{"gene":"SEC23A","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2006,"finding":"SEC23A is an essential component of COPII-coated vesicles mediating ER-to-Golgi transport; the F382L missense mutation causes loss of SEC23A function in cell-free vesicle budding assays, leading to gross ER dilation and cytoplasmic mislocalization of SEC31 in patient fibroblasts, causing cranio-lenticulo-sutural dysplasia (CLSD).","method":"Positional cloning, cell-free vesicle budding assay, electron microscopy, immunofluorescence, zebrafish morpholino knockdown","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro vesicle budding assay with mutant, structural context, EM validation, and in vivo morpholino model","pmids":["16980979"],"is_preprint":false},{"year":2006,"finding":"SEC23A is a core component of the COPII complex required for anterograde ER-to-Golgi trafficking; loss-of-function nonsense mutation (L402X) in zebrafish crusher mutant causes protein accumulation in distended ER of chondrocytes, severe reduction of type II collagen and cartilage ECM secretion, and craniofacial skeletal defects. The paralog SEC23B is also required for ECM secretion in chondrocytes, while COPI knockdown does not impair craniofacial morphogenesis.","method":"Positional cloning, live zebrafish imaging, immunofluorescence, electron microscopy, morpholino epistasis (COPI vs COPII)","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vertebrate model, multiple orthogonal methods, replicated independently same year","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; Sec23a expression downstream of BBF2H7 is required for ER-to-Golgi transport of type II collagen and COMP in chondrocytes, and reintroduction of Sec23a into Bbf2h7−/− chondrocytes fully restores impaired transport and secretion of cartilage matrix proteins.","method":"Bbf2h7 knockout mouse, promoter binding assay, rescue by Sec23a re-expression, immunofluorescence, EM","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined molecular rescue, direct promoter binding, replicated in vivo","pmids":["19767744"],"is_preprint":false},{"year":2011,"finding":"miR-200s directly target the SEC23A 3′-UTR to suppress SEC23A expression, thereby reducing secretion of metastasis-suppressive proteins Igfbp4 and Tinagl1 from the COPII secretory pathway and promoting metastatic colonization.","method":"3′-UTR luciferase reporter, genomic and proteomic (secretome) analysis, functional rescue experiments, mouse metastasis models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — direct targeting validated by reporter assay, proteomic secretome profiling, in vivo models with functional rescue","pmids":["21822286"],"is_preprint":false},{"year":2011,"finding":"SEC23A protein is downregulated by miR-375 and miR-200c via their binding to the SEC23A 3′-UTR; ectopic overexpression of SEC23A in prostate cancer cell lines reduces cell growth without inducing apoptosis, whereas inhibition of SEC23A stimulates proliferation.","method":"3′-UTR reporter assay, Western blot, qRT-PCR, cell growth assays in LNCaP and DU145 cells","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 3 — validated miRNA targeting by reporter, functional phenotype but single lab","pmids":["21593139"],"is_preprint":false},{"year":2012,"finding":"BBF2H7-mediated induction of Sec23A via IGF-I signaling (through MAPK and PI3K pathways) is required for ER-to-Golgi trafficking of procollagen in dermal fibroblasts; knockdown of BBF2H7 reduces type I and III collagen expression and causes Golgi dysmorphology due to COPII hypoplasia.","method":"siRNA knockdown, immunofluorescence microscopy, Western blot, pathway inhibitor experiments","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined molecular pathway and morphological phenotype, single lab","pmids":["22495181"],"is_preprint":false},{"year":2013,"finding":"ER stress impairs membrane association of Sec23A at ER exit sites (ERES), reducing COPII vesicle formation and modifying Sec23A cycling, establishing a dynamic interplay between protein folding status and COPII assembly.","method":"Immunofluorescence, membrane fractionation, ER stress induction with pharmacological agents","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiments with functional implication, single lab","pmids":["23994533"],"is_preprint":false},{"year":2015,"finding":"SEC23A deficiency in mice causes mid-embryonic lethality with defective extraembryonic membrane development and neural tube opening; SEC23A is specifically required for secretion of multiple collagen types (but not fibronectin) in connective tissue cells, and its loss induces strong unfolded protein response in collagen-producing cells. SEC23B deficiency causes E-cadherin accumulation in pancreatic and salivary gland acini. Haploinsufficiency of one paralog on top of homozygous loss of the other causes earlier lethality, indicating partial functional overlap.","method":"Sec23a knockout mouse, immunofluorescence, Western blot, fractionation, genetic interaction (compound heterozygotes)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — full KO mouse with defined cargo-specific secretion defects, genetic epistasis between paralogs, multiple orthogonal assays","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, causing aggregation of ERES and inhibition of ER-to-Golgi cargo transport during autophagy induction by amino acid starvation, rapamycin, or ULK1 overexpression.","method":"In vitro kinase assay, phospho-site mutagenesis, Co-IP (SEC23A–SEC31A interaction), live imaging of ERES, cargo transport assay","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 1 — phosphorylation sites mapped by mutagenesis, in vitro kinase assay, interaction disruption confirmed by Co-IP","pmids":["28486929"],"is_preprint":false},{"year":2017,"finding":"CREB3L2/BBF2H7 transcription factor drives isoform-specific upregulation of Sec23A (and Sec24D) during hepatic stellate cell (HSC) activation; knockdown of Sec23A abrogates HSC activation, indicating that Sec23A-mediated ER-to-Golgi trafficking is required for the differentiation of HSCs into myofibroblast-like cells.","method":"siRNA knockdown, Western blot, qRT-PCR, immunofluorescence, HSC activation model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with clear cell-biological phenotype, defined transcription factor upstream, single lab","pmids":["28801610"],"is_preprint":false},{"year":2017,"finding":"SEC23A is ubiquitylated on cysteine residues at positions 432 and 449 (unconventional cysteine ubiquitylation rather than lysine); this monoubiquitylation is not required for SEC23A degradation but modulates SEC23A interaction with the ER membrane and thereby influences COPII vesicle formation.","method":"Co-immunoprecipitation, mass spectrometry (Gly-Gly remnant detection), site-directed mutagenesis, immunofluorescence","journal":"The open biochemistry journal","confidence":"Medium","confidence_rationale":"Tier 1 — sites identified by MS and validated by mutagenesis, functional consequence shown by immunofluorescence; single lab","pmids":["28553408"],"is_preprint":false},{"year":2018,"finding":"Human SEC23A and SEC23B have indistinguishable intracellular protein interactomes; both complement yeast Sec23, and a sec23a-expressing transgene rescues sec23b-deficient zebrafish lethality. In mice, a Sec23a coding sequence knocked into the Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype, demonstrating equivalent molecular function with tissue-specific expression differences accounting for distinct disease phenotypes.","method":"Mass spectrometry interactome, yeast complementation, zebrafish transgenic rescue, mouse knock-in","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods across species, knock-in rescue in mammals","pmids":["30065114"],"is_preprint":false},{"year":2018,"finding":"Sec23a acts downstream of miR-200c; Sec23a expression suppresses oligometastatic-to-polymetastatic progression through its secretome, which modifies the tumor microenvironment, as shown by mass spectrometric profiling of secreted proteins from Sec23a-manipulated cells.","method":"In vitro and in vivo metastasis assays, miR-200c overexpression/Sec23a knockdown epistasis, mass spectrometry secretome analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established, secretome profiled by MS, in vivo validation; single lab","pmids":["30301603"],"is_preprint":false},{"year":2020,"finding":"SEC23A transports S100A8 in COPII vesicles into the extracellular space; secreted S100A8 inhibits metastatic colonization via autocrine activation of BECLIN1-dependent autophagy, defining a SEC23A–S100A8–BECLIN1–autophagy axis.","method":"Secretome mass spectrometry, siRNA knockdown, in vivo metastasis assay, autophagy markers (LC3, BECLIN1)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — cargo identification by MS, pathway placement by genetic manipulation, in vivo validation; single lab","pmids":["32811814"],"is_preprint":false},{"year":2021,"finding":"SEC23A transports PF4 via COPII vesicles; secreted PF4 cooperates with SPARC to inhibit the MAPK/ERK signaling pathway and suppress melanoma metastasis.","method":"Secretome analysis, Co-IP, siRNA knockdown, ERK phosphorylation assays, in vivo metastasis model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — cargo-pathway linkage established with in vivo confirmation; single lab","pmids":["34421345"],"is_preprint":false},{"year":2021,"finding":"SEC23B-deficient HUDEP-2 erythroid cells exhibit features of congenital dyserythropoietic anemia type II (CDAII) upon differentiation; increased expression of SEC23A rescues this phenotype, confirming functional equivalence of the paralogs in human erythroid cells and suggesting a therapeutic strategy for CDAII.","method":"CRISPR knockout of SEC23B in HUDEP-2 cells, SEC23A overexpression rescue, erythroid differentiation assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — human cell KO with defined rescue, mechanistic equivalence established across paralogs","pmids":["34818036"],"is_preprint":false},{"year":2021,"finding":"miR-1227 directly targets SEC23A; inhibition of SEC23A by miR-1227 is sufficient to shift extracellular vesicle shedding from small EVs (exosomes) toward large EVs (large oncosomes), revealing a COPII-dependent mechanism controlling EV size distribution.","method":"RISCTRAP assay, RNA sequencing, luciferase reporter, Western blot, qPCR, EV size profiling","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — direct miRNA targeting validated, SEC23A knockdown phenocopies miR-1227 effect on EV shedding; single lab","pmids":["34831007"],"is_preprint":false},{"year":2022,"finding":"Sec23a inhibits self-renewal of melanoma cancer stem cells by promoting ER stress, which activates FAM134B-induced ER-phagy (selective autophagy of the ER); inhibition of Sec23a reduces ER stress and consequently suppresses FAM134B-mediated ER-phagy, enhancing CSC self-renewal.","method":"CSC spheroid enrichment, siRNA knockdown, transmission electron microscopy, LC3/P62 autophagy markers, ER stress assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined molecular pathway (SEC23A→ER stress→FAM134B→ER-phagy), EM validation; single lab","pmids":["35236368"],"is_preprint":false},{"year":2023,"finding":"ER stress-induced pY705-STAT3 transcriptionally upregulates SEC23A; elevated SEC23A then promotes autophagy by regulating the cellular localization of ANXA2, and the resulting SEC23A–ANXA2–autophagy axis protects gastric cancer cells from ER stress-induced apoptosis, forming a negative feedback loop.","method":"Luciferase reporter, ChIP assay, Co-IP, mass spectrometry, subcellular fractionation, in vitro and in vivo functional assays","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — STAT3 binding to SEC23A promoter confirmed by ChIP, SEC23A–ANXA2 interaction by Co-IP/MS, in vivo validation; single lab","pmids":["37670384"],"is_preprint":false},{"year":2021,"finding":"The E599K variant in SEC23A (monoallelic, inherited in dominant fashion) affects an ultra-conserved residue predicted by 3D structural modeling to be involved in direct binding between SEC23 and SAR1 subunits of the COPII coat, suggesting a dominant-negative mechanism disrupting SEC23 multimer function.","method":"Trio genome sequencing, 3D structural modeling of yeast SEC23–SAR1 interface, familial segregation","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 4 — structural inference only, no direct biochemical validation of binding disruption","pmids":["34580982"],"is_preprint":false},{"year":2012,"finding":"TFII-I transcription factors (GTF2I/GTF2IRD1) are directly recruited to the SEC23A promoter in human neural crest progenitor cells, as shown by ChIP-chip, establishing SEC23A as a direct transcriptional target of TFII-I in craniofacial development.","method":"ChIP-chip with human RefSeq tiling promoter arrays in neural crest progenitor cells","journal":"The Cleft palate-craniofacial journal","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide direct promoter binding assay, but functional consequence of binding not directly tested","pmids":["23145914"],"is_preprint":false}],"current_model":"SEC23A is a core inner-coat component of COPII vesicles that mediates anterograde ER-to-Golgi trafficking of secretory cargoes (particularly collagens and other ECM proteins); its activity is regulated transcriptionally by ER-stress-activated bZIP factors (BBF2H7/CREB3L2) and STAT3, post-translationally by ULK1 phosphorylation (at S207/S312/T405) that disrupts SEC23A–SEC31A interaction to inhibit ERES function during autophagy, and by unconventional cysteine ubiquitylation (C432/C449) that modulates ER-membrane association; loss of SEC23A function causes cargo accumulation in dilated ER, unfolded protein response, and developmental defects (skeletal, craniofacial), while its secretome controls tumor microenvironment and metastatic colonization through transport of specific cargoes including S100A8 and PF4."},"narrative":{"teleology":[{"year":2006,"claim":"Identification of SEC23A as essential for COPII vesicle budding established that this gene encodes a coat protein indispensable for ER-to-Golgi transport, with human loss-of-function causing cranio-lenticulo-sutural dysplasia and zebrafish loss-of-function causing craniofacial cartilage defects due to failed collagen secretion.","evidence":"Positional cloning of F382L (human CLSD) and L402X (zebrafish crusher), cell-free budding assays, EM, morpholino knockdown","pmids":["16980979","16980978"],"confidence":"High","gaps":["Cargo selectivity beyond collagen was not defined","Relative contributions of SEC23A versus SEC23B in different tissues were unknown","Mechanism by which F382L disrupts coat assembly was inferred structurally but not reconstituted"]},{"year":2009,"claim":"Discovery that the ER-stress-activated transcription factor CREB3L2/BBF2H7 directly transactivates the Sec23a promoter revealed how cells couple protein folding demand to COPII capacity, explaining why Bbf2h7-null chondrocytes phenocopy Sec23a loss.","evidence":"Bbf2h7 knockout mouse, promoter binding assay, Sec23a re-expression rescue of collagen secretion","pmids":["19767744"],"confidence":"High","gaps":["Whether other ER-stress-responsive transcription factors also regulate SEC23A was not tested","Quantitative relationship between SEC23A protein level and COPII flux was not measured"]},{"year":2011,"claim":"Demonstration that miR-200 family members and miR-375 directly target the SEC23A 3′-UTR connected post-transcriptional SEC23A regulation to metastatic colonization, revealing that SEC23A-dependent secretion of metastasis-suppressive proteins (Igfbp4, Tinagl1) controls the tumor microenvironment.","evidence":"3′-UTR luciferase reporters, secretome proteomics, mouse metastasis models, rescue experiments","pmids":["21822286","21593139"],"confidence":"High","gaps":["Full complement of anti-metastatic cargoes dependent on SEC23A was not catalogued","Whether SEC23A loss alters COPII composition or only flux was unclear"]},{"year":2012,"claim":"Additional transcriptional regulators of SEC23A were identified: BBF2H7 induction downstream of IGF-I/MAPK/PI3K in dermal fibroblasts extended the CREB3L2–SEC23A axis beyond chondrocytes, and TFII-I family factors were found at the SEC23A promoter in neural crest progenitors, linking SEC23A to craniofacial developmental gene regulation.","evidence":"siRNA knockdown with pathway inhibitors in fibroblasts; ChIP-chip in human neural crest progenitor cells","pmids":["22495181","23145914"],"confidence":"Medium","gaps":["Functional consequence of TFII-I binding on SEC23A transcription was not directly tested","Whether IGF-I/MAPK pathway regulation of SEC23A operates in vivo was not confirmed"]},{"year":2013,"claim":"Observation that ER stress reduces SEC23A membrane association at ER exit sites established that protein folding status dynamically regulates COPII coat assembly, providing a feedback mechanism limiting vesicle budding when cargo cannot fold.","evidence":"Immunofluorescence and membrane fractionation under pharmacological ER stress","pmids":["23994533"],"confidence":"Medium","gaps":["Molecular mechanism by which unfolded protein signals displace SEC23A from ERES was not identified","Whether this is SEC23A-specific or affects all COPII subunits equally was not resolved"]},{"year":2015,"claim":"Full Sec23a knockout in mice revealed embryonic lethality with neural tube and extraembryonic membrane defects, and demonstrated that SEC23A is selectively required for collagen (but not fibronectin) secretion, while genetic interaction with Sec23b showed partial functional overlap.","evidence":"Sec23a knockout mouse, compound heterozygotes with Sec23b, cargo-specific immunofluorescence and Western blot","pmids":["26494538"],"confidence":"High","gaps":["Basis for cargo selectivity (collagen vs. fibronectin) was not mechanistically explained","Whether SEC23A loss triggers UPR in all collagen-producing tissues or only selected ones was not fully mapped"]},{"year":2017,"claim":"Two key post-translational regulatory mechanisms were defined: ULK1 phosphorylation of SEC23A at S207/S312/T405 disrupts the SEC23A–SEC31A outer coat interaction to suppress COPII during autophagy, while unconventional cysteine ubiquitylation at C432/C449 modulates SEC23A membrane association without targeting it for degradation.","evidence":"In vitro kinase assay with phospho-site mutagenesis and Co-IP for ULK1; mass spectrometry Gly-Gly detection and site-directed mutagenesis for ubiquitylation","pmids":["28486929","28553408"],"confidence":"High","gaps":["E3 ligase responsible for cysteine ubiquitylation was not identified","Physiological significance of S312 and T405 phosphorylation beyond S207 was not dissected","Whether ULK1-mediated suppression of COPII is required for efficient autophagosome formation was not directly tested"]},{"year":2017,"claim":"CREB3L2-driven upregulation of Sec23a was shown to be required for hepatic stellate cell activation into myofibroblasts, extending the functional importance of SEC23A-dependent COPII trafficking beyond skeletal tissues to fibrogenic cell differentiation.","evidence":"siRNA knockdown of Sec23a in hepatic stellate cell activation model","pmids":["28801610"],"confidence":"Medium","gaps":["Specific cargoes whose secretion is disrupted during failed HSC activation were not identified","In vivo relevance in liver fibrosis models was not tested"]},{"year":2018,"claim":"Systematic comparison of SEC23A and SEC23B demonstrated indistinguishable protein interactomes and full cross-species complementation, establishing that the paralogs are molecularly equivalent and that disease specificity arises from tissue-specific expression rather than biochemical divergence.","evidence":"AP-MS interactome, yeast complementation, zebrafish transgenic rescue, mouse Sec23a knock-in at Sec23b locus","pmids":["30065114"],"confidence":"High","gaps":["Whether subtle kinetic differences exist between SEC23A and SEC23B in COPII coat cycling was not addressed","Transcriptional regulatory basis for tissue-specific expression differences was not fully mapped"]},{"year":2020,"claim":"Identification of S100A8 as a SEC23A-dependent COPII cargo that suppresses metastatic colonization through BECLIN1-dependent autophagy provided the first defined cargo–pathway link explaining SEC23A's anti-metastatic function.","evidence":"Secretome mass spectrometry, siRNA knockdown, in vivo metastasis assay, autophagy marker analysis","pmids":["32811814"],"confidence":"Medium","gaps":["How S100A8 is recognized and loaded into COPII vesicles was not determined","Relative contribution of S100A8 versus other SEC23A-dependent cargoes to metastasis suppression was not quantified"]},{"year":2021,"claim":"PF4 was identified as another SEC23A-dependent secretory cargo that cooperates with SPARC to inhibit MAPK/ERK signaling and suppress melanoma metastasis, broadening the set of anti-metastatic effectors transported by SEC23A-containing COPII vesicles.","evidence":"Secretome analysis, Co-IP, ERK phosphorylation assays, in vivo metastasis model","pmids":["34421345"],"confidence":"Medium","gaps":["Whether PF4 and S100A8 act redundantly or in parallel pathways was not tested","Direct binding of PF4 to SEC24 cargo adaptors was not shown"]},{"year":2021,"claim":"Increased SEC23A expression fully rescues SEC23B-deficient human erythroid cells from congenital dyserythropoietic anemia type II features, providing direct therapeutic proof-of-concept for paralog compensation in a human disease-relevant cell type.","evidence":"CRISPR knockout of SEC23B in HUDEP-2 cells, SEC23A overexpression rescue during erythroid differentiation","pmids":["34818036"],"confidence":"High","gaps":["Mechanism for upregulating endogenous SEC23A in patient erythroid progenitors was not developed","Whether SEC23A compensation is sufficient in terminally differentiated erythrocytes in vivo was not tested"]},{"year":2022,"claim":"SEC23A was linked to cancer stem cell biology through its ability to promote ER stress that activates FAM134B-mediated ER-phagy, thereby limiting melanoma CSC self-renewal.","evidence":"CSC spheroid assays, siRNA knockdown, EM, autophagy and ER stress markers","pmids":["35236368"],"confidence":"Medium","gaps":["Whether SEC23A promotes ER stress directly through COPII cargo retention or indirectly was not dissected","Generalizability to non-melanoma CSCs was not tested"]},{"year":2023,"claim":"STAT3 was identified as a new transcriptional activator of SEC23A under ER stress, and SEC23A was shown to regulate ANXA2 localization to promote autophagy, forming a negative feedback loop that protects against ER-stress-induced apoptosis.","evidence":"ChIP assay for STAT3 at SEC23A promoter, Co-IP and MS for SEC23A–ANXA2 interaction, in vivo gastric cancer model","pmids":["37670384"],"confidence":"Medium","gaps":["Mechanism by which SEC23A alters ANXA2 localization is unknown","Whether STAT3-SEC23A axis operates in non-cancer contexts was not assessed","Relative importance of STAT3 versus CREB3L2 in driving SEC23A under ER stress was not compared"]},{"year":null,"claim":"Key unresolved questions include the structural basis of SEC23A cargo selectivity (e.g., collagen versus fibronectin), the identity of the E3 ligase for cysteine ubiquitylation, and whether the multiple transcriptional inputs (CREB3L2, STAT3, TFII-I) operate combinatorially in specific tissues to tune COPII capacity.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of SEC23A cargo recognition determinants exists","E3 ligase for unconventional cysteine ubiquitylation is unidentified","Integrated transcriptional regulation of SEC23A across tissues has not been systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,8,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,6,7,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,7,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,7,8]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,13,17,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7,17,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,10,11]}],"complexes":["COPII coat complex"],"partners":["SEC31A","SEC24D","SAR1","CREB3L2","ULK1","ANXA2","SEC23B"],"other_free_text":[]},"mechanistic_narrative":"SEC23A is a core inner-coat component of the COPII vesicle complex that mediates anterograde ER-to-Golgi transport, with particular importance for secretion of collagens and other extracellular matrix proteins in connective tissues [PMID:16980979, PMID:16980978, PMID:26494538]. Its transcription is activated by ER-stress-responsive factors including CREB3L2/BBF2H7 and STAT3, while post-translationally, ULK1 phosphorylation at S207 disrupts the SEC23A–SEC31A interaction to inhibit COPII function during autophagy, and unconventional cysteine ubiquitylation at C432/C449 modulates its ER membrane association [PMID:19767744, PMID:28486929, PMID:28553408, PMID:37670384]. Loss-of-function mutations in SEC23A cause cranio-lenticulo-sutural dysplasia (CLSD) characterized by ER dilation, cargo accumulation, and craniofacial skeletal defects, while SEC23A and its paralog SEC23B are functionally interchangeable at the molecular level with tissue-specific expression differences accounting for their distinct disease associations [PMID:16980979, PMID:30065114, PMID:34818036]. SEC23A-dependent secretion of specific cargoes including S100A8 and PF4 shapes the tumor microenvironment and suppresses metastatic colonization [PMID:32811814, PMID:34421345, PMID:21822286]."},"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":531,"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":254,"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":191,"is_preprint":false},{"pmid":"16980978","id":"PMC_16980978","title":"Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34580982","citation_count":4,"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 genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35190931","citation_count":4,"is_preprint":false},{"pmid":"39177202","id":"PMC_39177202","title":"Myotubularin 2 interacts with SEC23A and negatively regulates autophagy at ER exit sites in Arabidopsis.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39177202","citation_count":3,"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":"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":1,"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":"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":0,"is_preprint":false},{"pmid":"41968478","id":"PMC_41968478","title":"SIB1-SEC23A undergo ER to chloroplast relocalization to mediate immunity in Arabidopsis thaliana.","date":"2026","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/41968478","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":20562,"output_tokens":4960,"usd":0.068043},"stage2":{"model":"claude-opus-4-6","input_tokens":8521,"output_tokens":4026,"usd":0.214883},"total_usd":0.282926,"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\": 2006,\n      \"finding\": \"SEC23A is an essential component of COPII-coated vesicles mediating ER-to-Golgi transport; the F382L missense mutation causes loss of SEC23A function in cell-free vesicle budding assays, leading to gross ER dilation and cytoplasmic mislocalization of SEC31 in patient fibroblasts, causing cranio-lenticulo-sutural dysplasia (CLSD).\",\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 — in vitro vesicle budding assay with mutant, structural context, EM validation, and in vivo morpholino model\",\n      \"pmids\": [\"16980979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SEC23A is a core component of the COPII complex required for anterograde ER-to-Golgi trafficking; loss-of-function nonsense mutation (L402X) in zebrafish crusher mutant causes protein accumulation in distended ER of chondrocytes, severe reduction of type II collagen and cartilage ECM secretion, and craniofacial skeletal defects. The paralog SEC23B is also required for ECM secretion in chondrocytes, while COPI knockdown does not impair craniofacial morphogenesis.\",\n      \"method\": \"Positional cloning, live zebrafish imaging, immunofluorescence, electron microscopy, morpholino epistasis (COPI vs COPII)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vertebrate model, multiple orthogonal methods, replicated independently same year\",\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; Sec23a expression downstream of BBF2H7 is required for ER-to-Golgi transport of type II collagen and COMP in chondrocytes, and reintroduction of Sec23a into Bbf2h7−/− chondrocytes fully restores impaired transport and secretion of cartilage matrix proteins.\",\n      \"method\": \"Bbf2h7 knockout mouse, promoter binding assay, rescue by Sec23a re-expression, immunofluorescence, EM\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular rescue, direct promoter binding, replicated in vivo\",\n      \"pmids\": [\"19767744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-200s directly target the SEC23A 3′-UTR to suppress SEC23A expression, thereby reducing secretion of metastasis-suppressive proteins Igfbp4 and Tinagl1 from the COPII secretory pathway and promoting metastatic colonization.\",\n      \"method\": \"3′-UTR luciferase reporter, genomic and proteomic (secretome) analysis, functional rescue experiments, mouse metastasis models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct targeting validated by reporter assay, proteomic secretome profiling, in vivo models with functional rescue\",\n      \"pmids\": [\"21822286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SEC23A protein is downregulated by miR-375 and miR-200c via their binding to the SEC23A 3′-UTR; ectopic overexpression of SEC23A in prostate cancer cell lines reduces cell growth without inducing apoptosis, whereas inhibition of SEC23A stimulates proliferation.\",\n      \"method\": \"3′-UTR 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 3 — validated miRNA targeting by reporter, functional phenotype but single lab\",\n      \"pmids\": [\"21593139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BBF2H7-mediated induction of Sec23A via IGF-I signaling (through MAPK and PI3K pathways) is required for ER-to-Golgi trafficking of procollagen in dermal fibroblasts; knockdown of BBF2H7 reduces type I and III collagen expression and causes Golgi dysmorphology due to COPII hypoplasia.\",\n      \"method\": \"siRNA knockdown, immunofluorescence microscopy, Western blot, pathway inhibitor experiments\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular pathway and morphological phenotype, single lab\",\n      \"pmids\": [\"22495181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ER stress impairs membrane association of Sec23A at ER exit sites (ERES), reducing COPII vesicle formation and modifying Sec23A cycling, establishing a dynamic interplay between protein folding status and COPII assembly.\",\n      \"method\": \"Immunofluorescence, membrane fractionation, ER stress induction with pharmacological agents\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiments with functional implication, single lab\",\n      \"pmids\": [\"23994533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC23A deficiency in mice causes mid-embryonic lethality with defective extraembryonic membrane development and neural tube opening; SEC23A is specifically required for secretion of multiple collagen types (but not fibronectin) in connective tissue cells, and its loss induces strong unfolded protein response in collagen-producing cells. SEC23B deficiency causes E-cadherin accumulation in pancreatic and salivary gland acini. Haploinsufficiency of one paralog on top of homozygous loss of the other causes earlier lethality, indicating partial functional overlap.\",\n      \"method\": \"Sec23a knockout mouse, immunofluorescence, Western blot, fractionation, genetic interaction (compound heterozygotes)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — full KO mouse with defined cargo-specific secretion defects, genetic epistasis between paralogs, multiple orthogonal assays\",\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, causing aggregation of ERES and inhibition of ER-to-Golgi cargo transport during autophagy induction by amino acid starvation, rapamycin, or ULK1 overexpression.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, Co-IP (SEC23A–SEC31A interaction), live imaging of ERES, cargo transport assay\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — phosphorylation sites mapped by mutagenesis, in vitro kinase assay, interaction disruption confirmed by Co-IP\",\n      \"pmids\": [\"28486929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREB3L2/BBF2H7 transcription factor drives isoform-specific upregulation of Sec23A (and Sec24D) during hepatic stellate cell (HSC) activation; knockdown of Sec23A abrogates HSC activation, indicating that Sec23A-mediated ER-to-Golgi trafficking is required for the differentiation of HSCs into myofibroblast-like cells.\",\n      \"method\": \"siRNA knockdown, Western blot, qRT-PCR, immunofluorescence, HSC activation model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with clear cell-biological phenotype, defined transcription factor upstream, single lab\",\n      \"pmids\": [\"28801610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SEC23A is ubiquitylated on cysteine residues at positions 432 and 449 (unconventional cysteine ubiquitylation rather than lysine); this monoubiquitylation is not required for SEC23A degradation but modulates SEC23A interaction with the ER membrane and thereby influences COPII vesicle formation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry (Gly-Gly remnant detection), site-directed mutagenesis, immunofluorescence\",\n      \"journal\": \"The open biochemistry journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — sites identified by MS and validated by mutagenesis, functional consequence shown by immunofluorescence; single lab\",\n      \"pmids\": [\"28553408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human SEC23A and SEC23B have indistinguishable intracellular protein interactomes; both complement yeast Sec23, and a sec23a-expressing transgene rescues sec23b-deficient zebrafish lethality. In mice, a Sec23a coding sequence knocked into the Sec23b locus completely rescues the lethal SEC23B-deficient pancreatic phenotype, demonstrating equivalent molecular function with tissue-specific expression differences accounting for distinct disease phenotypes.\",\n      \"method\": \"Mass spectrometry interactome, yeast complementation, zebrafish transgenic rescue, mouse knock-in\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods across species, knock-in rescue in mammals\",\n      \"pmids\": [\"30065114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec23a acts downstream of miR-200c; Sec23a expression suppresses oligometastatic-to-polymetastatic progression through its secretome, which modifies the tumor microenvironment, as shown by mass spectrometric profiling of secreted proteins from Sec23a-manipulated cells.\",\n      \"method\": \"In vitro and in vivo metastasis assays, miR-200c overexpression/Sec23a knockdown epistasis, mass spectrometry secretome analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established, secretome profiled by MS, in vivo validation; single lab\",\n      \"pmids\": [\"30301603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEC23A transports S100A8 in COPII vesicles into the extracellular space; secreted S100A8 inhibits metastatic colonization via autocrine activation of BECLIN1-dependent autophagy, defining a SEC23A–S100A8–BECLIN1–autophagy axis.\",\n      \"method\": \"Secretome mass spectrometry, siRNA knockdown, in vivo metastasis assay, autophagy markers (LC3, BECLIN1)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cargo identification by MS, pathway placement by genetic manipulation, in vivo validation; single lab\",\n      \"pmids\": [\"32811814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC23A transports PF4 via COPII vesicles; secreted PF4 cooperates with SPARC to inhibit the MAPK/ERK signaling pathway and suppress melanoma metastasis.\",\n      \"method\": \"Secretome analysis, Co-IP, siRNA knockdown, ERK phosphorylation assays, in vivo metastasis model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cargo-pathway linkage established with in vivo confirmation; single lab\",\n      \"pmids\": [\"34421345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC23B-deficient HUDEP-2 erythroid cells exhibit features of congenital dyserythropoietic anemia type II (CDAII) upon differentiation; increased expression of SEC23A rescues this phenotype, confirming functional equivalence of the paralogs in human erythroid cells and suggesting a therapeutic strategy for CDAII.\",\n      \"method\": \"CRISPR knockout of SEC23B in HUDEP-2 cells, SEC23A overexpression rescue, erythroid differentiation assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human cell KO with defined rescue, mechanistic equivalence established across paralogs\",\n      \"pmids\": [\"34818036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-1227 directly targets SEC23A; inhibition of SEC23A by miR-1227 is sufficient to shift extracellular vesicle shedding from small EVs (exosomes) toward large EVs (large oncosomes), revealing a COPII-dependent mechanism controlling EV size distribution.\",\n      \"method\": \"RISCTRAP assay, RNA sequencing, luciferase reporter, Western blot, qPCR, EV size profiling\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miRNA targeting validated, SEC23A knockdown phenocopies miR-1227 effect on EV shedding; single lab\",\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, which activates FAM134B-induced ER-phagy (selective autophagy of the ER); inhibition of Sec23a reduces ER stress and consequently suppresses FAM134B-mediated ER-phagy, enhancing CSC self-renewal.\",\n      \"method\": \"CSC spheroid enrichment, siRNA knockdown, transmission electron microscopy, LC3/P62 autophagy markers, ER stress assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined molecular pathway (SEC23A→ER stress→FAM134B→ER-phagy), EM validation; single lab\",\n      \"pmids\": [\"35236368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ER stress-induced pY705-STAT3 transcriptionally upregulates SEC23A; elevated SEC23A then promotes autophagy by regulating the cellular localization of ANXA2, and the resulting SEC23A–ANXA2–autophagy axis protects gastric cancer cells from ER stress-induced apoptosis, forming a negative feedback loop.\",\n      \"method\": \"Luciferase reporter, ChIP assay, Co-IP, mass spectrometry, subcellular fractionation, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — STAT3 binding to SEC23A promoter confirmed by ChIP, SEC23A–ANXA2 interaction by Co-IP/MS, in vivo validation; single lab\",\n      \"pmids\": [\"37670384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The E599K variant in SEC23A (monoallelic, inherited in dominant fashion) affects an ultra-conserved residue predicted by 3D structural modeling to be involved in direct binding between SEC23 and SAR1 subunits of the COPII coat, suggesting a dominant-negative mechanism disrupting SEC23 multimer function.\",\n      \"method\": \"Trio genome sequencing, 3D structural modeling of yeast SEC23–SAR1 interface, familial segregation\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — structural inference only, no direct biochemical validation of binding disruption\",\n      \"pmids\": [\"34580982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TFII-I transcription factors (GTF2I/GTF2IRD1) are directly recruited to the SEC23A promoter in human neural crest progenitor cells, as shown by ChIP-chip, establishing SEC23A as a direct transcriptional target of TFII-I in craniofacial development.\",\n      \"method\": \"ChIP-chip with human RefSeq tiling promoter arrays in neural crest progenitor cells\",\n      \"journal\": \"The Cleft palate-craniofacial journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide direct promoter binding assay, but functional consequence of binding not directly tested\",\n      \"pmids\": [\"23145914\"],\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 trafficking of secretory cargoes (particularly collagens and other ECM proteins); its activity is regulated transcriptionally by ER-stress-activated bZIP factors (BBF2H7/CREB3L2) and STAT3, post-translationally by ULK1 phosphorylation (at S207/S312/T405) that disrupts SEC23A–SEC31A interaction to inhibit ERES function during autophagy, and by unconventional cysteine ubiquitylation (C432/C449) that modulates ER-membrane association; loss of SEC23A function causes cargo accumulation in dilated ER, unfolded protein response, and developmental defects (skeletal, craniofacial), while its secretome controls tumor microenvironment and metastatic colonization through transport of specific cargoes including S100A8 and PF4.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC23A is a core inner-coat component of the COPII vesicle complex that mediates anterograde ER-to-Golgi transport, with particular importance for secretion of collagens and other extracellular matrix proteins in connective tissues [PMID:16980979, PMID:16980978, PMID:26494538]. Its transcription is activated by ER-stress-responsive factors including CREB3L2/BBF2H7 and STAT3, while post-translationally, ULK1 phosphorylation at S207 disrupts the SEC23A–SEC31A interaction to inhibit COPII function during autophagy, and unconventional cysteine ubiquitylation at C432/C449 modulates its ER membrane association [PMID:19767744, PMID:28486929, PMID:28553408, PMID:37670384]. Loss-of-function mutations in SEC23A cause cranio-lenticulo-sutural dysplasia (CLSD) characterized by ER dilation, cargo accumulation, and craniofacial skeletal defects, while SEC23A and its paralog SEC23B are functionally interchangeable at the molecular level with tissue-specific expression differences accounting for their distinct disease associations [PMID:16980979, PMID:30065114, PMID:34818036]. SEC23A-dependent secretion of specific cargoes including S100A8 and PF4 shapes the tumor microenvironment and suppresses metastatic colonization [PMID:32811814, PMID:34421345, PMID:21822286].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of SEC23A as essential for COPII vesicle budding established that this gene encodes a coat protein indispensable for ER-to-Golgi transport, with human loss-of-function causing cranio-lenticulo-sutural dysplasia and zebrafish loss-of-function causing craniofacial cartilage defects due to failed collagen secretion.\",\n      \"evidence\": \"Positional cloning of F382L (human CLSD) and L402X (zebrafish crusher), cell-free budding assays, EM, morpholino knockdown\",\n      \"pmids\": [\"16980979\", \"16980978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cargo selectivity beyond collagen was not defined\",\n        \"Relative contributions of SEC23A versus SEC23B in different tissues were unknown\",\n        \"Mechanism by which F382L disrupts coat assembly was inferred structurally but not reconstituted\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that the ER-stress-activated transcription factor CREB3L2/BBF2H7 directly transactivates the Sec23a promoter revealed how cells couple protein folding demand to COPII capacity, explaining why Bbf2h7-null chondrocytes phenocopy Sec23a loss.\",\n      \"evidence\": \"Bbf2h7 knockout mouse, promoter binding assay, Sec23a re-expression rescue of collagen secretion\",\n      \"pmids\": [\"19767744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other ER-stress-responsive transcription factors also regulate SEC23A was not tested\",\n        \"Quantitative relationship between SEC23A protein level and COPII flux was not measured\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that miR-200 family members and miR-375 directly target the SEC23A 3′-UTR connected post-transcriptional SEC23A regulation to metastatic colonization, revealing that SEC23A-dependent secretion of metastasis-suppressive proteins (Igfbp4, Tinagl1) controls the tumor microenvironment.\",\n      \"evidence\": \"3′-UTR luciferase reporters, secretome proteomics, mouse metastasis models, rescue experiments\",\n      \"pmids\": [\"21822286\", \"21593139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full complement of anti-metastatic cargoes dependent on SEC23A was not catalogued\",\n        \"Whether SEC23A loss alters COPII composition or only flux was unclear\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Additional transcriptional regulators of SEC23A were identified: BBF2H7 induction downstream of IGF-I/MAPK/PI3K in dermal fibroblasts extended the CREB3L2–SEC23A axis beyond chondrocytes, and TFII-I family factors were found at the SEC23A promoter in neural crest progenitors, linking SEC23A to craniofacial developmental gene regulation.\",\n      \"evidence\": \"siRNA knockdown with pathway inhibitors in fibroblasts; ChIP-chip in human neural crest progenitor cells\",\n      \"pmids\": [\"22495181\", \"23145914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of TFII-I binding on SEC23A transcription was not directly tested\",\n        \"Whether IGF-I/MAPK pathway regulation of SEC23A operates in vivo was not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Observation that ER stress reduces SEC23A membrane association at ER exit sites established that protein folding status dynamically regulates COPII coat assembly, providing a feedback mechanism limiting vesicle budding when cargo cannot fold.\",\n      \"evidence\": \"Immunofluorescence and membrane fractionation under pharmacological ER stress\",\n      \"pmids\": [\"23994533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism by which unfolded protein signals displace SEC23A from ERES was not identified\",\n        \"Whether this is SEC23A-specific or affects all COPII subunits equally was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Full Sec23a knockout in mice revealed embryonic lethality with neural tube and extraembryonic membrane defects, and demonstrated that SEC23A is selectively required for collagen (but not fibronectin) secretion, while genetic interaction with Sec23b showed partial functional overlap.\",\n      \"evidence\": \"Sec23a knockout mouse, compound heterozygotes with Sec23b, cargo-specific immunofluorescence and Western blot\",\n      \"pmids\": [\"26494538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Basis for cargo selectivity (collagen vs. fibronectin) was not mechanistically explained\",\n        \"Whether SEC23A loss triggers UPR in all collagen-producing tissues or only selected ones was not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two key post-translational regulatory mechanisms were defined: ULK1 phosphorylation of SEC23A at S207/S312/T405 disrupts the SEC23A–SEC31A outer coat interaction to suppress COPII during autophagy, while unconventional cysteine ubiquitylation at C432/C449 modulates SEC23A membrane association without targeting it for degradation.\",\n      \"evidence\": \"In vitro kinase assay with phospho-site mutagenesis and Co-IP for ULK1; mass spectrometry Gly-Gly detection and site-directed mutagenesis for ubiquitylation\",\n      \"pmids\": [\"28486929\", \"28553408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"E3 ligase responsible for cysteine ubiquitylation was not identified\",\n        \"Physiological significance of S312 and T405 phosphorylation beyond S207 was not dissected\",\n        \"Whether ULK1-mediated suppression of COPII is required for efficient autophagosome formation was not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CREB3L2-driven upregulation of Sec23a was shown to be required for hepatic stellate cell activation into myofibroblasts, extending the functional importance of SEC23A-dependent COPII trafficking beyond skeletal tissues to fibrogenic cell differentiation.\",\n      \"evidence\": \"siRNA knockdown of Sec23a in hepatic stellate cell activation model\",\n      \"pmids\": [\"28801610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific cargoes whose secretion is disrupted during failed HSC activation were not identified\",\n        \"In vivo relevance in liver fibrosis models was not tested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Systematic comparison of SEC23A and SEC23B demonstrated indistinguishable protein interactomes and full cross-species complementation, establishing that the paralogs are molecularly equivalent and that disease specificity arises from tissue-specific expression rather than biochemical divergence.\",\n      \"evidence\": \"AP-MS interactome, yeast complementation, zebrafish transgenic rescue, mouse Sec23a knock-in at Sec23b locus\",\n      \"pmids\": [\"30065114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether subtle kinetic differences exist between SEC23A and SEC23B in COPII coat cycling was not addressed\",\n        \"Transcriptional regulatory basis for tissue-specific expression differences was not fully mapped\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of S100A8 as a SEC23A-dependent COPII cargo that suppresses metastatic colonization through BECLIN1-dependent autophagy provided the first defined cargo–pathway link explaining SEC23A's anti-metastatic function.\",\n      \"evidence\": \"Secretome mass spectrometry, siRNA knockdown, in vivo metastasis assay, autophagy marker analysis\",\n      \"pmids\": [\"32811814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How S100A8 is recognized and loaded into COPII vesicles was not determined\",\n        \"Relative contribution of S100A8 versus other SEC23A-dependent cargoes to metastasis suppression was not quantified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PF4 was identified as another SEC23A-dependent secretory cargo that cooperates with SPARC to inhibit MAPK/ERK signaling and suppress melanoma metastasis, broadening the set of anti-metastatic effectors transported by SEC23A-containing COPII vesicles.\",\n      \"evidence\": \"Secretome analysis, Co-IP, ERK phosphorylation assays, in vivo metastasis model\",\n      \"pmids\": [\"34421345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PF4 and S100A8 act redundantly or in parallel pathways was not tested\",\n        \"Direct binding of PF4 to SEC24 cargo adaptors was not shown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Increased SEC23A expression fully rescues SEC23B-deficient human erythroid cells from congenital dyserythropoietic anemia type II features, providing direct therapeutic proof-of-concept for paralog compensation in a human disease-relevant cell type.\",\n      \"evidence\": \"CRISPR knockout of SEC23B in HUDEP-2 cells, SEC23A overexpression rescue during erythroid differentiation\",\n      \"pmids\": [\"34818036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism for upregulating endogenous SEC23A in patient erythroid progenitors was not developed\",\n        \"Whether SEC23A compensation is sufficient in terminally differentiated erythrocytes in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SEC23A was linked to cancer stem cell biology through its ability to promote ER stress that activates FAM134B-mediated ER-phagy, thereby limiting melanoma CSC self-renewal.\",\n      \"evidence\": \"CSC spheroid assays, siRNA knockdown, EM, autophagy and ER stress markers\",\n      \"pmids\": [\"35236368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SEC23A promotes ER stress directly through COPII cargo retention or indirectly was not dissected\",\n        \"Generalizability to non-melanoma CSCs was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"STAT3 was identified as a new transcriptional activator of SEC23A under ER stress, and SEC23A was shown to regulate ANXA2 localization to promote autophagy, forming a negative feedback loop that protects against ER-stress-induced apoptosis.\",\n      \"evidence\": \"ChIP assay for STAT3 at SEC23A promoter, Co-IP and MS for SEC23A–ANXA2 interaction, in vivo gastric cancer model\",\n      \"pmids\": [\"37670384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which SEC23A alters ANXA2 localization is unknown\",\n        \"Whether STAT3-SEC23A axis operates in non-cancer contexts was not assessed\",\n        \"Relative importance of STAT3 versus CREB3L2 in driving SEC23A under ER stress was not compared\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of SEC23A cargo selectivity (e.g., collagen versus fibronectin), the identity of the E3 ligase for cysteine ubiquitylation, and whether the multiple transcriptional inputs (CREB3L2, STAT3, TFII-I) operate combinatorially in specific tissues to tune COPII capacity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of SEC23A cargo recognition determinants exists\",\n        \"E3 ligase for unconventional cysteine ubiquitylation is unidentified\",\n        \"Integrated transcriptional regulation of SEC23A across tissues has not been systematically mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 7, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 7, 8]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 13, 17, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7, 17, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 10, 11]}\n    ],\n    \"complexes\": [\n      \"COPII coat complex\"\n    ],\n    \"partners\": [\n      \"SEC31A\",\n      \"SEC24D\",\n      \"SAR1\",\n      \"CREB3L2\",\n      \"ULK1\",\n      \"ANXA2\",\n      \"SEC23B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}