{"gene":"SEC24D","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2007,"finding":"SEC24D directly binds to a C-terminal RL motif (566RL567) of the GABA transporter 1 (GAT1) via residues 733DD734 in SEC24D, and this interaction is required for concentrative ER export of GAT1; knockdown of SEC24D, dominant-negative SEC24D-VN (DD→VN), or mutation of the RL motif all impair ER export of GAT1 and related SLC6 family transporters (SERT, DAT).","method":"RNA interference knockdown, dominant-negative overexpression (SEC24D-VN), site-directed mutagenesis of cargo (GAT1-RL/AS) and SEC24D (DD734VN), co-immunoprecipitation, ER export assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal mutagenesis approaches (both cargo and adaptor sides), functional ER export assays, dominant-negative and RNAi in same study","pmids":["17210573"],"is_preprint":false},{"year":2010,"finding":"Sec24D (zebrafish bulldog mutant) is specifically required for ER export of extracellular matrix proteins (type II collagen, matrilin) in chondrocytes; loss of Sec24D causes ER dilation, ER stress (BiP upregulation), and failure of ECM secretion, while membrane-bound β1-Integrin and Cadherins exit the ER in a Sec24D-independent manner. Sec24C can partially compensate early but not during chondrocyte maturation.","method":"Forward genetic screen, positional cloning, immunofluorescence microscopy, electron microscopy, NBD-ceramide Golgi staining, RT-PCR (BiP), morpholino knockdown of Sec24C","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (EM, IF, genetic rescue), replicated in medaka (vbi) model, establishes cargo selectivity","pmids":["20442775"],"is_preprint":false},{"year":2010,"finding":"sec24d (medaka vbi mutant) is essential for secretion of ECM components (type II collagen) from craniofacial chondrocytes and notochord cells; loss causes ER dilation and defective ECM secretion leading to skeletal defects.","method":"Positional cloning, immunofluorescence microscopy, electron microscopy","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — orthologous finding to zebrafish bulldog, replicated across two independent vertebrate models with EM and IF","pmids":["20346938"],"is_preprint":false},{"year":2013,"finding":"SEC24D is essential for early mammalian embryonic development (required before the 8-cell stage in mouse); complete Sec24d knockout causes early embryonic lethality not compensated by other SEC24 paralogs, while haploinsufficiency produces no phenotype and a BAC transgene rescues lethality.","method":"Targeted gene disruption (knockout mouse), BAC transgene rescue, hypomorphic allele characterization","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with transgenic rescue, establishes non-redundant essential role in vivo","pmids":["23596517"],"is_preprint":false},{"year":2015,"finding":"Missense mutations in SEC24D (p.Ser1015Phe in the cargo-binding pocket; p.Gln978Pro in the gelsolin-like domain) cause inefficient ER export of procollagen and ER tubule dilation in patient skin fibroblasts, phenocopying SEC23A-mutant CLSD, establishing SEC24D as a cargo adaptor critical for procollagen trafficking.","method":"Whole-exome sequencing, electron microscopy, immunofluorescence microscopy of patient fibroblasts","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 — direct cellular imaging of patient-derived cells with multiple microscopy modalities; replicated across three individuals","pmids":["25683121"],"is_preprint":false},{"year":2017,"finding":"CREB3L2/BBF2H7 transcriptionally upregulates SEC24D (along with SEC23A) during hepatic stellate cell activation, and SEC24D-mediated ER-to-Golgi trafficking is required for HSC activation, as knockdown of SEC24D abrogates this process.","method":"Gene expression analysis, siRNA knockdown, HSC activation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, knockdown with phenotypic readout but limited mechanistic follow-up on SEC24D specifically","pmids":["28801610"],"is_preprint":false},{"year":2021,"finding":"SEC24D can functionally substitute for SEC24C during embryonic development when knocked into the Sec24c locus (Sec24c→Sec24d knock-in mice survive to birth vs. E7.5 lethality of Sec24c null), indicating that tissue/stage-specific expression rather than cargo specificity differences primarily explains their distinct developmental requirements.","method":"Dual recombinase-mediated cassette exchange to generate Sec24c^c-d knock-in mice, developmental phenotyping","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — precise genetic replacement experiment with survival rescue demonstrating functional overlap at the molecular level","pmids":["34702932"],"is_preprint":false},{"year":2024,"finding":"SEC24D is required for autophagosome closure in mammalian cells; depletion of SEC24D leads to accumulation of unsealed isolation membranes, and under starvation conditions SEC24D interacts with casein kinase 1δ (CK1δ) and ATG9A.","method":"SEC24D siRNA knockdown, autophagosome closure assay, co-immunoprecipitation (SEC24D–CK1δ, SEC24D–ATG9A), starvation-induced autophagy assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — KD with defined cellular phenotype (unsealed membranes) and co-IP of interactors; single lab","pmids":["39056365"],"is_preprint":false},{"year":2025,"finding":"SEC24D depletion or mutation impairs osteogenic differentiation of mesenchymal stem cells by inducing ER stress and inactivating the ATF6/TGF-β/Runx2 regulatory loop; ATF6 mediates the effect of SEC24D on TGF-β pathway activity and osteogenic biomarkers.","method":"SEC24D knockdown and patient-derived mutation in MSCs, transcriptomic sequencing, in vitro osteogenic differentiation assay, functional ATF6/TGF-β pathway analysis","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomics + functional pathway validation; single lab","pmids":["40374976"],"is_preprint":false},{"year":2025,"finding":"Sec24D is modified by site-specific O-linked β-N-acetylglucosamine (O-GlcNAc) in its N-terminal intrinsically disordered region upon induction of collagen transport; these glycosylations are required for collagen trafficking in human cells and developing zebrafish, and crosslinking proteomics showed each O-GlcNAcylation site distinctly regulates the Sec24D interactome. Specifically, Sec24D glycosylation is required for interaction with myoferlin, which facilitates fusion of ER exit sites (ERES) and the ERGIC to enable collagen transport.","method":"Mass spectrometry (O-GlcNAc site mapping), crosslinking proteomics, mutagenesis of glycosylation sites, collagen trafficking assays in human cells and zebrafish, co-immunoprecipitation (Sec24D–myoferlin)","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — crosslinking proteomics + site mutagenesis + in vivo rescue in zebrafish; multiple orthogonal methods in single preprint study","pmids":["40661455"],"is_preprint":true},{"year":2025,"finding":"SEC24D-positive ER exit sites preferentially recruit lipid raft-associated cargo for rapid ER export, dependent on p24-family cargo adaptors TMED2/10; raft-excluded cargo localizes to SEC24A-positive ERES, while raft-preferring cargo localizes to SEC24D ERES, and SEC24D ERES accumulate a fluorescent cholesterol analog.","method":"RUSH (Retention Using Selective Hooks) synchronized trafficking assay, fluorescence microscopy, SEC24A/SEC24D isoform-specific ERES localization, TMED2/10 dependency assay, fluorescent cholesterol analog labeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — synchronized trafficking system with multiple cargo types, isoform-specific localization, and mechanistic dependence on TMED2/10 established","pmids":["41309618"],"is_preprint":false},{"year":2025,"finding":"A synonymous variant in SEC24D (c.2361C>T; p.Asn787=) causes aberrant skipping of exon 18, markedly reducing SEC24D protein expression, demonstrating that splicing regulation is a mechanism controlling SEC24D levels; this leads to defective collagen secretion and OI.","method":"Whole-exome sequencing, RNA-seq, qPCR, Western blot in patient cells","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional RNA and protein analysis in patient-derived cells; single lab","pmids":["41188448"],"is_preprint":false},{"year":2026,"finding":"A 5'UTR variant in SEC24D (c.-167C>T) introduces an upstream ATG that reduces translational efficiency of the canonical SEC24D protein without altering mRNA levels; antisense oligonucleotides (ASOs) targeting this uATG restore SEC24D protein levels in patient fibroblasts.","method":"Functional studies in patient-derived fibroblasts (Western blot, qPCR), ASO treatment to modulate translation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — protein vs. mRNA dissociation establishes post-transcriptional mechanism; functional ASO rescue provides orthogonal support; single lab","pmids":["41495099"],"is_preprint":false}],"current_model":"SEC24D is a cargo-selective COPII coat adaptor that mediates ER export of specific cargoes—including procollagen/ECM proteins (via its cargo-binding pocket), SLC6 family neurotransmitter transporters (via direct binding to their RL motif through SEC24D residues DD733–734), and lipid raft-preferring membrane proteins (at SEC24D-marked ERES dependent on TMED2/10)—and is dynamically regulated by site-specific O-GlcNAcylation in its disordered N-terminal region, which remodels its interactome (including recruitment of myoferlin for ERES–ERGIC fusion) to accommodate large collagen cargo; SEC24D is also required for autophagosome closure (interacting with CK1δ and ATG9A), and its loss activates ER stress and impairs osteogenic differentiation via the ATF6/TGF-β/Runx2 axis."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that SEC24D is a cargo-selective COPII adaptor resolved whether individual SEC24 paralogs have distinct cargo specificities; SEC24D was shown to directly bind the RL motif of GAT1 through its DD733–734 residues, with this interaction required for ER export of SLC6 family transporters.","evidence":"RNAi, dominant-negative overexpression, site-directed mutagenesis of both cargo and adaptor, co-IP, and ER export assays in mammalian cells","pmids":["17210573"],"confidence":"High","gaps":["Whether DD733–734 recognizes additional non-SLC6 cargo motifs was not tested","Structural basis of the RL–DD interaction was not resolved"]},{"year":2010,"claim":"Forward genetic screens in zebrafish and medaka independently demonstrated that Sec24D is specifically required for ER export of ECM proteins (type II collagen, matrilin) from chondrocytes, while transmembrane proteins like integrins and cadherins exit the ER independently of Sec24D, establishing cargo-class selectivity in vivo.","evidence":"Positional cloning in two vertebrate models, EM showing ER dilation, immunofluorescence for cargo retention, BiP upregulation for ER stress","pmids":["20442775","20346938"],"confidence":"High","gaps":["Direct biochemical interaction between Sec24D and procollagen cargo signals was not demonstrated","Whether ER stress is a secondary consequence or contributes to pathology was unclear"]},{"year":2013,"claim":"Mouse knockout showed SEC24D is non-redundantly essential before the 8-cell stage, establishing that no other SEC24 paralog compensates for its loss during early mammalian embryogenesis despite overlapping cargo recognition.","evidence":"Targeted gene disruption in mouse with BAC transgene rescue","pmids":["23596517"],"confidence":"High","gaps":["The specific essential cargo at the pre-8-cell stage was not identified","Whether lethality reflects a unique cargo or expression-level requirement was unresolved"]},{"year":2015,"claim":"Patient-derived mutations in SEC24D's cargo-binding pocket and gelsolin-like domain were shown to impair procollagen ER export and cause ER tubule dilation, directly linking SEC24D cargo recognition to human skeletal disease resembling cranio-lenticulo-sutural dysplasia.","evidence":"Whole-exome sequencing of three affected individuals, EM and immunofluorescence of patient fibroblasts","pmids":["25683121"],"confidence":"High","gaps":["Whether SEC24D directly contacts a procollagen sorting signal or acts via a co-receptor was not established","Genotype–phenotype correlation across the SEC24D structure was limited"]},{"year":2021,"claim":"A knock-in experiment replacing Sec24c with Sec24d coding sequence rescued the early lethality of Sec24c-null mice, demonstrating that SEC24C and SEC24D share sufficient molecular function and that their distinct developmental requirements primarily reflect tissue-specific expression patterns rather than cargo-specificity differences.","evidence":"Dual recombinase-mediated cassette exchange generating Sec24c→Sec24d knock-in mice with developmental phenotyping","pmids":["34702932"],"confidence":"High","gaps":["Post-natal and tissue-specific phenotypes of the knock-in were not fully characterized","Whether any cargo discriminates between SEC24C and SEC24D in vivo remained unresolved"]},{"year":2024,"claim":"Identifying SEC24D as required for autophagosome closure expanded its function beyond canonical ER-to-Golgi transport; depletion caused accumulation of unsealed isolation membranes, and SEC24D interacted with CK1δ and ATG9A under starvation.","evidence":"siRNA knockdown, autophagosome closure assay, co-immunoprecipitation under starvation conditions","pmids":["39056365"],"confidence":"Medium","gaps":["Whether SEC24D acts at the autophagosome membrane directly or through ERES-derived vesicles is unknown","Reciprocal validation of the CK1δ and ATG9A interactions was not reported","The mechanism by which SEC24D promotes membrane sealing was not defined"]},{"year":2025,"claim":"Multiple 2025 studies collectively defined how SEC24D achieves cargo-class specificity at ER exit sites and how its activity is dynamically regulated: SEC24D-positive ERES preferentially handle lipid raft-associated cargo via TMED2/10, and O-GlcNAcylation of SEC24D's N-terminal disordered region remodels its interactome to recruit myoferlin for ERES–ERGIC fusion during collagen transport; meanwhile, SEC24D loss impairs osteogenesis through ER stress and ATF6/TGF-β/Runx2 axis inactivation.","evidence":"RUSH synchronized trafficking with isoform-specific ERES localization and TMED2/10 dependency (peer-reviewed); crosslinking proteomics and site-specific O-GlcNAc mutagenesis with in vivo zebrafish rescue (preprint); transcriptomics and pathway analysis in MSCs (peer-reviewed)","pmids":["41309618","40661455","40374976"],"confidence":"High","gaps":["Structural basis for how O-GlcNAcylation remodels the SEC24D interactome is unknown","Whether myoferlin-mediated ERES–ERGIC fusion is specific to collagen-transporting cells or a general mechanism is untested","The direct interaction between SEC24D and lipid raft cargo versus indirect recruitment by TMED2/10 is not resolved"]},{"year":2025,"claim":"Identification of a synonymous variant and a 5'UTR variant in SEC24D causing disease through splicing disruption and translational repression, respectively, established that SEC24D protein levels are rate-limiting and subject to post-transcriptional control mechanisms relevant to osteogenesis imperfecta.","evidence":"RNA-seq and Western blot in patient fibroblasts; ASO-mediated rescue of translation from uATG-containing 5'UTR","pmids":["41188448","41495099"],"confidence":"Medium","gaps":["Whether ASO rescue of SEC24D levels is sufficient to restore collagen secretion in patient cells was not shown","Prevalence of post-transcriptional regulatory variants in SEC24D across OI cohorts is unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for how SEC24D directly engages procollagen or its sorting receptor, how O-GlcNAcylation-driven interactome remodeling is spatiotemporally regulated, and whether SEC24D's role in autophagosome closure operates through ERES-derived membrane supply or a distinct mechanism.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal structure of SEC24D bound to procollagen or a collagen-specific sorting receptor","Mechanism linking O-GlcNAcylation to specific interactome changes is unresolved","SEC24D's contribution to autophagosome closure versus canonical COPII transport has not been mechanistically delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,4,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,4,9,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,4,9,10]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,4,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2,4,9]}],"complexes":["COPII coat"],"partners":["SEC23A","TMED2","TMED10","MYOF","CSNK1D","ATG9A","GAT1"],"other_free_text":[]},"mechanistic_narrative":"SEC24D is a cargo-selective component of the COPII coat that mediates ER-to-Golgi transport of specific client proteins, with a particularly critical role in the secretion of extracellular matrix components including procollagen. SEC24D directly recognizes cargo sorting signals—such as the RL motif of SLC6 family neurotransmitter transporters via its DD733–734 residues—and its cargo-binding pocket is essential for procollagen export, as demonstrated by patient mutations causing osteogenesis imperfecta and cranio-lenticulo-sutural dysplasia-like skeletal phenotypes [PMID:17210573, PMID:25683121, PMID:20442775]. SEC24D-marked ER exit sites preferentially recruit lipid raft-associated cargo in a TMED2/10-dependent manner, and site-specific O-GlcNAcylation of SEC24D's disordered N-terminus remodels its interactome—including recruitment of myoferlin to facilitate ERES–ERGIC fusion—to accommodate large collagen cargo [PMID:41309618, PMID:40661455]. Beyond canonical secretory trafficking, SEC24D is required for autophagosome closure through interactions with CK1δ and ATG9A, and its depletion impairs osteogenic differentiation via ER stress-mediated inactivation of the ATF6/TGF-β/Runx2 axis [PMID:39056365, PMID:40374976]."},"prefetch_data":{"uniprot":{"accession":"O94855","full_name":"Protein transport protein Sec24D","aliases":["SEC24-related protein D"],"length_aa":1032,"mass_kda":113.0,"function":"Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:17499046, PubMed:18843296, PubMed:20427317). Plays a central role in cargo selection within the COPII complex and together with SEC24C may have a different specificity compared to SEC24A and SEC24B (PubMed:17499046, PubMed:18843296, PubMed:20427317). May more specifically package GPI-anchored proteins through the cargo receptor TMED10 (PubMed:20427317). May also be specific for IxM motif-containing cargos like the SNAREs GOSR2 and STX5 (PubMed:18843296)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O94855/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC24D","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000150961","cell_line_id":"CID001910","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"SEC23A","stoichiometry":10.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SEC23B","stoichiometry":0.2},{"gene":"NRBF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001910","total_profiled":1310},"omim":[{"mim_id":"616294","title":"COLE-CARPENTER SYNDROME 2; CLCRP2","url":"https://www.omim.org/entry/616294"},{"mim_id":"616215","title":"cAMP RESPONSE ELEMENT-BINDING PROTEIN 3-LIKE 1; CREB3L1","url":"https://www.omim.org/entry/616215"},{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"},{"mim_id":"607186","title":"SEC24-RELATED GENE FAMILY, MEMBER D; SEC24D","url":"https://www.omim.org/entry/607186"},{"mim_id":"607185","title":"SEC24-RELATED GENE FAMILY, MEMBER C; SEC24C","url":"https://www.omim.org/entry/607185"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC24D"},"hgnc":{"alias_symbol":["KIAA0755"],"prev_symbol":[]},"alphafold":{"accession":"O94855","domains":[{"cath_id":"3.40.50.410","chopping":"441-596_629-684","consensus_level":"high","plddt":97.3795,"start":441,"end":684},{"cath_id":"3.40.20.10","chopping":"888-1005","consensus_level":"medium","plddt":93.0481,"start":888,"end":1005}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94855","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94855-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94855-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC24D","jax_strain_url":"https://www.jax.org/strain/search?query=SEC24D"},"sequence":{"accession":"O94855","fasta_url":"https://rest.uniprot.org/uniprotkb/O94855.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94855/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94855"}},"corpus_meta":[{"pmid":"25683121","id":"PMC_25683121","title":"Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25683121","citation_count":135,"is_preprint":false},{"pmid":"20442775","id":"PMC_20442775","title":"Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20442775","citation_count":118,"is_preprint":false},{"pmid":"17210573","id":"PMC_17210573","title":"Concentrative export from the endoplasmic reticulum of the gamma-aminobutyric acid transporter 1 requires binding to SEC24D.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17210573","citation_count":90,"is_preprint":false},{"pmid":"23596517","id":"PMC_23596517","title":"Disruption of the Sec24d gene results in early embryonic lethality in the mouse.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23596517","citation_count":51,"is_preprint":false},{"pmid":"20346938","id":"PMC_20346938","title":"sec24d encoding a component of COPII is essential for vertebra formation, revealed by the analysis of the medaka mutant, vbi.","date":"2010","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/20346938","citation_count":49,"is_preprint":false},{"pmid":"27942778","id":"PMC_27942778","title":"Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta.","date":"2016","source":"Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA","url":"https://pubmed.ncbi.nlm.nih.gov/27942778","citation_count":29,"is_preprint":false},{"pmid":"28801610","id":"PMC_28801610","title":"CREB3L2-mediated expression of Sec23A/Sec24D is involved in 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41432301","citation_count":0,"is_preprint":false},{"pmid":"41495099","id":"PMC_41495099","title":"A rare 5'UTR variant in SEC24D reveals translational dysfunction in osteogenesis imperfecta: a roadmap for RNA therapeutic rescue.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41495099","citation_count":0,"is_preprint":false},{"pmid":"37303662","id":"PMC_37303662","title":"SEC24D gene as a biomarker in human cancers and its association with CD8+ T cell immune cell infiltration.","date":"2023","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/37303662","citation_count":0,"is_preprint":false},{"pmid":"41188448","id":"PMC_41188448","title":"Elucidating the impact of a synonymous SEC24D variant on aberrant splicing in a patient with cole-carpenter syndrome 2.","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41188448","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.23.661175","title":"Genetically encoded nAChR upregulation is neuroprotective in female parkinsonian mice","date":"2025-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.661175","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12574,"output_tokens":3295,"usd":0.043574},"stage2":{"model":"claude-opus-4-6","input_tokens":6726,"output_tokens":2714,"usd":0.15222},"total_usd":0.195794,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"SEC24D directly binds to a C-terminal RL motif (566RL567) of the GABA transporter 1 (GAT1) via residues 733DD734 in SEC24D, and this interaction is required for concentrative ER export of GAT1; knockdown of SEC24D, dominant-negative SEC24D-VN (DD→VN), or mutation of the RL motif all impair ER export of GAT1 and related SLC6 family transporters (SERT, DAT).\",\n      \"method\": \"RNA interference knockdown, dominant-negative overexpression (SEC24D-VN), site-directed mutagenesis of cargo (GAT1-RL/AS) and SEC24D (DD734VN), co-immunoprecipitation, ER export assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal mutagenesis approaches (both cargo and adaptor sides), functional ER export assays, dominant-negative and RNAi in same study\",\n      \"pmids\": [\"17210573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sec24D (zebrafish bulldog mutant) is specifically required for ER export of extracellular matrix proteins (type II collagen, matrilin) in chondrocytes; loss of Sec24D causes ER dilation, ER stress (BiP upregulation), and failure of ECM secretion, while membrane-bound β1-Integrin and Cadherins exit the ER in a Sec24D-independent manner. Sec24C can partially compensate early but not during chondrocyte maturation.\",\n      \"method\": \"Forward genetic screen, positional cloning, immunofluorescence microscopy, electron microscopy, NBD-ceramide Golgi staining, RT-PCR (BiP), morpholino knockdown of Sec24C\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (EM, IF, genetic rescue), replicated in medaka (vbi) model, establishes cargo selectivity\",\n      \"pmids\": [\"20442775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"sec24d (medaka vbi mutant) is essential for secretion of ECM components (type II collagen) from craniofacial chondrocytes and notochord cells; loss causes ER dilation and defective ECM secretion leading to skeletal defects.\",\n      \"method\": \"Positional cloning, immunofluorescence microscopy, electron microscopy\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthologous finding to zebrafish bulldog, replicated across two independent vertebrate models with EM and IF\",\n      \"pmids\": [\"20346938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEC24D is essential for early mammalian embryonic development (required before the 8-cell stage in mouse); complete Sec24d knockout causes early embryonic lethality not compensated by other SEC24 paralogs, while haploinsufficiency produces no phenotype and a BAC transgene rescues lethality.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), BAC transgene rescue, hypomorphic allele characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with transgenic rescue, establishes non-redundant essential role in vivo\",\n      \"pmids\": [\"23596517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Missense mutations in SEC24D (p.Ser1015Phe in the cargo-binding pocket; p.Gln978Pro in the gelsolin-like domain) cause inefficient ER export of procollagen and ER tubule dilation in patient skin fibroblasts, phenocopying SEC23A-mutant CLSD, establishing SEC24D as a cargo adaptor critical for procollagen trafficking.\",\n      \"method\": \"Whole-exome sequencing, electron microscopy, immunofluorescence microscopy of patient fibroblasts\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cellular imaging of patient-derived cells with multiple microscopy modalities; replicated across three individuals\",\n      \"pmids\": [\"25683121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREB3L2/BBF2H7 transcriptionally upregulates SEC24D (along with SEC23A) during hepatic stellate cell activation, and SEC24D-mediated ER-to-Golgi trafficking is required for HSC activation, as knockdown of SEC24D abrogates this process.\",\n      \"method\": \"Gene expression analysis, siRNA knockdown, HSC activation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with phenotypic readout but limited mechanistic follow-up on SEC24D specifically\",\n      \"pmids\": [\"28801610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC24D can functionally substitute for SEC24C during embryonic development when knocked into the Sec24c locus (Sec24c→Sec24d knock-in mice survive to birth vs. E7.5 lethality of Sec24c null), indicating that tissue/stage-specific expression rather than cargo specificity differences primarily explains their distinct developmental requirements.\",\n      \"method\": \"Dual recombinase-mediated cassette exchange to generate Sec24c^c-d knock-in mice, developmental phenotyping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — precise genetic replacement experiment with survival rescue demonstrating functional overlap at the molecular level\",\n      \"pmids\": [\"34702932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC24D is required for autophagosome closure in mammalian cells; depletion of SEC24D leads to accumulation of unsealed isolation membranes, and under starvation conditions SEC24D interacts with casein kinase 1δ (CK1δ) and ATG9A.\",\n      \"method\": \"SEC24D siRNA knockdown, autophagosome closure assay, co-immunoprecipitation (SEC24D–CK1δ, SEC24D–ATG9A), starvation-induced autophagy assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — KD with defined cellular phenotype (unsealed membranes) and co-IP of interactors; single lab\",\n      \"pmids\": [\"39056365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC24D depletion or mutation impairs osteogenic differentiation of mesenchymal stem cells by inducing ER stress and inactivating the ATF6/TGF-β/Runx2 regulatory loop; ATF6 mediates the effect of SEC24D on TGF-β pathway activity and osteogenic biomarkers.\",\n      \"method\": \"SEC24D knockdown and patient-derived mutation in MSCs, transcriptomic sequencing, in vitro osteogenic differentiation assay, functional ATF6/TGF-β pathway analysis\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomics + functional pathway validation; single lab\",\n      \"pmids\": [\"40374976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sec24D is modified by site-specific O-linked β-N-acetylglucosamine (O-GlcNAc) in its N-terminal intrinsically disordered region upon induction of collagen transport; these glycosylations are required for collagen trafficking in human cells and developing zebrafish, and crosslinking proteomics showed each O-GlcNAcylation site distinctly regulates the Sec24D interactome. Specifically, Sec24D glycosylation is required for interaction with myoferlin, which facilitates fusion of ER exit sites (ERES) and the ERGIC to enable collagen transport.\",\n      \"method\": \"Mass spectrometry (O-GlcNAc site mapping), crosslinking proteomics, mutagenesis of glycosylation sites, collagen trafficking assays in human cells and zebrafish, co-immunoprecipitation (Sec24D–myoferlin)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crosslinking proteomics + site mutagenesis + in vivo rescue in zebrafish; multiple orthogonal methods in single preprint study\",\n      \"pmids\": [\"40661455\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC24D-positive ER exit sites preferentially recruit lipid raft-associated cargo for rapid ER export, dependent on p24-family cargo adaptors TMED2/10; raft-excluded cargo localizes to SEC24A-positive ERES, while raft-preferring cargo localizes to SEC24D ERES, and SEC24D ERES accumulate a fluorescent cholesterol analog.\",\n      \"method\": \"RUSH (Retention Using Selective Hooks) synchronized trafficking assay, fluorescence microscopy, SEC24A/SEC24D isoform-specific ERES localization, TMED2/10 dependency assay, fluorescent cholesterol analog labeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — synchronized trafficking system with multiple cargo types, isoform-specific localization, and mechanistic dependence on TMED2/10 established\",\n      \"pmids\": [\"41309618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A synonymous variant in SEC24D (c.2361C>T; p.Asn787=) causes aberrant skipping of exon 18, markedly reducing SEC24D protein expression, demonstrating that splicing regulation is a mechanism controlling SEC24D levels; this leads to defective collagen secretion and OI.\",\n      \"method\": \"Whole-exome sequencing, RNA-seq, qPCR, Western blot in patient cells\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional RNA and protein analysis in patient-derived cells; single lab\",\n      \"pmids\": [\"41188448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A 5'UTR variant in SEC24D (c.-167C>T) introduces an upstream ATG that reduces translational efficiency of the canonical SEC24D protein without altering mRNA levels; antisense oligonucleotides (ASOs) targeting this uATG restore SEC24D protein levels in patient fibroblasts.\",\n      \"method\": \"Functional studies in patient-derived fibroblasts (Western blot, qPCR), ASO treatment to modulate translation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — protein vs. mRNA dissociation establishes post-transcriptional mechanism; functional ASO rescue provides orthogonal support; single lab\",\n      \"pmids\": [\"41495099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC24D is a cargo-selective COPII coat adaptor that mediates ER export of specific cargoes—including procollagen/ECM proteins (via its cargo-binding pocket), SLC6 family neurotransmitter transporters (via direct binding to their RL motif through SEC24D residues DD733–734), and lipid raft-preferring membrane proteins (at SEC24D-marked ERES dependent on TMED2/10)—and is dynamically regulated by site-specific O-GlcNAcylation in its disordered N-terminal region, which remodels its interactome (including recruitment of myoferlin for ERES–ERGIC fusion) to accommodate large collagen cargo; SEC24D is also required for autophagosome closure (interacting with CK1δ and ATG9A), and its loss activates ER stress and impairs osteogenic differentiation via the ATF6/TGF-β/Runx2 axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC24D is a cargo-selective component of the COPII coat that mediates ER-to-Golgi transport of specific client proteins, with a particularly critical role in the secretion of extracellular matrix components including procollagen. SEC24D directly recognizes cargo sorting signals—such as the RL motif of SLC6 family neurotransmitter transporters via its DD733–734 residues—and its cargo-binding pocket is essential for procollagen export, as demonstrated by patient mutations causing osteogenesis imperfecta and cranio-lenticulo-sutural dysplasia-like skeletal phenotypes [PMID:17210573, PMID:25683121, PMID:20442775]. SEC24D-marked ER exit sites preferentially recruit lipid raft-associated cargo in a TMED2/10-dependent manner, and site-specific O-GlcNAcylation of SEC24D's disordered N-terminus remodels its interactome—including recruitment of myoferlin to facilitate ERES–ERGIC fusion—to accommodate large collagen cargo [PMID:41309618, PMID:40661455]. Beyond canonical secretory trafficking, SEC24D is required for autophagosome closure through interactions with CK1δ and ATG9A, and its depletion impairs osteogenic differentiation via ER stress-mediated inactivation of the ATF6/TGF-β/Runx2 axis [PMID:39056365, PMID:40374976].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that SEC24D is a cargo-selective COPII adaptor resolved whether individual SEC24 paralogs have distinct cargo specificities; SEC24D was shown to directly bind the RL motif of GAT1 through its DD733–734 residues, with this interaction required for ER export of SLC6 family transporters.\",\n      \"evidence\": \"RNAi, dominant-negative overexpression, site-directed mutagenesis of both cargo and adaptor, co-IP, and ER export assays in mammalian cells\",\n      \"pmids\": [\"17210573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DD733–734 recognizes additional non-SLC6 cargo motifs was not tested\", \"Structural basis of the RL–DD interaction was not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Forward genetic screens in zebrafish and medaka independently demonstrated that Sec24D is specifically required for ER export of ECM proteins (type II collagen, matrilin) from chondrocytes, while transmembrane proteins like integrins and cadherins exit the ER independently of Sec24D, establishing cargo-class selectivity in vivo.\",\n      \"evidence\": \"Positional cloning in two vertebrate models, EM showing ER dilation, immunofluorescence for cargo retention, BiP upregulation for ER stress\",\n      \"pmids\": [\"20442775\", \"20346938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical interaction between Sec24D and procollagen cargo signals was not demonstrated\", \"Whether ER stress is a secondary consequence or contributes to pathology was unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mouse knockout showed SEC24D is non-redundantly essential before the 8-cell stage, establishing that no other SEC24 paralog compensates for its loss during early mammalian embryogenesis despite overlapping cargo recognition.\",\n      \"evidence\": \"Targeted gene disruption in mouse with BAC transgene rescue\",\n      \"pmids\": [\"23596517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific essential cargo at the pre-8-cell stage was not identified\", \"Whether lethality reflects a unique cargo or expression-level requirement was unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Patient-derived mutations in SEC24D's cargo-binding pocket and gelsolin-like domain were shown to impair procollagen ER export and cause ER tubule dilation, directly linking SEC24D cargo recognition to human skeletal disease resembling cranio-lenticulo-sutural dysplasia.\",\n      \"evidence\": \"Whole-exome sequencing of three affected individuals, EM and immunofluorescence of patient fibroblasts\",\n      \"pmids\": [\"25683121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SEC24D directly contacts a procollagen sorting signal or acts via a co-receptor was not established\", \"Genotype–phenotype correlation across the SEC24D structure was limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A knock-in experiment replacing Sec24c with Sec24d coding sequence rescued the early lethality of Sec24c-null mice, demonstrating that SEC24C and SEC24D share sufficient molecular function and that their distinct developmental requirements primarily reflect tissue-specific expression patterns rather than cargo-specificity differences.\",\n      \"evidence\": \"Dual recombinase-mediated cassette exchange generating Sec24c→Sec24d knock-in mice with developmental phenotyping\",\n      \"pmids\": [\"34702932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-natal and tissue-specific phenotypes of the knock-in were not fully characterized\", \"Whether any cargo discriminates between SEC24C and SEC24D in vivo remained unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying SEC24D as required for autophagosome closure expanded its function beyond canonical ER-to-Golgi transport; depletion caused accumulation of unsealed isolation membranes, and SEC24D interacted with CK1δ and ATG9A under starvation.\",\n      \"evidence\": \"siRNA knockdown, autophagosome closure assay, co-immunoprecipitation under starvation conditions\",\n      \"pmids\": [\"39056365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SEC24D acts at the autophagosome membrane directly or through ERES-derived vesicles is unknown\", \"Reciprocal validation of the CK1δ and ATG9A interactions was not reported\", \"The mechanism by which SEC24D promotes membrane sealing was not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies collectively defined how SEC24D achieves cargo-class specificity at ER exit sites and how its activity is dynamically regulated: SEC24D-positive ERES preferentially handle lipid raft-associated cargo via TMED2/10, and O-GlcNAcylation of SEC24D's N-terminal disordered region remodels its interactome to recruit myoferlin for ERES–ERGIC fusion during collagen transport; meanwhile, SEC24D loss impairs osteogenesis through ER stress and ATF6/TGF-β/Runx2 axis inactivation.\",\n      \"evidence\": \"RUSH synchronized trafficking with isoform-specific ERES localization and TMED2/10 dependency (peer-reviewed); crosslinking proteomics and site-specific O-GlcNAc mutagenesis with in vivo zebrafish rescue (preprint); transcriptomics and pathway analysis in MSCs (peer-reviewed)\",\n      \"pmids\": [\"41309618\", \"40661455\", \"40374976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how O-GlcNAcylation remodels the SEC24D interactome is unknown\", \"Whether myoferlin-mediated ERES–ERGIC fusion is specific to collagen-transporting cells or a general mechanism is untested\", \"The direct interaction between SEC24D and lipid raft cargo versus indirect recruitment by TMED2/10 is not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of a synonymous variant and a 5'UTR variant in SEC24D causing disease through splicing disruption and translational repression, respectively, established that SEC24D protein levels are rate-limiting and subject to post-transcriptional control mechanisms relevant to osteogenesis imperfecta.\",\n      \"evidence\": \"RNA-seq and Western blot in patient fibroblasts; ASO-mediated rescue of translation from uATG-containing 5'UTR\",\n      \"pmids\": [\"41188448\", \"41495099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ASO rescue of SEC24D levels is sufficient to restore collagen secretion in patient cells was not shown\", \"Prevalence of post-transcriptional regulatory variants in SEC24D across OI cohorts is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for how SEC24D directly engages procollagen or its sorting receptor, how O-GlcNAcylation-driven interactome remodeling is spatiotemporally regulated, and whether SEC24D's role in autophagosome closure operates through ERES-derived membrane supply or a distinct mechanism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal structure of SEC24D bound to procollagen or a collagen-specific sorting receptor\", \"Mechanism linking O-GlcNAcylation to specific interactome changes is unresolved\", \"SEC24D's contribution to autophagosome closure versus canonical COPII transport has not been mechanistically delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 4, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 4, 9, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 4, 9, 10]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 4, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2, 4, 9]}\n    ],\n    \"complexes\": [\n      \"COPII coat\"\n    ],\n    \"partners\": [\n      \"SEC23A\",\n      \"TMED2\",\n      \"TMED10\",\n      \"MYOF\",\n      \"CSNK1D\",\n      \"ATG9A\",\n      \"GAT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}