexpression/knockdown, co-IP, confocal co-localization with TRAM/TLR4 in late endosomes, IRF3 reporter and RANTES ELISA\",\n      \"pmids\": [\"22426228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which TMED7 enables TAG-mediated TRAM/TRIF disruption unresolved\", \"Direct binding interface with TRAM not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the cargo-adaptor mechanism, demonstrating TMED7 binds the TLR4 ectodomain via its coiled-coil/GOLD domains and uses its COPII motif for forward transport.\",\n      \"evidence\": \"Co-IP with domain deletion/truncation mapping, siRNA knockdown with MyD88- vs TRIF-specific reporters, confocal microscopy\",\n      \"pmids\": [\"25074978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ectodomain recognition not determined\", \"How a single adaptor reconciles trafficking versus endosomal signaling-inhibition roles unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a signal-dependent switch that disables the TMED7 brake, linking MyD88/IRAK1 activity to enhanced TRIF-branch cytokine output.\",\n      \"evidence\": \"Co-IP, Ser58 phosphorylation assay, overexpression/knockdown, IFN-beta and IL-10 ELISA\",\n      \"pmids\": [\"26678074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Direct effect of GAPR-1 binding on the TMED7-TRAM-TRIF interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized TMED7's adaptor function across the surface-TLR family, showing selective binding and export control for TLR2/4/5 but not endosomal TLR3/9.\",\n      \"evidence\": \"Protein interaction studies, dominant-negative TMED7 expression, confocal microscopy of TLR ER-to-Golgi export\",\n      \"pmids\": [\"37491993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants distinguishing surface- from endosome-TLRs as cargo not defined\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Closed the regulatory loop by identifying RHBDL4 as the protease that degrades TMED7 to dampen TLR4 surface delivery, providing in vivo relevance to infection and sepsis.\",\n      \"evidence\": \"RHBDL4 gain/loss-of-function, western blot of TMED7, flow cytometry of surface TLR4, cytokine assays, macrophage M. tuberculosis infection and mouse septic shock models\",\n      \"pmids\": [\"38453906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site and processing intermediates of TMED7 by RHBDL4 not mapped\", \"Whether RHBDL4 also regulates TMED7-dependent non-TLR cargo unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMED7 mechanistically partitions between forward cargo transport (TLR2/4/5, E-cadherin, GLUT-3) and its endosomal signaling-inhibitory function, and the structural basis of its cargo selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TMED7-cargo recognition\", \"Full set of physiological cargoes undefined\", \"Coordination between trafficking and signaling roles unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 8, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\"TMED2/TMED7/TMED10 p24 hetero-oligomer\"],\n    \"partners\": [\"TLR4\", \"TLR2\", \"TLR5\", \"TMED2\", \"TMED10\", \"TRAM\", \"GAPR-1\", \"RHBDL4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}