{"gene":"MIA2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2016,"finding":"TALI (MIA2/cTAGE5 fusion product) physically binds TANGO1, and both interact with apolipoprotein B (ApoB). TANGO1 and TALI are both required for recruitment of ApoB-containing lipid particles (pre-chylomicrons/pre-VLDLs) to ER exit sites and their subsequent export from the ER, whereas procollagen XII export by the same cells requires only TANGO1.","method":"Co-immunoprecipitation, siRNA knockdown with cargo-export readouts, cell fractionation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding demonstrated, functional knockdown with specific cargo-export phenotypes, cargo specificity established by parallel depletion experiments in same cells","pmids":["27138255"],"is_preprint":false},{"year":2011,"finding":"Mia2 localizes to ER exit sites in hepatocytes. Its cytosolic C-terminus directly interacts with COPII proteins Sec23 and Sec24. A recessive point mutation (couch potato) in the SH3 domain of Mia2 reduces plasma VLDL, LDL, HDL, and triglycerides in mice, establishing Mia2 as a hepatic ER-to-Golgi trafficking protein regulating cholesterol and lipid metabolism.","method":"Forward genetic screen in mice, subcellular fractionation/localization, direct binding assay with COPII proteins (Sec23/Sec24), plasma lipoprotein fractionation","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with defined mutation, direct protein-protein interaction assay, ER exit-site localization, multiple lipid phenotypes measured","pmids":["21807889"],"is_preprint":false},{"year":2016,"finding":"Hepatocyte-specific deletion of Mea6/cTAGE5 in mice causes severe fatty liver and hypolipemia. Mea6/cTAGE5 interacts with COPII components, and its loss impairs secretion of lipids (including VLDL) and proteins from the liver, demonstrating a critical role in coordinating COPII assembly for ER-to-Golgi lipid transport.","method":"Conditional knockout mice, quantitative lipidomics, quantitative proteomics, co-immunoprecipitation with COPII components","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal readouts (lipidomics, proteomics, Co-IP), replicated the COPII interaction finding independently of Pitman et al.","pmids":["27311593"],"is_preprint":false},{"year":2018,"finding":"Conditional knockout of cTAGE5/MEA6 in the brain reveals it is required for COPII vesicle formation by regulating the interaction between SAR1 and SEC23; its loss leads to persistent SAR1 activation, defective ER-to-Golgi transport, impaired trafficking of membrane components in neurons, and severe defects in dendrite outgrowth, spine formation, and astrocyte activation.","method":"Conditional knockout mice (brain-specific), co-immunoprecipitation of COPII components (SAR1, SEC23), intracellular trafficking assays, morphological and behavioral analyses","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal methods (Co-IP, trafficking assays, morphological readouts, behavior), mechanistic link to SAR1-SEC23 interaction","pmids":["30224460"],"is_preprint":false},{"year":2007,"finding":"MIA2 expression in hepatocytes is driven by HNF-1 binding to its promoter at position -236. Loss of HNF-1 in HCC reduces MIA2 expression. Re-expression of MIA2 in HCC cells reduces invasive potential and proliferation in vitro and in vivo. Recombinant MIA2 protein also inhibits HCC cell proliferation and invasion.","method":"Promoter mutagenesis, stable transfection of HCC cell lines, invasion assays, proliferation assays, nude mouse xenograft model, recombinant protein treatment","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in vitro and in vivo, promoter mutagenesis; single lab","pmids":["17881540"],"is_preprint":false},{"year":2003,"finding":"MIA2 promoter contains an HNF-1 binding site at position -236 that controls hepatocyte-specific expression; mutation of this site abolishes promoter activity in HepG2 cells. SMAD and STAT3 binding sites are also present, and MIA2 mRNA is induced by IL-6, TGF-β, and conditioned medium from activated hepatic stellate cells.","method":"Promoter reporter assays, site-directed mutagenesis, RT-PCR, cytokine stimulation experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis with functional reporter readout, cytokine stimulation; single lab","pmids":["12586826"],"is_preprint":false},{"year":2019,"finding":"MEA6/cTAGE5 ablation in Purkinje cells or all neurons leads to arrested secretory proteins (Slit2, BDNF) in the ER, establishing that MEA6 is required for ER export of these signaling proteins in the cerebellum and that its loss disrupts cerebellar development and motor performance.","method":"Conditional knockout mice (Nestin-Cre and pCP2-Cre), immunohistochemistry for ER-retained proteins, behavioral tests","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific cargo retention demonstrated by immunohistochemistry; single lab","pmids":["31244610"],"is_preprint":false},{"year":2021,"finding":"Deletion of Mea6 specifically in cerebellar granule cells impairs intracellular transport of vesicular glutamate transporter 1 (VGLUT1) and BDNF, disrupts parallel fiber-Purkinje cell synaptic development, and causes abnormal motor behavior, indicating Mea6 is required for trafficking of synaptic components in granule cells.","method":"Math1-Cre conditional knockout mice, immunohistochemistry, behavioral tests (rotarod, balance beam)","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined cargo trafficking defect; single lab","pmids":["33718348"],"is_preprint":false},{"year":2023,"finding":"Conditional knockout of Mea6/cTAGE5 in oligodendrocytes impairs white matter microstructure and significantly alters myelin lipid composition, particularly reducing very long chain fatty acid (VLCFA)-containing phosphatidylcholines, likely due to downregulated ELOVL elongase expression.","method":"Conditional knockout mice, diffusion MRI, lipidomic analysis of purified myelin sheath","journal":"Life metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with quantitative lipidomics of purified myelin; single lab","pmids":["39872732"],"is_preprint":false},{"year":2024,"finding":"Mea6/cTAGE5 interacts with TRAPPC12, and both localize to ER exit sites where they regulate COPII component distribution (SEC13, SEC31A, SAR1). Loss of Mea6 in oligodendrocyte progenitor cells (OPCs) disrupts TRAPPC12 distribution and impairs secretion of pleiotrophin (PTN); exogenous PTN supplementation rescues OPC differentiation deficits.","method":"Co-immunoprecipitation, conditional knockout mice, rescue experiment with exogenous PTN, immunofluorescence for COPII components","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional rescue experiment; single lab","pmids":["38439956"],"is_preprint":false},{"year":2025,"finding":"cTAGE5/MEA6 localizes not only to ER exit sites but also to other ER structures where it directly interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR localization to the inner nuclear membrane (causing its ER retention and instability), leading to abnormal nuclear envelope morphology, cellular senescence via the P53/P21 pathway, premature aging, and embryonic lethality in conditional knockout mice.","method":"Conditional knockout mice, co-immunoprecipitation of cTAGE5 with LBR, immunofluorescence for LBR localization, MEF cell senescence assays, P53/P21 pathway analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus localization with functional consequence; single lab, single publication","pmids":["40739853"],"is_preprint":false},{"year":2025,"finding":"In medaka fish, knockout of Tali (the MIA2-encoded transmembrane isoform) does not produce a lethal phenotype and does not impair export of type II collagen from the ER, indicating that in this vertebrate model Tali is dispensable for large cargo export (in contrast to findings in mammalian systems).","method":"CRISPR/Cas9 knockout of individual splicing variants (Tali-KO, cTAGE5-KO) in medaka fish, collagen export assays","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific cargo readout; single lab, negative/null result for Tali in this species","pmids":["39842788"],"is_preprint":false}],"current_model":"MIA2/cTAGE5/MEA6 encodes a transmembrane ER exit-site protein that coordinates COPII vesicle assembly—by directly binding COPII components Sec23/Sec24 and regulating SAR1-SEC23 interactions—and cooperates with TANGO1 to enable ER export of bulky cargoes including ApoB-containing lipid particles (VLDL/chylomicrons); it also interacts with TRAPPC12 and LBR to regulate broader ER trafficking and nuclear envelope integrity, with loss-of-function causing fatty liver, dyslipidemia, neuronal and glial development defects, and premature aging in mice."},"narrative":{"mechanistic_narrative":"MIA2 (also known as cTAGE5/MEA6, with the transmembrane fusion isoform TALI) is a resident ER exit-site protein that organizes COPII-dependent export of secretory cargo from the endoplasmic reticulum [PMID:21807889, PMID:27311593]. Its cytosolic C-terminus directly binds the COPII inner-coat proteins Sec23 and Sec24, and it coordinates productive coat assembly by regulating the SAR1–SEC23 interaction; loss of the protein causes persistent SAR1 activation and blocks ER-to-Golgi transport [PMID:21807889, PMID:30224460]. A central function is the ER export of bulky and specialized cargo: together with TANGO1, MIA2/TALI binds apolipoprotein B and is required to recruit and export ApoB-containing lipid particles (pre-VLDLs/pre-chylomicrons), whereas procollagen export in the same cells depends only on TANGO1 [PMID:27138255]. Consistent with this, hepatic loss-of-function disrupts secretion of VLDL and other lipoproteins, producing fatty liver and dyslipidemia [PMID:21807889, PMID:27311593]. In the nervous system the protein is required for ER export of signaling and synaptic cargoes—Slit2, BDNF, and VGLUT1—and its loss disrupts dendrite and synapse development, cerebellar function, oligodendrocyte differentiation, and myelin lipid composition [PMID:30224460, PMID:31244610, PMID:33718348, PMID:39872732]. Beyond ER exit sites it interacts with TRAPPC12 to control COPII component distribution and with the lamin B receptor (LBR) to maintain inner nuclear membrane localization and nuclear envelope integrity, with loss driving cellular senescence via the P53/P21 pathway [PMID:38439956, PMID:40739853]. Hepatic MIA2 expression is driven by HNF-1 and induced by IL-6 and TGF-β [PMID:12586826].","teleology":[{"year":2003,"claim":"Established how MIA2 transcription is controlled, identifying the cis-regulatory basis for its hepatocyte-restricted expression and its responsiveness to inflammatory and fibrogenic signals.","evidence":"Promoter reporter assays, site-directed mutagenesis, and cytokine stimulation in HepG2 cells","pmids":["12586826"],"confidence":"Medium","gaps":["Did not address protein function or subcellular role","SMAD/STAT3 site occupancy inferred from sequence, not direct binding"]},{"year":2007,"claim":"Linked MIA2 expression to HCC behavior, showing re-expression suppresses proliferation and invasion, raising a possible tumor-suppressive role downstream of HNF-1.","evidence":"Promoter mutagenesis, HCC cell transfection, invasion/proliferation assays, nude mouse xenografts, recombinant protein treatment","pmids":["17881540"],"confidence":"Medium","gaps":["Molecular mechanism of growth suppression unresolved","Relationship between secretory function and tumor phenotype not established","Single lab"]},{"year":2011,"claim":"Defined MIA2 as an ER exit-site protein that directly binds COPII coat components and regulates systemic lipid metabolism, converting a transcription-focused gene into a trafficking factor.","evidence":"Forward genetic screen (couch potato mutant), subcellular fractionation, direct Sec23/Sec24 binding assay, plasma lipoprotein fractionation in mice","pmids":["21807889"],"confidence":"High","gaps":["Did not establish the cargo selectivity mechanism","Role of TANGO1 cooperation not yet defined"]},{"year":2016,"claim":"Resolved the cargo logic of ER export: MIA2/TALI cooperates with TANGO1 and binds ApoB to selectively export lipoprotein particles, distinguishing this pathway from TANGO1-only collagen export.","evidence":"Co-IP, siRNA knockdown with cargo-export readouts, cell fractionation (TALI study); conditional hepatocyte KO with lipidomics, proteomics, and COPII Co-IP (cTAGE5 study)","pmids":["27138255","27311593"],"confidence":"High","gaps":["Stoichiometry and assembly order of the TANGO1/TALI/COPII machinery unresolved","How bulky cargo size is sensed not defined"]},{"year":2018,"claim":"Provided the COPII regulatory mechanism, showing the protein controls the SAR1–SEC23 interaction and that its loss causes persistent SAR1 activation and trafficking failure in neurons.","evidence":"Brain-specific conditional KO mice, Co-IP of SAR1/SEC23, trafficking assays, morphological and behavioral analyses","pmids":["30224460"],"confidence":"High","gaps":["Direct biochemical mechanism of SAR1 cycling regulation not reconstituted","Generalizability beyond neurons to other cargoes untested"]},{"year":2021,"claim":"Extended the neuronal role to defined cargoes (Slit2, BDNF, VGLUT1) across cerebellar cell types, establishing the protein as essential for secretion of specific developmental and synaptic factors.","evidence":"Purkinje-cell, pan-neuronal, and granule-cell conditional KO mice; IHC for ER-retained cargo; behavioral testing","pmids":["31244610","33718348"],"confidence":"Medium","gaps":["Whether cargo selectivity reflects direct interactions or general COPII dependence unclear","Single lab"]},{"year":2024,"claim":"Identified TRAPPC12 as an ER exit-site partner controlling COPII component distribution, and showed pleiotrophin secretion underlies the oligodendrocyte differentiation requirement.","evidence":"Co-IP, conditional KO in OPCs, immunofluorescence for COPII components, rescue with exogenous PTN","pmids":["38439956"],"confidence":"Medium","gaps":["Functional hierarchy between MEA6 and TRAPPC12 at exit sites unresolved","Single lab"]},{"year":2025,"claim":"Revealed a non-canonical role beyond ER exit sites: direct interaction with LBR maintains inner nuclear membrane localization and nuclear envelope integrity, with loss driving P53/P21-dependent senescence and premature aging.","evidence":"Conditional KO mice, Co-IP of cTAGE5 with LBR, LBR localization imaging, MEF senescence and P53/P21 assays (aging study); medaka CRISPR KO of TALI isoform with collagen export readout (species comparison)","pmids":["40739853","39842788"],"confidence":"Medium","gaps":["Mechanism linking nuclear envelope defects to senescence not fully dissected","Medaka data indicate TALI is dispensable for large cargo export in fish, leaving species-specific requirements unexplained","Single lab per finding"]},{"year":null,"claim":"How the protein integrates its ER exit-site COPII function with its nuclear envelope (LBR) role, and how cargo selectivity is achieved mechanistically, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstituted biochemistry defining SAR1/SEC23 regulation","Structural basis of TANGO1/TALI/ApoB recruitment unknown","Reconciliation of mammalian vs. medaka cargo-export requirements unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,9,10]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["TANGO1","SEC23","SEC24","SAR1","TRAPPC12","LBR","APOB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PC5","full_name":"Melanoma inhibitory activity protein 2","aliases":["CTAGE family member 5 ER export factor","Cutaneous T-cell lymphoma-associated antigen 5","Meningioma-expressed antigen 6/11"],"length_aa":1412,"mass_kda":159.8,"function":"Plays a role in the transport of cargos that are too large to fit into COPII-coated vesicles and require specific mechanisms to be incorporated into membrane-bound carriers and exported from the endoplasmic reticulum (PubMed:21525241, PubMed:25202031, PubMed:27138255, PubMed:27170179). Plays a role in the secretion of lipoproteins, pre-chylomicrons and pre-VLDLs, by participating in their export from the endoplasmic reticulum (PubMed:27138255). Thereby, may play a role in cholesterol and triglyceride homeostasis (By similarity). Required for collagen VII (COL7A1) secretion by loading COL7A1 into transport carriers and recruiting PREB/SEC12 at the endoplasmic reticulum exit sites (PubMed:21525241, PubMed:25202031, PubMed:27170179)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96PC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MIA2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MIA2","total_profiled":1310},"omim":[{"mim_id":"619392","title":"CHROMOSOME 14 OPEN READING FRAME 180; C14ORF180","url":"https://www.omim.org/entry/619392"},{"mim_id":"609532","title":"HEPATITIS C VIRUS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609532"},{"mim_id":"602132","title":"MIA SH3 DOMAIN ER EXPORT FACTOR 2; MIA2","url":"https://www.omim.org/entry/602132"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":126.3}],"url":"https://www.proteinatlas.org/search/MIA2"},"hgnc":{"alias_symbol":["FLJ22404","TALI","MEA6","cTAGE-5A","cTAGE-5B","cTAGE-5C","cTAGE-5D","MGEA11"],"prev_symbol":["CTAGE5","MGEA","MGEA6"]},"alphafold":{"accession":"Q96PC5","domains":[{"cath_id":"2.30.30.40","chopping":"24-117","consensus_level":"high","plddt":87.7247,"start":24,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PC5-F1-predicted_aligned_error_v6.png","plddt_mean":54.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MIA2","jax_strain_url":"https://www.jax.org/strain/search?query=MIA2"},"sequence":{"accession":"Q96PC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PC5"}},"corpus_meta":[{"pmid":"27138255","id":"PMC_27138255","title":"TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum.","date":"2016","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27138255","citation_count":95,"is_preprint":false},{"pmid":"7980563","id":"PMC_7980563","title":"Isolation, sequence and expression of a novel mouse brain cDNA, mIA-2, and its relatedness to members of the protein tyrosine phosphatase family.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/7980563","citation_count":64,"is_preprint":false},{"pmid":"17881540","id":"PMC_17881540","title":"The novel gene MIA2 acts as a tumour suppressor in hepatocellular carcinoma.","date":"2007","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/17881540","citation_count":57,"is_preprint":false},{"pmid":"12586826","id":"PMC_12586826","title":"Specific expression and regulation of the new melanoma inhibitory activity-related gene MIA2 in hepatocytes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12586826","citation_count":42,"is_preprint":false},{"pmid":"27311593","id":"PMC_27311593","title":"Mea6 controls VLDL transport through the coordinated regulation of COPII assembly.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27311593","citation_count":42,"is_preprint":false},{"pmid":"21807889","id":"PMC_21807889","title":"Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites.","date":"2011","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/21807889","citation_count":35,"is_preprint":false},{"pmid":"30224460","id":"PMC_30224460","title":"cTAGE5/MEA6 plays a critical role in neuronal cellular components trafficking and brain development.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30224460","citation_count":22,"is_preprint":false},{"pmid":"18324751","id":"PMC_18324751","title":"TALI: local alignment of protein structures using backbone torsion angles.","date":"2008","source":"Journal of bioinformatics and computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/18324751","citation_count":15,"is_preprint":false},{"pmid":"22127256","id":"PMC_22127256","title":"Assessment of GFP expression and viability using the tali image-based cytometer.","date":"2011","source":"Journal of visualized experiments : JoVE","url":"https://pubmed.ncbi.nlm.nih.gov/22127256","citation_count":13,"is_preprint":false},{"pmid":"31244610","id":"PMC_31244610","title":"MEA6 Deficiency Impairs Cerebellar Development and Motor Performance by Tethering Protein Trafficking.","date":"2019","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31244610","citation_count":9,"is_preprint":false},{"pmid":"40274761","id":"PMC_40274761","title":"Novel humanized CD19-CAR-T (Now talicabtagene autoleucel, Tali-cel™) cells in relapsed/ refractory pediatric B-acute lymphoblastic leukemia- an open-label single-arm phase-I/Ib study.","date":"2025","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/40274761","citation_count":9,"is_preprint":false},{"pmid":"33718348","id":"PMC_33718348","title":"Deletion of Mea6 in Cerebellar Granule Cells Impairs Synaptic Development and Motor Performance.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33718348","citation_count":8,"is_preprint":false},{"pmid":"11838022","id":"PMC_11838022","title":"Characterization of the elusive disulfide bridge forming human Hb variant: Hb Ta-Li beta83 (EF7)Gly --> Cys by electrospray mass spectrometry.","date":"2002","source":"Journal of the American Society for Mass Spectrometry","url":"https://pubmed.ncbi.nlm.nih.gov/11838022","citation_count":8,"is_preprint":false},{"pmid":"39872732","id":"PMC_39872732","title":"Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content.","date":"2023","source":"Life metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39872732","citation_count":6,"is_preprint":false},{"pmid":"35436610","id":"PMC_35436610","title":"Molecular mechanisms underlying cTAGE5/MEA6-mediated cargo transport and biological functions.","date":"2022","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/35436610","citation_count":5,"is_preprint":false},{"pmid":"35812061","id":"PMC_35812061","title":"CircNRIP1 acts as a sponge of miR-1200 to suppress osteosarcoma progression via upregulation of MIA2.","date":"2022","source":"American journal of cancer 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science","url":"https://pubmed.ncbi.nlm.nih.gov/37530404","citation_count":2,"is_preprint":false},{"pmid":"39842788","id":"PMC_39842788","title":"Tango1L but not Tango1S, Tali and cTAGE5 is required for export of type II collagen in medaka fish.","date":"2025","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/39842788","citation_count":2,"is_preprint":false},{"pmid":"16529012","id":"PMC_16529012","title":"[Osteonecroses of the bilateral tali during maintenance therapy in a child with acute lymphoblastic leukemia].","date":"2006","source":"[Rinsho ketsueki] The Japanese journal of clinical hematology","url":"https://pubmed.ncbi.nlm.nih.gov/16529012","citation_count":1,"is_preprint":false},{"pmid":"40739853","id":"PMC_40739853","title":"cTAGE5/MEA6 Regulates LBR Localization to Maintain Nuclear Envelope Integrity and Safeguard Against Aging.","date":"2025","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/40739853","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.02.673840","title":"STX4 is indispensable for mitochondrial homeostasis in skeletal muscle","date":"2025-09-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.02.673840","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13722,"output_tokens":3073,"usd":0.043631,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10476,"output_tokens":3275,"usd":0.067128,"stage2_stop_reason":"end_turn"},"total_usd":0.110759,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"TALI (MIA2/cTAGE5 fusion product) physically binds TANGO1, and both interact with apolipoprotein B (ApoB). TANGO1 and TALI are both required for recruitment of ApoB-containing lipid particles (pre-chylomicrons/pre-VLDLs) to ER exit sites and their subsequent export from the ER, whereas procollagen XII export by the same cells requires only TANGO1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with cargo-export readouts, cell fractionation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding demonstrated, functional knockdown with specific cargo-export phenotypes, cargo specificity established by parallel depletion experiments in same cells\",\n      \"pmids\": [\"27138255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mia2 localizes to ER exit sites in hepatocytes. Its cytosolic C-terminus directly interacts with COPII proteins Sec23 and Sec24. A recessive point mutation (couch potato) in the SH3 domain of Mia2 reduces plasma VLDL, LDL, HDL, and triglycerides in mice, establishing Mia2 as a hepatic ER-to-Golgi trafficking protein regulating cholesterol and lipid metabolism.\",\n      \"method\": \"Forward genetic screen in mice, subcellular fractionation/localization, direct binding assay with COPII proteins (Sec23/Sec24), plasma lipoprotein fractionation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with defined mutation, direct protein-protein interaction assay, ER exit-site localization, multiple lipid phenotypes measured\",\n      \"pmids\": [\"21807889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hepatocyte-specific deletion of Mea6/cTAGE5 in mice causes severe fatty liver and hypolipemia. Mea6/cTAGE5 interacts with COPII components, and its loss impairs secretion of lipids (including VLDL) and proteins from the liver, demonstrating a critical role in coordinating COPII assembly for ER-to-Golgi lipid transport.\",\n      \"method\": \"Conditional knockout mice, quantitative lipidomics, quantitative proteomics, co-immunoprecipitation with COPII components\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal readouts (lipidomics, proteomics, Co-IP), replicated the COPII interaction finding independently of Pitman et al.\",\n      \"pmids\": [\"27311593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional knockout of cTAGE5/MEA6 in the brain reveals it is required for COPII vesicle formation by regulating the interaction between SAR1 and SEC23; its loss leads to persistent SAR1 activation, defective ER-to-Golgi transport, impaired trafficking of membrane components in neurons, and severe defects in dendrite outgrowth, spine formation, and astrocyte activation.\",\n      \"method\": \"Conditional knockout mice (brain-specific), co-immunoprecipitation of COPII components (SAR1, SEC23), intracellular trafficking assays, morphological and behavioral analyses\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal methods (Co-IP, trafficking assays, morphological readouts, behavior), mechanistic link to SAR1-SEC23 interaction\",\n      \"pmids\": [\"30224460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MIA2 expression in hepatocytes is driven by HNF-1 binding to its promoter at position -236. Loss of HNF-1 in HCC reduces MIA2 expression. Re-expression of MIA2 in HCC cells reduces invasive potential and proliferation in vitro and in vivo. Recombinant MIA2 protein also inhibits HCC cell proliferation and invasion.\",\n      \"method\": \"Promoter mutagenesis, stable transfection of HCC cell lines, invasion assays, proliferation assays, nude mouse xenograft model, recombinant protein treatment\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in vitro and in vivo, promoter mutagenesis; single lab\",\n      \"pmids\": [\"17881540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MIA2 promoter contains an HNF-1 binding site at position -236 that controls hepatocyte-specific expression; mutation of this site abolishes promoter activity in HepG2 cells. SMAD and STAT3 binding sites are also present, and MIA2 mRNA is induced by IL-6, TGF-β, and conditioned medium from activated hepatic stellate cells.\",\n      \"method\": \"Promoter reporter assays, site-directed mutagenesis, RT-PCR, cytokine stimulation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis with functional reporter readout, cytokine stimulation; single lab\",\n      \"pmids\": [\"12586826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEA6/cTAGE5 ablation in Purkinje cells or all neurons leads to arrested secretory proteins (Slit2, BDNF) in the ER, establishing that MEA6 is required for ER export of these signaling proteins in the cerebellum and that its loss disrupts cerebellar development and motor performance.\",\n      \"method\": \"Conditional knockout mice (Nestin-Cre and pCP2-Cre), immunohistochemistry for ER-retained proteins, behavioral tests\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific cargo retention demonstrated by immunohistochemistry; single lab\",\n      \"pmids\": [\"31244610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Deletion of Mea6 specifically in cerebellar granule cells impairs intracellular transport of vesicular glutamate transporter 1 (VGLUT1) and BDNF, disrupts parallel fiber-Purkinje cell synaptic development, and causes abnormal motor behavior, indicating Mea6 is required for trafficking of synaptic components in granule cells.\",\n      \"method\": \"Math1-Cre conditional knockout mice, immunohistochemistry, behavioral tests (rotarod, balance beam)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined cargo trafficking defect; single lab\",\n      \"pmids\": [\"33718348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional knockout of Mea6/cTAGE5 in oligodendrocytes impairs white matter microstructure and significantly alters myelin lipid composition, particularly reducing very long chain fatty acid (VLCFA)-containing phosphatidylcholines, likely due to downregulated ELOVL elongase expression.\",\n      \"method\": \"Conditional knockout mice, diffusion MRI, lipidomic analysis of purified myelin sheath\",\n      \"journal\": \"Life metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with quantitative lipidomics of purified myelin; single lab\",\n      \"pmids\": [\"39872732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mea6/cTAGE5 interacts with TRAPPC12, and both localize to ER exit sites where they regulate COPII component distribution (SEC13, SEC31A, SAR1). Loss of Mea6 in oligodendrocyte progenitor cells (OPCs) disrupts TRAPPC12 distribution and impairs secretion of pleiotrophin (PTN); exogenous PTN supplementation rescues OPC differentiation deficits.\",\n      \"method\": \"Co-immunoprecipitation, conditional knockout mice, rescue experiment with exogenous PTN, immunofluorescence for COPII components\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional rescue experiment; single lab\",\n      \"pmids\": [\"38439956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"cTAGE5/MEA6 localizes not only to ER exit sites but also to other ER structures where it directly interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR localization to the inner nuclear membrane (causing its ER retention and instability), leading to abnormal nuclear envelope morphology, cellular senescence via the P53/P21 pathway, premature aging, and embryonic lethality in conditional knockout mice.\",\n      \"method\": \"Conditional knockout mice, co-immunoprecipitation of cTAGE5 with LBR, immunofluorescence for LBR localization, MEF cell senescence assays, P53/P21 pathway analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus localization with functional consequence; single lab, single publication\",\n      \"pmids\": [\"40739853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In medaka fish, knockout of Tali (the MIA2-encoded transmembrane isoform) does not produce a lethal phenotype and does not impair export of type II collagen from the ER, indicating that in this vertebrate model Tali is dispensable for large cargo export (in contrast to findings in mammalian systems).\",\n      \"method\": \"CRISPR/Cas9 knockout of individual splicing variants (Tali-KO, cTAGE5-KO) in medaka fish, collagen export assays\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific cargo readout; single lab, negative/null result for Tali in this species\",\n      \"pmids\": [\"39842788\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIA2/cTAGE5/MEA6 encodes a transmembrane ER exit-site protein that coordinates COPII vesicle assembly—by directly binding COPII components Sec23/Sec24 and regulating SAR1-SEC23 interactions—and cooperates with TANGO1 to enable ER export of bulky cargoes including ApoB-containing lipid particles (VLDL/chylomicrons); it also interacts with TRAPPC12 and LBR to regulate broader ER trafficking and nuclear envelope integrity, with loss-of-function causing fatty liver, dyslipidemia, neuronal and glial development defects, and premature aging in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MIA2 (also known as cTAGE5/MEA6, with the transmembrane fusion isoform TALI) is a resident ER exit-site protein that organizes COPII-dependent export of secretory cargo from the endoplasmic reticulum [#1, #2]. Its cytosolic C-terminus directly binds the COPII inner-coat proteins Sec23 and Sec24, and it coordinates productive coat assembly by regulating the SAR1–SEC23 interaction; loss of the protein causes persistent SAR1 activation and blocks ER-to-Golgi transport [#1, #3]. A central function is the ER export of bulky and specialized cargo: together with TANGO1, MIA2/TALI binds apolipoprotein B and is required to recruit and export ApoB-containing lipid particles (pre-VLDLs/pre-chylomicrons), whereas procollagen export in the same cells depends only on TANGO1 [#0]. Consistent with this, hepatic loss-of-function disrupts secretion of VLDL and other lipoproteins, producing fatty liver and dyslipidemia [#1, #2]. In the nervous system the protein is required for ER export of signaling and synaptic cargoes—Slit2, BDNF, and VGLUT1—and its loss disrupts dendrite and synapse development, cerebellar function, oligodendrocyte differentiation, and myelin lipid composition [#3, #6, #7, #8]. Beyond ER exit sites it interacts with TRAPPC12 to control COPII component distribution and with the lamin B receptor (LBR) to maintain inner nuclear membrane localization and nuclear envelope integrity, with loss driving cellular senescence via the P53/P21 pathway [#9, #10]. Hepatic MIA2 expression is driven by HNF-1 and induced by IL-6 and TGF-\\u03b2 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established how MIA2 transcription is controlled, identifying the cis-regulatory basis for its hepatocyte-restricted expression and its responsiveness to inflammatory and fibrogenic signals.\",\n      \"evidence\": \"Promoter reporter assays, site-directed mutagenesis, and cytokine stimulation in HepG2 cells\",\n      \"pmids\": [\"12586826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address protein function or subcellular role\", \"SMAD/STAT3 site occupancy inferred from sequence, not direct binding\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked MIA2 expression to HCC behavior, showing re-expression suppresses proliferation and invasion, raising a possible tumor-suppressive role downstream of HNF-1.\",\n      \"evidence\": \"Promoter mutagenesis, HCC cell transfection, invasion/proliferation assays, nude mouse xenografts, recombinant protein treatment\",\n      \"pmids\": [\"17881540\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of growth suppression unresolved\", \"Relationship between secretory function and tumor phenotype not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined MIA2 as an ER exit-site protein that directly binds COPII coat components and regulates systemic lipid metabolism, converting a transcription-focused gene into a trafficking factor.\",\n      \"evidence\": \"Forward genetic screen (couch potato mutant), subcellular fractionation, direct Sec23/Sec24 binding assay, plasma lipoprotein fractionation in mice\",\n      \"pmids\": [\"21807889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the cargo selectivity mechanism\", \"Role of TANGO1 cooperation not yet defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the cargo logic of ER export: MIA2/TALI cooperates with TANGO1 and binds ApoB to selectively export lipoprotein particles, distinguishing this pathway from TANGO1-only collagen export.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with cargo-export readouts, cell fractionation (TALI study); conditional hepatocyte KO with lipidomics, proteomics, and COPII Co-IP (cTAGE5 study)\",\n      \"pmids\": [\"27138255\", \"27311593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the TANGO1/TALI/COPII machinery unresolved\", \"How bulky cargo size is sensed not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the COPII regulatory mechanism, showing the protein controls the SAR1\\u2013SEC23 interaction and that its loss causes persistent SAR1 activation and trafficking failure in neurons.\",\n      \"evidence\": \"Brain-specific conditional KO mice, Co-IP of SAR1/SEC23, trafficking assays, morphological and behavioral analyses\",\n      \"pmids\": [\"30224460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of SAR1 cycling regulation not reconstituted\", \"Generalizability beyond neurons to other cargoes untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the neuronal role to defined cargoes (Slit2, BDNF, VGLUT1) across cerebellar cell types, establishing the protein as essential for secretion of specific developmental and synaptic factors.\",\n      \"evidence\": \"Purkinje-cell, pan-neuronal, and granule-cell conditional KO mice; IHC for ER-retained cargo; behavioral testing\",\n      \"pmids\": [\"31244610\", \"33718348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether cargo selectivity reflects direct interactions or general COPII dependence unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified TRAPPC12 as an ER exit-site partner controlling COPII component distribution, and showed pleiotrophin secretion underlies the oligodendrocyte differentiation requirement.\",\n      \"evidence\": \"Co-IP, conditional KO in OPCs, immunofluorescence for COPII components, rescue with exogenous PTN\",\n      \"pmids\": [\"38439956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional hierarchy between MEA6 and TRAPPC12 at exit sites unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-canonical role beyond ER exit sites: direct interaction with LBR maintains inner nuclear membrane localization and nuclear envelope integrity, with loss driving P53/P21-dependent senescence and premature aging.\",\n      \"evidence\": \"Conditional KO mice, Co-IP of cTAGE5 with LBR, LBR localization imaging, MEF senescence and P53/P21 assays (aging study); medaka CRISPR KO of TALI isoform with collagen export readout (species comparison)\",\n      \"pmids\": [\"40739853\", \"39842788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking nuclear envelope defects to senescence not fully dissected\", \"Medaka data indicate TALI is dispensable for large cargo export in fish, leaving species-specific requirements unexplained\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the protein integrates its ER exit-site COPII function with its nuclear envelope (LBR) role, and how cargo selectivity is achieved mechanistically, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstituted biochemistry defining SAR1/SEC23 regulation\", \"Structural basis of TANGO1/TALI/ApoB recruitment unknown\", \"Reconciliation of mammalian vs. medaka cargo-export requirements unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 9, 10]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TANGO1\", \"SEC23\", \"SEC24\", \"SAR1\", \"TRAPPC12\", \"LBR\", \"APOB\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}