{"gene":"SEC23A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2006,"finding":"SEC23A is an essential component of COPII-coated vesicles mediating ER-to-Golgi transport; the disease-causing F382L substitution results in loss of SEC23A function in cell-free vesicle budding assays, causing gross ER dilatation and cytoplasmic mislocalization of SEC31 in patient fibroblasts.","method":"Positional cloning, cell-free vesicle budding assay, electron microscopy, immunofluorescence, zebrafish morpholino knockdown","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro vesicle budding reconstitution with mutant protein, corroborated by EM ultrastructure, immunofluorescence, and in vivo zebrafish model; replicated conceptually by parallel zebrafish paper (PMID:16980978)","pmids":["16980979"],"is_preprint":false},{"year":2006,"finding":"Zebrafish sec23a loss-of-function (crusher nonsense mutation L402X) causes chondrocyte ER distension and failure to secrete type II collagen and other ECM proteins into cartilage extracellular matrix, establishing SEC23A as an integral COPII component required for ECM secretion in chondrocytes.","method":"Positional cloning, zebrafish genetic mutant analysis, immunofluorescence, electron microscopy; sec23b knockdown (morpholino) shows paralog is also required","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with clear cellular phenotype (ER distension, collagen retention), replicated concept in parallel CLSD paper (PMID:16980979)","pmids":["16980978"],"is_preprint":false},{"year":2009,"finding":"BBF2H7 (CREB3L2) directly binds a CRE-like sequence in the Sec23a promoter to activate its transcription in response to ER stress; introduction of Sec23a into Bbf2h7-/- chondrocytes fully restores impaired cartilage matrix protein transport and secretion, placing SEC23A downstream of BBF2H7 in ER stress-to-ER-Golgi trafficking signaling.","method":"Bbf2h7 knockout mouse generation, promoter binding assay (ChIP/luciferase), Sec23a rescue experiment in knockout chondrocytes, immunofluorescence, genetic epistasis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockout rescue experiment with defined promoter binding plus multiple orthogonal methods; well-cited mechanistic study","pmids":["19767744"],"is_preprint":false},{"year":2011,"finding":"miR-200s directly target the 3'-UTR of SEC23A mRNA to suppress its expression, reducing secretion of metastasis-suppressive proteins Igfbp4 and Tinagl1 from the tumor cell secretome, thereby promoting metastatic colonization.","method":"3'-UTR reporter assay, proteomic/genomic analysis of secretome, functional rescue experiments in mouse breast cancer metastasis models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'-UTR targeting validated, secretome proteomics, in vivo mouse metastasis models with functional readout; highly cited, multiple orthogonal methods","pmids":["21822286"],"is_preprint":false},{"year":2011,"finding":"miR-375 and miR-200c each target the 3'-UTR of SEC23A mRNA to downregulate SEC23A protein expression; ectopic overexpression of SEC23A in prostate cancer cell lines reduces cell growth without inducing apoptosis, while inhibition of SEC23A stimulates proliferation.","method":"3'-UTR luciferase reporter assay, Western blot, qRT-PCR, cell growth assays in LNCaP and DU145 cells","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — 3'-UTR reporter validation plus functional overexpression/knockdown, single lab, two orthogonal methods","pmids":["21593139"],"is_preprint":false},{"year":2013,"finding":"ER stress impairs membrane association of COPII components, particularly Sec23a, reducing COPII vesicle formation at ER exit sites, and alters Sec23a cycling at ERESs.","method":"Fluorescence microscopy (ERES imaging), COPII vesicle formation assay, ER stress induction with pharmacological agents","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — live-cell imaging with functional assay, single lab, two methods","pmids":["23994533"],"is_preprint":false},{"year":2015,"finding":"SEC23A-deficient mice exhibit mid-embryonic lethality with defective extraembryonic membrane development and neural tube opening; multiple collagen types accumulate intracellularly in SEC23A-deficient connective tissue cells, triggering unfolded protein response, while fibronectin secretion is unaffected, showing SEC23A preferentially transports collagen cargo. SEC23A and SEC23B transport overlapping but distinct cargo spectra in vivo.","method":"Sec23a knockout mouse, immunofluorescence, Western blot for secreted vs. intracellular collagen/fibronectin, UPR markers; Sec23a/Sec23b compound null analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple cargo specificity experiments and UPR measurement; multiple orthogonal methods in single rigorous study","pmids":["26494538"],"is_preprint":false},{"year":2017,"finding":"ULK1 phosphorylates SEC23A at serine 207, serine 312, and threonine 405; phosphorylation at S207 reduces the interaction between SEC23A and SEC31A, causes ERES aggregation, and inhibits ER-to-Golgi cargo transport during autophagy induction.","method":"In vitro kinase assay, site-directed mutagenesis (S207A/D, S312A/D, T405A/E), Co-immunoprecipitation (SEC23A–SEC31A interaction), live-cell imaging of ERES, cargo transport assays under amino acid starvation/rapamycin/ULK1 overexpression","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation plus mutagenesis plus Co-IP plus functional transport assay; multiple orthogonal methods, single lab","pmids":["28486929"],"is_preprint":false},{"year":2017,"finding":"Sec23a ubiquitylation occurs at non-canonical cysteine residues (C432 and C449) as mono-ubiquitin attachment; mutation of these sites affects Sec23a interaction with ER membrane and modulates COPII formation, without targeting Sec23a for degradation.","method":"Co-immunoprecipitation, mass spectrometry (Gly-Gly remnant identification), site-directed mutagenesis of C432 and C449, immunofluorescence","journal":"The open biochemistry journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — MS identification of modification sites plus mutagenesis functional follow-up; single lab, two orthogonal methods","pmids":["28553408"],"is_preprint":false},{"year":2017,"finding":"CREB3L2/BBF2H7 transcriptionally upregulates SEC23A (and SEC24D) expression during hepatic stellate cell (HSC) activation; knockdown of SEC23A abrogates HSC activation, establishing that SEC23A-mediated ER-to-Golgi trafficking is required for this differentiation process.","method":"siRNA knockdown, Western blot, RT-PCR, HSC activation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown with defined cellular phenotype plus transcription factor target identification; single lab","pmids":["28801610"],"is_preprint":false},{"year":2018,"finding":"SEC23A and SEC23B have indistinguishable intracellular protein interactomes; both complement yeast Sec23; a Sec23a coding sequence knocked into the Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype in mice, demonstrating equivalent biochemical function with tissue-specific expression differences accounting for distinct phenotypes.","method":"Mass spectrometry interactome, yeast complementation, zebrafish transgene rescue, mouse knock-in (Sec23a coding sequence into Sec23b locus)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including knock-in rescue, yeast complementation, and interactome MS; rigorous in vivo genetic approach","pmids":["30065114"],"is_preprint":false},{"year":2018,"finding":"Sec23a functions downstream of miR-200c to suppress oligometastatic-to-polymetastatic progression via its secretome; mass spectrometric analysis of secretory protein profiles shows Sec23a-dependent secretome modifies the tumor microenvironment.","method":"miR-200c overexpression/Sec23a knockdown in paired oligometastatic/polymetastatic melanoma lines, in vivo metastasis assays, mass spectrometry of secretome","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis (Sec23a downstream of miR-200c), secretome MS, in vivo validation; single lab","pmids":["30301603"],"is_preprint":false},{"year":2020,"finding":"S100A8 is transported by SEC23A (as COPII cargo) and inhibits metastatic colonization via autocrine activation of autophagy through a SEC23A–S100A8–BECLIN1–autophagy axis.","method":"SEC23A knockdown/overexpression, secretome analysis, autophagy assays (LC3, BECLIN1), paired oligometastatic/polymetastatic melanoma cell lines, in vivo colonization assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional knockdown with defined secretome cargo and autophagy pathway readout; single lab, multiple assays","pmids":["32811814"],"is_preprint":false},{"year":2021,"finding":"SEC23A transports PF4 as COPII cargo; secreted PF4, cooperating with SPARC, inhibits melanoma metastasis through inhibition of the MAPK/ERK signaling pathway.","method":"SEC23A overexpression/knockdown in paired melanoma lines, secretome analysis, MAPK/ERK phosphorylation assays, in vivo metastasis assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional knockdown/overexpression with defined cargo and signaling pathway readout; single lab","pmids":["34421345"],"is_preprint":false},{"year":2021,"finding":"SEC23A expression is rescued in SEC23B-deficient HUDEP-2 human erythroid cells and reverses CDAII-like features upon differentiation, demonstrating functional interchangeability of the paralogs in human erythroid cells.","method":"CRISPR-generated SEC23B-deficient HUDEP-2 cells, SEC23A overexpression rescue, erythroid differentiation assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue in human erythroid cell model with differentiation phenotype readout; complements parallel mouse knock-in study (PMID:30065114)","pmids":["34818036"],"is_preprint":false},{"year":2021,"finding":"A monoallelic SEC23A E599K variant disrupts a residue predicted by 3D structural modeling to be involved in direct binding between SEC23 and SAR1 subunits of the COPII coat, suggesting dominant-negative disruption of the SEC23 multimer as the pathomechanism.","method":"Trio genome sequencing, familial segregation, 3D structural modeling of SEC23–SAR1 interface","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 4 / Weak — mechanism proposed via structural modeling only; no direct binding or functional assay performed","pmids":["34580982"],"is_preprint":false},{"year":2021,"finding":"miR-1227 directly targets SEC23A (validated by luciferase assay); inhibition of SEC23A is sufficient to shift extracellular vesicle shedding toward large EVs (large oncosomes) and away from small EVs (exosomes).","method":"Luciferase 3'-UTR assay, qPCR, Western blot, SEC23A siRNA knockdown, EV size/population analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — 3'-UTR reporter plus direct knockdown with EV phenotype readout; single lab, two orthogonal methods","pmids":["34831007"],"is_preprint":false},{"year":2022,"finding":"SEC23A inhibits self-renewal of melanoma cancer stem cells by promoting ER stress and thereby inducing FAM134B-mediated ER-phagy; inhibition of SEC23A reduces ER stress and consequently suppresses FAM134B-induced ER-phagy, increasing stemness.","method":"Stable CSC cell lines from M14 and A375 melanoma, SEC23A knockdown/overexpression, LC3/P62 autophagy markers, transmission electron microscopy of ER morphology, spheroid formation and single-cell cloning assays, subcutaneous xenograft","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional knockdown/overexpression with ER morphology (TEM) and autophagy markers; single lab, multiple assays","pmids":["35236368"],"is_preprint":false},{"year":2023,"finding":"SEC23A is transcriptionally upregulated by ER stress-induced pY705-STAT3; elevated SEC23A promotes autophagy by regulating cellular localization of ANXA2, and the SEC23A–ANXA2–autophagy axis protects gastric cancer cells from ER stress-induced apoptosis, creating a negative feedback loop.","method":"ChIP assay and luciferase reporter (STAT3 binding to SEC23A promoter), Co-immunoprecipitation and mass spectrometry (SEC23A–ANXA2 interaction), subcellular localization experiments, autophagy assays, in vitro and in vivo functional experiments","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP/MS for interaction, and functional rescue; single lab with multiple orthogonal methods","pmids":["37670384"],"is_preprint":false},{"year":2012,"finding":"The BBF2H7-mediated SEC23A pathway is required for ER-to-Golgi procollagen (COL1 and COL3) trafficking in dermal fibroblasts; BBF2H7 knockdown reduces collagen expression and causes Golgi dysmorphology due to COPII hypoplasia, phenotypes rescued by the pathway.","method":"siRNA knockdown of BBF2H7, immunofluorescence microscopy of Golgi and COPII, RT-PCR/Western blot for collagen expression, IGF-I stimulation assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with defined Golgi/collagen phenotype and imaging; single lab, two orthogonal methods","pmids":["22495181"],"is_preprint":false},{"year":2012,"finding":"TFII-I transcription factors (GTF2I/GTF2IRD1) are recruited to the promoter of SEC23A in human neural crest progenitor cells, identifying SEC23A as a direct TFII-I target gene.","method":"ChIP-chip (chromatin immunoprecipitation with tiling promoter arrays) in human neural crest progenitor cells","journal":"The Cleft palate-craniofacial journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP-chip experiment identifying promoter occupancy; no functional follow-up on SEC23A expression or activity","pmids":["23145914"],"is_preprint":false},{"year":2026,"finding":"Salidroside directly binds SEC23A (identified by DARTS assay and molecular docking); stress factors (Substance P/cortisol) specifically upregulate SEC23A, which salidroside suppresses; SEC23A knockdown potentiates salidroside's anti-melanogenic effects in the stress model via dual activation of the SEC23A–p-ERK–MITF axis and inhibition of NK1R–p38–MITF axis.","method":"DARTS (Drug Affinity Responsive Target Stability) assay, molecular docking, SEC23A siRNA knockdown, Western blot for p-ERK/MITF/p38, melanin content and tyrosinase activity assays, in vivo zebrafish and mouse models","journal":"Pharmaceuticals (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — DARTS binding assay plus molecular docking plus functional siRNA knockdown with signaling readout; single lab, multiple methods","pmids":["41901332"],"is_preprint":false}],"current_model":"SEC23A is a core inner coat component of COPII vesicles that mediates anterograde ER-to-Golgi transport of secretory cargo (especially collagens and other ECM proteins); its transcription is activated by ER stress through the BBF2H7/CREB3L2 transcription factor and by pY705-STAT3; its activity is post-translationally regulated by ULK1 phosphorylation at S207/S312/T405 (reducing SEC31A interaction and inhibiting transport during autophagy) and by non-canonical cysteine mono-ubiquitylation at C432/C449 (modulating ER membrane association); SEC23A and its paralog SEC23B are functionally interchangeable in vivo with tissue-specific expression differences explaining distinct disease phenotypes; through control of the tumor cell secretome (including Igfbp4, Tinagl1, S100A8, and PF4), SEC23A suppresses metastatic colonization and is directly silenced by multiple miRNAs (miR-200, miR-375, miR-21, miR-1227); SEC23A also regulates ER-phagy (via FAM134B) and autophagy (via ANXA2) to influence cancer cell survival and stem cell self-renewal."},"narrative":{"mechanistic_narrative":"SEC23A is an essential inner-coat component of COPII-coated vesicles that mediates anterograde ER-to-Golgi transport of secretory cargo, with a preferential role in trafficking large extracellular-matrix proteins such as collagens [PMID:16980979, PMID:26494538]. Loss of SEC23A function—through the disease-causing F382L substitution in human cranio-lenticulo-sutural dysplasia or nonsense mutation in zebrafish—abolishes cell-free vesicle budding, mislocalizes the outer-coat protein SEC31, distends the ER, and blocks secretion of type II collagen and other ECM proteins into cartilage matrix [PMID:16980979, PMID:16980978]. In mice, SEC23A deficiency causes mid-embryonic lethality with intracellular collagen accumulation and unfolded protein response activation while sparing fibronectin secretion, establishing cargo selectivity [PMID:26494538]; SEC23A and its paralog SEC23B share an indistinguishable interactome and are biochemically interchangeable, so distinct human diseases reflect tissue-specific expression rather than functional divergence [PMID:30065114, PMID:34818036]. SEC23A transcription is driven by the ER-stress transcription factor BBF2H7/CREB3L2, which binds the SEC23A promoter to support collagen trafficking and chondrocyte and hepatic stellate cell differentiation [PMID:19767744, PMID:28801610, PMID:22495181], and by pY705-STAT3 [PMID:37670384]. Its trafficking activity is post-translationally regulated: ULK1 phosphorylates SEC23A at S207/S312/T405, reducing SEC23A–SEC31A interaction, aggregating ER exit sites, and inhibiting cargo transport during autophagy [PMID:28486929], while non-canonical mono-ubiquitylation at cysteines C432/C449 modulates ER-membrane association without driving degradation [PMID:28553408]. Through control of the tumor-cell secretome—exporting metastasis-suppressive proteins including Igfbp4, Tinagl1, S100A8 and PF4—SEC23A suppresses metastatic colonization and is silenced by multiple miRNAs (miR-200, miR-375, miR-1227) that target its 3'-UTR [PMID:21822286, PMID:21593139, PMID:32811814, PMID:34421345, PMID:34831007]. SEC23A further links ER homeostasis to cancer cell survival and stem-cell self-renewal by promoting FAM134B-mediated ER-phagy and ANXA2-dependent autophagy [PMID:35236368, PMID:37670384].","teleology":[{"year":2006,"claim":"Established that SEC23A is a functionally essential COPII coat component whose loss disrupts ER-to-Golgi vesicle budding and ECM secretion, explaining a human Mendelian skeletal disorder.","evidence":"Positional cloning of a disease mutation, cell-free vesicle budding assay with mutant protein, EM/immunofluorescence in patient fibroblasts and zebrafish mutants","pmids":["16980979","16980978"],"confidence":"High","gaps":["Did not define the full cargo spectrum","Mechanism of SEC31 mislocalization not resolved at structural level"]},{"year":2009,"claim":"Identified the transcriptional control of SEC23A by placing it downstream of the ER-stress transcription factor BBF2H7/CREB3L2, linking the UPR to secretory capacity.","evidence":"Bbf2h7 knockout mice, promoter ChIP/luciferase, Sec23a rescue of knockout chondrocytes","pmids":["19767744"],"confidence":"High","gaps":["Did not address whether other ER-stress factors converge on the same promoter","Tissue scope beyond chondrocytes unaddressed"]},{"year":2011,"claim":"Revealed a non-cell-autonomous role: SEC23A controls the secretome to suppress metastasis, and is silenced by miRNAs in cancer.","evidence":"3'-UTR reporter assays, secretome proteomics, mouse metastasis and prostate cancer growth models","pmids":["21822286","21593139"],"confidence":"High","gaps":["Whether secretory defect or specific cargo loss drives the phenotype not fully separated","miR-375 study is single-lab Medium confidence"]},{"year":2015,"claim":"Demonstrated cargo selectivity in vivo—SEC23A is preferentially required for collagen export but dispensable for fibronectin—and that paralogs handle overlapping but distinct cargo.","evidence":"Sec23a knockout mice with secreted vs. intracellular cargo analysis and UPR markers; Sec23a/Sec23b compound null analysis","pmids":["26494538"],"confidence":"High","gaps":["Molecular basis for collagen-over-fibronectin preference unresolved","Cargo adaptor requirements not defined"]},{"year":2017,"claim":"Uncovered post-translational regulation of SEC23A trafficking activity by ULK1 phosphorylation and by non-canonical cysteine mono-ubiquitylation, coupling COPII output to autophagy and ER-membrane association.","evidence":"In vitro kinase assays, phosphosite mutagenesis, SEC23A-SEC31A Co-IP, ERES imaging; MS Gly-Gly mapping and cysteine mutagenesis","pmids":["28486929","28553408"],"confidence":"High","gaps":["Ubiquitin ligase/deubiquitinase for C432/C449 not identified","In vivo physiological context of these modifications untested","Ubiquitylation study is single-lab Medium confidence"]},{"year":2018,"claim":"Proved biochemical equivalence of SEC23A and SEC23B, redefining their distinct disease phenotypes as a consequence of differential expression rather than functional divergence.","evidence":"Interactome MS, yeast complementation, zebrafish rescue, mouse knock-in of Sec23a coding sequence into the Sec23b locus","pmids":["30065114"],"confidence":"High","gaps":["Determinants of tissue-specific expression not mapped","Does not exclude subtle paralog-specific kinetics"]},{"year":2021,"claim":"Extended paralog interchangeability to human cells and identified specific secreted anti-metastatic cargoes (S100A8, PF4) and their downstream pathways.","evidence":"CRISPR SEC23B-deficient HUDEP-2 rescue; secretome analysis with autophagy (S100A8-BECLIN1) and MAPK/ERK (PF4-SPARC) readouts in melanoma lines","pmids":["34818036","32811814","34421345"],"confidence":"High","gaps":["Cargo-specific recognition mechanisms not defined","Cancer cargo studies are single-lab Medium confidence"]},{"year":2023,"claim":"Connected SEC23A to ER-stress survival circuits, showing it both responds to pY705-STAT3 transcriptionally and drives ER-phagy (FAM134B) and autophagy (ANXA2) to govern stem-cell self-renewal and apoptosis resistance.","evidence":"ChIP/luciferase for STAT3, Co-IP/MS for SEC23A-ANXA2, autophagy markers, TEM, xenografts in melanoma and gastric cancer","pmids":["35236368","37670384"],"confidence":"Medium","gaps":["Direct vs. indirect link between COPII trafficking and ER-phagy unclear","Single-lab studies without independent replication","Mechanism of ANXA2 relocalization not resolved"]},{"year":null,"claim":"How SEC23A achieves cargo selectivity (e.g., preferential collagen export), and the structural basis by which disease variants disrupt the SEC23-SAR1 coat interface, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["E599K dominant-negative mechanism rests only on structural modeling without binding assay [#15]","No high-resolution structure of human SEC23A-SAR1 in the corpus","Cargo adaptor logic for large vs. small cargoes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,19]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,6,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,12,17,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,5,18]}],"complexes":["COPII coat"],"partners":["SEC31A","SAR1","ANXA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15436","full_name":"Protein transport protein Sec23A","aliases":["SEC23-related protein A"],"length_aa":765,"mass_kda":86.2,"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. Required for the translocation of insulin-induced glucose transporter SLC2A4/GLUT4 to the cell membrane (By similarity)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q15436/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC23A","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100934","cell_line_id":"CID000894","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"PRRC1","stoichiometry":10.0},{"gene":"SEC24B","stoichiometry":10.0},{"gene":"SEC24D","stoichiometry":10.0},{"gene":"SEC24C","stoichiometry":10.0},{"gene":"SEC24A","stoichiometry":4.0},{"gene":"CLTA","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2},{"gene":"PLGRKT","stoichiometry":0.2},{"gene":"AP1M1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000894","total_profiled":1310},"omim":[{"mim_id":"621550","title":"TRANSMEMBRANE PROTEIN 39A; TMEM39A","url":"https://www.omim.org/entry/621550"},{"mim_id":"621301","title":"PROLINE-RICH COILED-COIL PROTEIN 1; PRRC1","url":"https://www.omim.org/entry/621301"},{"mim_id":"617852","title":"SEC23-INTERACTING PROTEIN; SEC23IP","url":"https://www.omim.org/entry/617852"},{"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"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC23A"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q15436","domains":[{"cath_id":"2.60.40.1670","chopping":"5-50_57-123_401-468_475-518","consensus_level":"medium","plddt":93.9532,"start":5,"end":518},{"cath_id":"3.40.50.410","chopping":"131-206_227-390","consensus_level":"high","plddt":96.0311,"start":131,"end":390},{"cath_id":"3.40.20.10","chopping":"622-723","consensus_level":"medium","plddt":95.0775,"start":622,"end":723}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15436","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15436-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15436-F1-predicted_aligned_error_v6.png","plddt_mean":92.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC23A","jax_strain_url":"https://www.jax.org/strain/search?query=SEC23A"},"sequence":{"accession":"Q15436","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15436.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15436/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15436"}},"corpus_meta":[{"pmid":"21822286","id":"PMC_21822286","title":"Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization.","date":"2011","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21822286","citation_count":532,"is_preprint":false},{"pmid":"16980979","id":"PMC_16980979","title":"Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16980979","citation_count":257,"is_preprint":false},{"pmid":"19767744","id":"PMC_19767744","title":"Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated Sec23a pathway is essential for chondrogenesis.","date":"2009","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19767744","citation_count":192,"is_preprint":false},{"pmid":"16980978","id":"PMC_16980978","title":"Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16980978","citation_count":163,"is_preprint":false},{"pmid":"27832783","id":"PMC_27832783","title":"miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1.","date":"2016","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27832783","citation_count":117,"is_preprint":false},{"pmid":"21593139","id":"PMC_21593139","title":"Downregulation of Sec23A protein by miRNA-375 in prostate carcinoma.","date":"2011","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/21593139","citation_count":94,"is_preprint":false},{"pmid":"30065114","id":"PMC_30065114","title":"Functions of the COPII gene paralogs SEC23A and SEC23B are interchangeable in vivo.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30065114","citation_count":65,"is_preprint":false},{"pmid":"27495250","id":"PMC_27495250","title":"MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression.","date":"2016","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27495250","citation_count":63,"is_preprint":false},{"pmid":"27036030","id":"PMC_27036030","title":"MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27036030","citation_count":45,"is_preprint":false},{"pmid":"28486929","id":"PMC_28486929","title":"ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic.","date":"2017","source":"BMC cell 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Sec23A/Sec24D is involved in hepatic stellate cell activation through ER-Golgi transport.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28801610","citation_count":24,"is_preprint":false},{"pmid":"37670384","id":"PMC_37670384","title":"SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/37670384","citation_count":21,"is_preprint":false},{"pmid":"27148587","id":"PMC_27148587","title":"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A.","date":"2016","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/27148587","citation_count":19,"is_preprint":false},{"pmid":"32811814","id":"PMC_32811814","title":"S100A8 transported by SEC23A inhibits metastatic colonization via autocrine activation of autophagy.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32811814","citation_count":18,"is_preprint":false},{"pmid":"34818036","id":"PMC_34818036","title":"SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34818036","citation_count":15,"is_preprint":false},{"pmid":"22495181","id":"PMC_22495181","title":"BBF2H7-mediated Sec23A pathway is required for endoplasmic reticulum-to-Golgi trafficking in dermal fibroblasts to promote collagen synthesis.","date":"2012","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22495181","citation_count":14,"is_preprint":false},{"pmid":"34421345","id":"PMC_34421345","title":"SEC23A Inhibit Melanoma Metastatic through Secretory PF4 Cooperation with SPARC to Inhibit MAPK Signaling Pathway.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34421345","citation_count":14,"is_preprint":false},{"pmid":"28553408","id":"PMC_28553408","title":"Identification of Cysteine Ubiquitylation Sites on the Sec23A Protein of the COPII Complex Required for Vesicle Formation from the ER.","date":"2017","source":"The open biochemistry journal","url":"https://pubmed.ncbi.nlm.nih.gov/28553408","citation_count":13,"is_preprint":false},{"pmid":"23145914","id":"PMC_23145914","title":"ChIP-Chip Identifies SEC23A, CFDP1, and NSD1 as TFII-I Target Genes in Human Neural Crest Progenitor Cells.","date":"2012","source":"The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association","url":"https://pubmed.ncbi.nlm.nih.gov/23145914","citation_count":13,"is_preprint":false},{"pmid":"34201102","id":"PMC_34201102","title":"The Metarhizium anisopliae Toxin, Destruxin A, Interacts with the SEC23A and TEME214 Proteins of Bombyx mori.","date":"2021","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34201102","citation_count":12,"is_preprint":false},{"pmid":"35236368","id":"PMC_35236368","title":"Sec23a inhibits the self-renewal of melanoma cancer stem cells via inactivation of ER-phagy.","date":"2022","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/35236368","citation_count":11,"is_preprint":false},{"pmid":"34831007","id":"PMC_34831007","title":"miR-1227 Targets SEC23A to Regulate the Shedding of Large Extracellular Vesicles.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34831007","citation_count":6,"is_preprint":false},{"pmid":"35190931","id":"PMC_35190931","title":"MiR-29b-3p Inhibits the Inflammation Injury in Human Umbilical Vein Endothelial Cells by Regulating SEC23A.","date":"2022","source":"Biochemical 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34580982","citation_count":4,"is_preprint":false},{"pmid":"40400443","id":"PMC_40400443","title":"Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression.","date":"2025","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40400443","citation_count":2,"is_preprint":false},{"pmid":"39904858","id":"PMC_39904858","title":"The impact of SEC23A on 5-FU chemotherapy sensitivity and its involvement in endoplasmic reticulum stress-induced apoptosis in colorectal cancer.","date":"2025","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/39904858","citation_count":2,"is_preprint":false},{"pmid":"36812724","id":"PMC_36812724","title":"Differential methylation in CD44 and SEC23A is associated with time preference in older individuals.","date":"2023","source":"Economics and human biology","url":"https://pubmed.ncbi.nlm.nih.gov/36812724","citation_count":2,"is_preprint":false},{"pmid":"37828500","id":"PMC_37828500","title":"Novel compound heterozygous variants of the SEC23A gene in a Chinese family with cranio-lenticulo-sutural dysplasia based on data from a large cohort of congenital cataract patients.","date":"2023","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37828500","citation_count":1,"is_preprint":false},{"pmid":"38275611","id":"PMC_38275611","title":"First Case of a Dominant De Novo SEC23A Mutation with Neurological and Psychiatric Features: New Insights into Cranio-Lenticulo-Sutural Dysplasia with Literature Review.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38275611","citation_count":0,"is_preprint":false},{"pmid":"41901332","id":"PMC_41901332","title":"Salidroside Selectively Binds to SEC23A and Ameliorates Psychological Stress-Induced Hyperpigmentation.","date":"2026","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41901332","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.17.657375","title":"Glycolipid transfer protein modulates vesicular trafficking from the endoplasmic reticulum in HeLa cells","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.17.657375","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20001,"output_tokens":5429,"usd":0.070719,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13913,"output_tokens":3497,"usd":0.078495,"stage2_stop_reason":"end_turn"},"total_usd":0.149214,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"SEC23A is an essential component of COPII-coated vesicles mediating ER-to-Golgi transport; the disease-causing F382L substitution results in loss of SEC23A function in cell-free vesicle budding assays, causing gross ER dilatation and cytoplasmic mislocalization of SEC31 in patient fibroblasts.\",\n      \"method\": \"Positional cloning, cell-free vesicle budding assay, electron microscopy, immunofluorescence, zebrafish morpholino knockdown\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro vesicle budding reconstitution with mutant protein, corroborated by EM ultrastructure, immunofluorescence, and in vivo zebrafish model; replicated conceptually by parallel zebrafish paper (PMID:16980978)\",\n      \"pmids\": [\"16980979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Zebrafish sec23a loss-of-function (crusher nonsense mutation L402X) causes chondrocyte ER distension and failure to secrete type II collagen and other ECM proteins into cartilage extracellular matrix, establishing SEC23A as an integral COPII component required for ECM secretion in chondrocytes.\",\n      \"method\": \"Positional cloning, zebrafish genetic mutant analysis, immunofluorescence, electron microscopy; sec23b knockdown (morpholino) shows paralog is also required\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with clear cellular phenotype (ER distension, collagen retention), replicated concept in parallel CLSD paper (PMID:16980979)\",\n      \"pmids\": [\"16980978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BBF2H7 (CREB3L2) directly binds a CRE-like sequence in the Sec23a promoter to activate its transcription in response to ER stress; introduction of Sec23a into Bbf2h7-/- chondrocytes fully restores impaired cartilage matrix protein transport and secretion, placing SEC23A downstream of BBF2H7 in ER stress-to-ER-Golgi trafficking signaling.\",\n      \"method\": \"Bbf2h7 knockout mouse generation, promoter binding assay (ChIP/luciferase), Sec23a rescue experiment in knockout chondrocytes, immunofluorescence, genetic epistasis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockout rescue experiment with defined promoter binding plus multiple orthogonal methods; well-cited mechanistic study\",\n      \"pmids\": [\"19767744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-200s directly target the 3'-UTR of SEC23A mRNA to suppress its expression, reducing secretion of metastasis-suppressive proteins Igfbp4 and Tinagl1 from the tumor cell secretome, thereby promoting metastatic colonization.\",\n      \"method\": \"3'-UTR reporter assay, proteomic/genomic analysis of secretome, functional rescue experiments in mouse breast cancer metastasis models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'-UTR targeting validated, secretome proteomics, in vivo mouse metastasis models with functional readout; highly cited, multiple orthogonal methods\",\n      \"pmids\": [\"21822286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-375 and miR-200c each target the 3'-UTR of SEC23A mRNA to downregulate SEC23A protein expression; ectopic overexpression of SEC23A in prostate cancer cell lines reduces cell growth without inducing apoptosis, while inhibition of SEC23A stimulates proliferation.\",\n      \"method\": \"3'-UTR luciferase reporter assay, Western blot, qRT-PCR, cell growth assays in LNCaP and DU145 cells\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — 3'-UTR reporter validation plus functional overexpression/knockdown, single lab, two orthogonal methods\",\n      \"pmids\": [\"21593139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ER stress impairs membrane association of COPII components, particularly Sec23a, reducing COPII vesicle formation at ER exit sites, and alters Sec23a cycling at ERESs.\",\n      \"method\": \"Fluorescence microscopy (ERES imaging), COPII vesicle formation assay, ER stress induction with pharmacological agents\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — live-cell imaging with functional assay, single lab, two methods\",\n      \"pmids\": [\"23994533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC23A-deficient mice exhibit mid-embryonic lethality with defective extraembryonic membrane development and neural tube opening; multiple collagen types accumulate intracellularly in SEC23A-deficient connective tissue cells, triggering unfolded protein response, while fibronectin secretion is unaffected, showing SEC23A preferentially transports collagen cargo. SEC23A and SEC23B transport overlapping but distinct cargo spectra in vivo.\",\n      \"method\": \"Sec23a knockout mouse, immunofluorescence, Western blot for secreted vs. intracellular collagen/fibronectin, UPR markers; Sec23a/Sec23b compound null analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple cargo specificity experiments and UPR measurement; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"26494538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ULK1 phosphorylates SEC23A at serine 207, serine 312, and threonine 405; phosphorylation at S207 reduces the interaction between SEC23A and SEC31A, causes ERES aggregation, and inhibits ER-to-Golgi cargo transport during autophagy induction.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S207A/D, S312A/D, T405A/E), Co-immunoprecipitation (SEC23A–SEC31A interaction), live-cell imaging of ERES, cargo transport assays under amino acid starvation/rapamycin/ULK1 overexpression\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation plus mutagenesis plus Co-IP plus functional transport assay; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"28486929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sec23a ubiquitylation occurs at non-canonical cysteine residues (C432 and C449) as mono-ubiquitin attachment; mutation of these sites affects Sec23a interaction with ER membrane and modulates COPII formation, without targeting Sec23a for degradation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry (Gly-Gly remnant identification), site-directed mutagenesis of C432 and C449, immunofluorescence\",\n      \"journal\": \"The open biochemistry journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — MS identification of modification sites plus mutagenesis functional follow-up; single lab, two orthogonal methods\",\n      \"pmids\": [\"28553408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREB3L2/BBF2H7 transcriptionally upregulates SEC23A (and SEC24D) expression during hepatic stellate cell (HSC) activation; knockdown of SEC23A abrogates HSC activation, establishing that SEC23A-mediated ER-to-Golgi trafficking is required for this differentiation process.\",\n      \"method\": \"siRNA knockdown, Western blot, RT-PCR, HSC activation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown with defined cellular phenotype plus transcription factor target identification; single lab\",\n      \"pmids\": [\"28801610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEC23A and SEC23B have indistinguishable intracellular protein interactomes; both complement yeast Sec23; a Sec23a coding sequence knocked into the Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype in mice, demonstrating equivalent biochemical function with tissue-specific expression differences accounting for distinct phenotypes.\",\n      \"method\": \"Mass spectrometry interactome, yeast complementation, zebrafish transgene rescue, mouse knock-in (Sec23a coding sequence into Sec23b locus)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including knock-in rescue, yeast complementation, and interactome MS; rigorous in vivo genetic approach\",\n      \"pmids\": [\"30065114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec23a functions downstream of miR-200c to suppress oligometastatic-to-polymetastatic progression via its secretome; mass spectrometric analysis of secretory protein profiles shows Sec23a-dependent secretome modifies the tumor microenvironment.\",\n      \"method\": \"miR-200c overexpression/Sec23a knockdown in paired oligometastatic/polymetastatic melanoma lines, in vivo metastasis assays, mass spectrometry of secretome\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis (Sec23a downstream of miR-200c), secretome MS, in vivo validation; single lab\",\n      \"pmids\": [\"30301603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S100A8 is transported by SEC23A (as COPII cargo) and inhibits metastatic colonization via autocrine activation of autophagy through a SEC23A–S100A8–BECLIN1–autophagy axis.\",\n      \"method\": \"SEC23A knockdown/overexpression, secretome analysis, autophagy assays (LC3, BECLIN1), paired oligometastatic/polymetastatic melanoma cell lines, in vivo colonization assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional knockdown with defined secretome cargo and autophagy pathway readout; single lab, multiple assays\",\n      \"pmids\": [\"32811814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC23A transports PF4 as COPII cargo; secreted PF4, cooperating with SPARC, inhibits melanoma metastasis through inhibition of the MAPK/ERK signaling pathway.\",\n      \"method\": \"SEC23A overexpression/knockdown in paired melanoma lines, secretome analysis, MAPK/ERK phosphorylation assays, in vivo metastasis assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional knockdown/overexpression with defined cargo and signaling pathway readout; single lab\",\n      \"pmids\": [\"34421345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC23A expression is rescued in SEC23B-deficient HUDEP-2 human erythroid cells and reverses CDAII-like features upon differentiation, demonstrating functional interchangeability of the paralogs in human erythroid cells.\",\n      \"method\": \"CRISPR-generated SEC23B-deficient HUDEP-2 cells, SEC23A overexpression rescue, erythroid differentiation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue in human erythroid cell model with differentiation phenotype readout; complements parallel mouse knock-in study (PMID:30065114)\",\n      \"pmids\": [\"34818036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A monoallelic SEC23A E599K variant disrupts a residue predicted by 3D structural modeling to be involved in direct binding between SEC23 and SAR1 subunits of the COPII coat, suggesting dominant-negative disruption of the SEC23 multimer as the pathomechanism.\",\n      \"method\": \"Trio genome sequencing, familial segregation, 3D structural modeling of SEC23–SAR1 interface\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — mechanism proposed via structural modeling only; no direct binding or functional assay performed\",\n      \"pmids\": [\"34580982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-1227 directly targets SEC23A (validated by luciferase assay); inhibition of SEC23A is sufficient to shift extracellular vesicle shedding toward large EVs (large oncosomes) and away from small EVs (exosomes).\",\n      \"method\": \"Luciferase 3'-UTR assay, qPCR, Western blot, SEC23A siRNA knockdown, EV size/population analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — 3'-UTR reporter plus direct knockdown with EV phenotype readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"34831007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEC23A inhibits self-renewal of melanoma cancer stem cells by promoting ER stress and thereby inducing FAM134B-mediated ER-phagy; inhibition of SEC23A reduces ER stress and consequently suppresses FAM134B-induced ER-phagy, increasing stemness.\",\n      \"method\": \"Stable CSC cell lines from M14 and A375 melanoma, SEC23A knockdown/overexpression, LC3/P62 autophagy markers, transmission electron microscopy of ER morphology, spheroid formation and single-cell cloning assays, subcutaneous xenograft\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional knockdown/overexpression with ER morphology (TEM) and autophagy markers; single lab, multiple assays\",\n      \"pmids\": [\"35236368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEC23A is transcriptionally upregulated by ER stress-induced pY705-STAT3; elevated SEC23A promotes autophagy by regulating cellular localization of ANXA2, and the SEC23A–ANXA2–autophagy axis protects gastric cancer cells from ER stress-induced apoptosis, creating a negative feedback loop.\",\n      \"method\": \"ChIP assay and luciferase reporter (STAT3 binding to SEC23A promoter), Co-immunoprecipitation and mass spectrometry (SEC23A–ANXA2 interaction), subcellular localization experiments, autophagy assays, in vitro and in vivo functional experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP/MS for interaction, and functional rescue; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37670384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The BBF2H7-mediated SEC23A pathway is required for ER-to-Golgi procollagen (COL1 and COL3) trafficking in dermal fibroblasts; BBF2H7 knockdown reduces collagen expression and causes Golgi dysmorphology due to COPII hypoplasia, phenotypes rescued by the pathway.\",\n      \"method\": \"siRNA knockdown of BBF2H7, immunofluorescence microscopy of Golgi and COPII, RT-PCR/Western blot for collagen expression, IGF-I stimulation assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with defined Golgi/collagen phenotype and imaging; single lab, two orthogonal methods\",\n      \"pmids\": [\"22495181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TFII-I transcription factors (GTF2I/GTF2IRD1) are recruited to the promoter of SEC23A in human neural crest progenitor cells, identifying SEC23A as a direct TFII-I target gene.\",\n      \"method\": \"ChIP-chip (chromatin immunoprecipitation with tiling promoter arrays) in human neural crest progenitor cells\",\n      \"journal\": \"The Cleft palate-craniofacial journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP-chip experiment identifying promoter occupancy; no functional follow-up on SEC23A expression or activity\",\n      \"pmids\": [\"23145914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Salidroside directly binds SEC23A (identified by DARTS assay and molecular docking); stress factors (Substance P/cortisol) specifically upregulate SEC23A, which salidroside suppresses; SEC23A knockdown potentiates salidroside's anti-melanogenic effects in the stress model via dual activation of the SEC23A–p-ERK–MITF axis and inhibition of NK1R–p38–MITF axis.\",\n      \"method\": \"DARTS (Drug Affinity Responsive Target Stability) assay, molecular docking, SEC23A siRNA knockdown, Western blot for p-ERK/MITF/p38, melanin content and tyrosinase activity assays, in vivo zebrafish and mouse models\",\n      \"journal\": \"Pharmaceuticals (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — DARTS binding assay plus molecular docking plus functional siRNA knockdown with signaling readout; single lab, multiple methods\",\n      \"pmids\": [\"41901332\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC23A is a core inner coat component of COPII vesicles that mediates anterograde ER-to-Golgi transport of secretory cargo (especially collagens and other ECM proteins); its transcription is activated by ER stress through the BBF2H7/CREB3L2 transcription factor and by pY705-STAT3; its activity is post-translationally regulated by ULK1 phosphorylation at S207/S312/T405 (reducing SEC31A interaction and inhibiting transport during autophagy) and by non-canonical cysteine mono-ubiquitylation at C432/C449 (modulating ER membrane association); SEC23A and its paralog SEC23B are functionally interchangeable in vivo with tissue-specific expression differences explaining distinct disease phenotypes; through control of the tumor cell secretome (including Igfbp4, Tinagl1, S100A8, and PF4), SEC23A suppresses metastatic colonization and is directly silenced by multiple miRNAs (miR-200, miR-375, miR-21, miR-1227); SEC23A also regulates ER-phagy (via FAM134B) and autophagy (via ANXA2) to influence cancer cell survival and stem cell self-renewal.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC23A is an essential inner-coat component of COPII-coated vesicles that mediates anterograde ER-to-Golgi transport of secretory cargo, with a preferential role in trafficking large extracellular-matrix proteins such as collagens [#0, #6]. Loss of SEC23A function—through the disease-causing F382L substitution in human cranio-lenticulo-sutural dysplasia or nonsense mutation in zebrafish—abolishes cell-free vesicle budding, mislocalizes the outer-coat protein SEC31, distends the ER, and blocks secretion of type II collagen and other ECM proteins into cartilage matrix [#0, #1]. In mice, SEC23A deficiency causes mid-embryonic lethality with intracellular collagen accumulation and unfolded protein response activation while sparing fibronectin secretion, establishing cargo selectivity [#6]; SEC23A and its paralog SEC23B share an indistinguishable interactome and are biochemically interchangeable, so distinct human diseases reflect tissue-specific expression rather than functional divergence [#10, #14]. SEC23A transcription is driven by the ER-stress transcription factor BBF2H7/CREB3L2, which binds the SEC23A promoter to support collagen trafficking and chondrocyte and hepatic stellate cell differentiation [#2, #9, #19], and by pY705-STAT3 [#18]. Its trafficking activity is post-translationally regulated: ULK1 phosphorylates SEC23A at S207/S312/T405, reducing SEC23A–SEC31A interaction, aggregating ER exit sites, and inhibiting cargo transport during autophagy [#7], while non-canonical mono-ubiquitylation at cysteines C432/C449 modulates ER-membrane association without driving degradation [#8]. Through control of the tumor-cell secretome—exporting metastasis-suppressive proteins including Igfbp4, Tinagl1, S100A8 and PF4—SEC23A suppresses metastatic colonization and is silenced by multiple miRNAs (miR-200, miR-375, miR-1227) that target its 3'-UTR [#3, #4, #12, #13, #16]. SEC23A further links ER homeostasis to cancer cell survival and stem-cell self-renewal by promoting FAM134B-mediated ER-phagy and ANXA2-dependent autophagy [#17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that SEC23A is a functionally essential COPII coat component whose loss disrupts ER-to-Golgi vesicle budding and ECM secretion, explaining a human Mendelian skeletal disorder.\",\n      \"evidence\": \"Positional cloning of a disease mutation, cell-free vesicle budding assay with mutant protein, EM/immunofluorescence in patient fibroblasts and zebrafish mutants\",\n      \"pmids\": [\"16980979\", \"16980978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the full cargo spectrum\", \"Mechanism of SEC31 mislocalization not resolved at structural level\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the transcriptional control of SEC23A by placing it downstream of the ER-stress transcription factor BBF2H7/CREB3L2, linking the UPR to secretory capacity.\",\n      \"evidence\": \"Bbf2h7 knockout mice, promoter ChIP/luciferase, Sec23a rescue of knockout chondrocytes\",\n      \"pmids\": [\"19767744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether other ER-stress factors converge on the same promoter\", \"Tissue scope beyond chondrocytes unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a non-cell-autonomous role: SEC23A controls the secretome to suppress metastasis, and is silenced by miRNAs in cancer.\",\n      \"evidence\": \"3'-UTR reporter assays, secretome proteomics, mouse metastasis and prostate cancer growth models\",\n      \"pmids\": [\"21822286\", \"21593139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether secretory defect or specific cargo loss drives the phenotype not fully separated\", \"miR-375 study is single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated cargo selectivity in vivo—SEC23A is preferentially required for collagen export but dispensable for fibronectin—and that paralogs handle overlapping but distinct cargo.\",\n      \"evidence\": \"Sec23a knockout mice with secreted vs. intracellular cargo analysis and UPR markers; Sec23a/Sec23b compound null analysis\",\n      \"pmids\": [\"26494538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for collagen-over-fibronectin preference unresolved\", \"Cargo adaptor requirements not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Uncovered post-translational regulation of SEC23A trafficking activity by ULK1 phosphorylation and by non-canonical cysteine mono-ubiquitylation, coupling COPII output to autophagy and ER-membrane association.\",\n      \"evidence\": \"In vitro kinase assays, phosphosite mutagenesis, SEC23A-SEC31A Co-IP, ERES imaging; MS Gly-Gly mapping and cysteine mutagenesis\",\n      \"pmids\": [\"28486929\", \"28553408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase/deubiquitinase for C432/C449 not identified\", \"In vivo physiological context of these modifications untested\", \"Ubiquitylation study is single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proved biochemical equivalence of SEC23A and SEC23B, redefining their distinct disease phenotypes as a consequence of differential expression rather than functional divergence.\",\n      \"evidence\": \"Interactome MS, yeast complementation, zebrafish rescue, mouse knock-in of Sec23a coding sequence into the Sec23b locus\",\n      \"pmids\": [\"30065114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of tissue-specific expression not mapped\", \"Does not exclude subtle paralog-specific kinetics\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended paralog interchangeability to human cells and identified specific secreted anti-metastatic cargoes (S100A8, PF4) and their downstream pathways.\",\n      \"evidence\": \"CRISPR SEC23B-deficient HUDEP-2 rescue; secretome analysis with autophagy (S100A8-BECLIN1) and MAPK/ERK (PF4-SPARC) readouts in melanoma lines\",\n      \"pmids\": [\"34818036\", \"32811814\", \"34421345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-specific recognition mechanisms not defined\", \"Cancer cargo studies are single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SEC23A to ER-stress survival circuits, showing it both responds to pY705-STAT3 transcriptionally and drives ER-phagy (FAM134B) and autophagy (ANXA2) to govern stem-cell self-renewal and apoptosis resistance.\",\n      \"evidence\": \"ChIP/luciferase for STAT3, Co-IP/MS for SEC23A-ANXA2, autophagy markers, TEM, xenografts in melanoma and gastric cancer\",\n      \"pmids\": [\"35236368\", \"37670384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect link between COPII trafficking and ER-phagy unclear\", \"Single-lab studies without independent replication\", \"Mechanism of ANXA2 relocalization not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC23A achieves cargo selectivity (e.g., preferential collagen export), and the structural basis by which disease variants disrupt the SEC23-SAR1 coat interface, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E599K dominant-negative mechanism rests only on structural modeling without binding assay [#15]\", \"No high-resolution structure of human SEC23A-SAR1 in the corpus\", \"Cargo adaptor logic for large vs. small cargoes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 6, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 12, 17, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 5, 18]}\n    ],\n    \"complexes\": [\"COPII coat\"],\n    \"partners\": [\"SEC31A\", \"SAR1\", \"ANXA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}