{"gene":"SEC24A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2013,"finding":"SEC24A is required for efficient ER exit of PCSK9 (a soluble cargo); SEC24A-deficient mice show reduced plasma PCSK9 and elevated hepatic LDLR, with Apoe and Ldlr mutations epistatic to Sec24a loss, establishing a receptor-mediated lipoprotein clearance mechanism downstream of SEC24A-dependent PCSK9 secretion.","method":"Genetic knockout mouse model, epistasis analysis (Apoe/Ldlr double mutants), plasma cholesterol and PCSK9 measurements, hepatic LDLR quantification","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic epistasis across multiple mutant combinations, replicated in vivo and in vitro","pmids":["23580231"],"is_preprint":false},{"year":2013,"finding":"SEC24A and SEC24B show partial overlap in cargo selectivity, including for both soluble and transmembrane cargoes, revealing heterogeneity in COPII cargo recruitment among SEC24 paralogs.","method":"Genetic analysis in SEC24A-deficient mouse; comparison of cargo secretion across paralog contexts","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic data from KO mouse with functional cargo readout, single lab","pmids":["23580231"],"is_preprint":false},{"year":2015,"finding":"SEC24A (the mammalian COPII cargo adaptor) is required for anterograde trafficking of the voltage-gated potassium channel Kv1.3; siRNA knockdown of Sec24a causes ER retention of Kv1.3 in vivo, and recombinant Kv1.3 and Sec24a proteins associate in vitro.","method":"siRNA knockdown in cells (ER retention assay), in vitro binding assay with recombinant proteins","journal":"BMC biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo knockdown phenotype plus in vitro binding, two orthogonal methods, single lab","pmids":["26156069"],"is_preprint":false},{"year":2018,"finding":"SEC24A is an essential mediator of thapsigargin-induced ER stress cell death in HAP1 cells, acting upstream of the UPR; this requirement is specific to thapsigargin and not to tunicamycin or brefeldin A.","method":"Genome-wide CRISPR/Cas9 loss-of-function screen, validation with individual SEC24A knockout, cell death assays with multiple ER stressors","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen plus targeted KO validation, single lab, functional phenotype with pathway placement (upstream of UPR)","pmids":["30588337"],"is_preprint":false},{"year":2020,"finding":"SEC24A selectively interacts with the HBV envelope S domain via its N-terminal half, and this interaction is required for ER export of HBV subviral envelope particles (SVPs); SEC24A and SEC23B form a specific complex co-opted by HBV that cannot be substituted by other paralogs, and HBV replication upregulates SEC24A transcription.","method":"Yeast-based proteomics (interaction discovery), siRNA silencing of Sec24 paralogs in HBV-expressing liver cells, SVP secretion assay, paralog specificity analysis, N-terminal domain interaction mapping","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomics interaction plus paralog-specific silencing and functional cargo secretion readout, single lab","pmids":["32017353"],"is_preprint":false},{"year":2021,"finding":"SEC24A specifically regulates the physical colocalization of peripheral tubular ER with mitochondria (~44% reduction in colocalization in KO cells) and Ca2+ flux from the ER to mitochondria; SEC24A-KO cells show impaired ER Ca2+ efflux, reduced mitochondrial Ca2+ influx, increased autophagic flux (~2.5-fold), and reduced apoptosis (~10-fold) upon SERCA inhibition. This function is paralog-specific and not shared by SEC24B, SEC24C, or SEC24D.","method":"SEC24A knockout (CRISPR), organelle-specific fluorescent Ca2+ indicator dyes, mitochondria-ER colocalization imaging, autophagic flux assay, apoptosis assay, paralog-specific rescue experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple orthogonal functional readouts (Ca2+ flux, colocalization, autophagy, apoptosis), paralog-specific rescue, single lab but multiple methods","pmids":["33622772"],"is_preprint":false}],"current_model":"SEC24A is a paralog-specific COPII cargo adaptor that selectively recruits soluble cargoes (notably PCSK9) and transmembrane cargoes (Kv1.3) into COPII vesicles for ER-to-Golgi transport, and additionally plays a non-canonical role in tethering peripheral tubular ER to mitochondria to facilitate ER-to-mitochondria Ca2+ flux, thereby regulating apoptosis and autophagy downstream of SERCA inhibition."},"narrative":{"mechanistic_narrative":"SEC24A is a paralog-specific COPII cargo adaptor that selects discrete cargoes for ER-to-Golgi anterograde transport while also serving a non-canonical role at ER–mitochondria contact sites [PMID:23580231, PMID:33622772]. As a cargo adaptor it is required for efficient ER exit of the soluble protein PCSK9, and its loss in mice lowers plasma PCSK9 and raises hepatic LDLR through a receptor-mediated lipoprotein clearance mechanism, with Apoe and Ldlr mutations epistatic to Sec24a loss [PMID:23580231]. SEC24A also mediates anterograde trafficking of the transmembrane voltage-gated potassium channel Kv1.3, with which it associates directly, while showing only partial overlap in cargo selectivity with the paralog SEC24B [PMID:23580231, PMID:26156069]. Beyond canonical secretion, SEC24A controls the physical colocalization of peripheral tubular ER with mitochondria and the resulting ER-to-mitochondria Ca2+ flux; its loss impairs ER Ca2+ efflux and mitochondrial Ca2+ influx, increases autophagic flux, and reduces apoptosis upon SERCA inhibition, a function not shared by SEC24B, SEC24C, or SEC24D [PMID:33622772]. Consistent with this Ca2+-coupled role, SEC24A is an essential mediator of thapsigargin-induced ER stress cell death acting upstream of the UPR, specifically for the SERCA inhibitor and not for tunicamycin or brefeldin A [PMID:30588337]. SEC24A is additionally co-opted by hepatitis B virus, forming a specific complex with SEC23B that exports HBV subviral envelope particles via interaction with the envelope S domain through its N-terminal half [PMID:32017353].","teleology":[{"year":2013,"claim":"Established that SEC24A is not a redundant COPII component but selects specific soluble cargo, defining a physiological pathway from ER export of PCSK9 to lipoprotein receptor regulation.","evidence":"Knockout mouse with epistasis analysis across Apoe/Ldlr mutants, plasma PCSK9 and hepatic LDLR measurements","pmids":["23580231"],"confidence":"High","gaps":["Does not define the cargo-recognition motif on PCSK9 or the binding interface on SEC24A","Mechanism of paralog discrimination not resolved"]},{"year":2013,"claim":"Showed that SEC24 paralogs have overlapping but non-identical cargo repertoires, raising the question of how cargo selectivity is partitioned between SEC24A and SEC24B.","evidence":"Genetic comparison of cargo secretion across paralog contexts in the SEC24A-deficient mouse","pmids":["23580231"],"confidence":"Medium","gaps":["Extent of overlap not quantified across the full cargo set","No structural basis for shared versus distinct recognition"]},{"year":2015,"claim":"Extended SEC24A's adaptor role from soluble to transmembrane cargo by demonstrating it is required for export of the Kv1.3 channel and binds it directly.","evidence":"siRNA knockdown ER retention assay plus in vitro binding of recombinant Kv1.3 and SEC24A","pmids":["26156069"],"confidence":"Medium","gaps":["ER-export signal on Kv1.3 not mapped","Single lab, no reciprocal validation of the interaction in vivo"]},{"year":2018,"claim":"Placed SEC24A upstream of the UPR as a selective mediator of cell death triggered by SERCA inhibition, distinguishing it from a general secretory requirement.","evidence":"Genome-wide CRISPR loss-of-function screen with targeted SEC24A knockout validation across multiple ER stressors in HAP1 cells","pmids":["30588337"],"confidence":"Medium","gaps":["Molecular link between SEC24A and thapsigargin-specific death not defined at this stage","Why tunicamycin and brefeldin A responses are spared unexplained"]},{"year":2020,"claim":"Demonstrated a virus-co-opted, paralog-specific SEC24A–SEC23B complex that exports HBV subviral particles, mapping the determinant to the SEC24A N-terminal half.","evidence":"Yeast-based interaction proteomics, paralog-specific siRNA silencing, SVP secretion assay, and N-terminal domain interaction mapping in HBV-expressing liver cells","pmids":["32017353"],"confidence":"Medium","gaps":["Structural definition of the S-domain/SEC24A interface absent","Whether the SEC23B pairing is HBV-specific or a general SEC24A preference unresolved"]},{"year":2021,"claim":"Revealed a non-canonical SEC24A function at ER–mitochondria contacts, linking ER tubule–mitochondria tethering and Ca2+ transfer to the control of autophagy and apoptosis, and explaining the thapsigargin-specific death phenotype.","evidence":"CRISPR knockout with organelle-specific Ca2+ indicators, ER–mitochondria colocalization imaging, autophagic flux and apoptosis assays, and paralog-specific rescue","pmids":["33622772"],"confidence":"High","gaps":["Whether tethering is direct or requires intermediary contact-site proteins is unknown","Relationship between the COPII cargo-adaptor function and the contact-site function not mechanistically reconciled"]},{"year":null,"claim":"How SEC24A reconciles its canonical COPII cargo-selection activity with its membrane-tethering role at ER–mitochondria contacts, and what structural features drive its cargo and paralog specificity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SEC24A cargo or partner interfaces in the corpus","Mechanism of ER–mitochondria tethering not molecularly defined","Determinants distinguishing SEC24A from other paralogs not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":["COPII coat","SEC24A-SEC23B complex"],"partners":["PCSK9","KCNA3","SEC23B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95486","full_name":"Protein transport protein Sec24A","aliases":["SEC24-related protein A"],"length_aa":1093,"mass_kda":119.7,"function":"Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules for their transport to the Golgi complex (PubMed:17499046, PubMed:18843296, PubMed:20427317). Plays a central role in cargo selection within the COPII complex and together with SEC24B may have a different specificity compared to SEC24C and SEC24D. May package preferentially cargos with cytoplasmic DxE or LxxLE motifs and may also recognize conformational epitopes (PubMed:17499046, PubMed:18843296)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O95486/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC24A","classification":"Not Classified","n_dependent_lines":41,"n_total_lines":1208,"dependency_fraction":0.03394039735099338},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SEC23B","stoichiometry":10.0},{"gene":"SEC23A","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/SEC24A","total_profiled":1310},"omim":[{"mim_id":"617852","title":"SEC23-INTERACTING PROTEIN; SEC23IP","url":"https://www.omim.org/entry/617852"},{"mim_id":"613455","title":"MIA SH3 DOMAIN ER EXPORT FACTOR 3; MIA3","url":"https://www.omim.org/entry/613455"},{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"},{"mim_id":"607690","title":"SECRETION-ASSOCIATED RAS-RELATED GTPase 1B; SAR1B","url":"https://www.omim.org/entry/607690"},{"mim_id":"607186","title":"SEC24-RELATED GENE FAMILY, MEMBER D; SEC24D","url":"https://www.omim.org/entry/607186"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC24A"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95486","domains":[{"cath_id":"1.20.120.730","chopping":"351-368_840-944_1075-1093","consensus_level":"medium","plddt":92.4755,"start":351,"end":1093},{"cath_id":"2.60.40.1670","chopping":"375-499_746-839","consensus_level":"medium","plddt":94.6992,"start":375,"end":839},{"cath_id":"3.40.50.410","chopping":"506-651_669-743","consensus_level":"high","plddt":96.6899,"start":506,"end":743},{"cath_id":"3.40.20.10","chopping":"945-1070","consensus_level":"medium","plddt":93.9659,"start":945,"end":1070}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95486","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95486-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95486-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC24A","jax_strain_url":"https://www.jax.org/strain/search?query=SEC24A"},"sequence":{"accession":"O95486","fasta_url":"https://rest.uniprot.org/uniprotkb/O95486.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95486/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95486"}},"corpus_meta":[{"pmid":"23580231","id":"PMC_23580231","title":"SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.","date":"2013","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/23580231","citation_count":105,"is_preprint":false},{"pmid":"25878114","id":"PMC_25878114","title":"The Vesicle-Forming 6K2 Protein of Turnip Mosaic Virus Interacts with the COPII Coatomer Sec24a for Viral Systemic Infection.","date":"2015","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/25878114","citation_count":77,"is_preprint":false},{"pmid":"32017353","id":"PMC_32017353","title":"Hepatitis B subviral envelope particles use the COPII machinery for intracellular transport via selective exploitation of Sec24A and Sec23B.","date":"2020","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32017353","citation_count":23,"is_preprint":false},{"pmid":"30588337","id":"PMC_30588337","title":"SEC24A identified as an essential mediator of thapsigargin-induced cell death in a genome-wide CRISPR/Cas9 screen.","date":"2018","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30588337","citation_count":18,"is_preprint":false},{"pmid":"26156069","id":"PMC_26156069","title":"Kv1.3 contains an alternative C-terminal ER exit motif and is recruited into COPII vesicles by Sec24a.","date":"2015","source":"BMC biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26156069","citation_count":16,"is_preprint":false},{"pmid":"34325283","id":"PMC_34325283","title":"CircRNA circ_SEC24A upregulates DNMT3A expression by sponging miR-26b-5p to aggravate osteoarthritis progression.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34325283","citation_count":13,"is_preprint":false},{"pmid":"33622772","id":"PMC_33622772","title":"SEC24A facilitates colocalization and Ca2+ flux between the endoplasmic reticulum and mitochondria.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33622772","citation_count":6,"is_preprint":false},{"pmid":"31949794","id":"PMC_31949794","title":"SEC24A stimulates oncogenicity of human gastric cancer cells.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31949794","citation_count":4,"is_preprint":false},{"pmid":"38828010","id":"PMC_38828010","title":"CircRNA SEC24A promotes osteoarthritis through miR-107-5p/CASP3 axis.","date":"2024","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38828010","citation_count":2,"is_preprint":false},{"pmid":"41378010","id":"PMC_41378010","title":"ING5-mediated regulation of lung cancer progression via the OIP5-AS1/miR-381-3p/SEC24A axis.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41378010","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.09.632146","title":"Involvement of PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1 in COPII assembly by interacting with SAR1 GTPase","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632146","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8126,"output_tokens":1551,"usd":0.023821,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8355,"output_tokens":2643,"usd":0.053925,"stage2_stop_reason":"end_turn"},"total_usd":0.077746,"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\": 2013,\n      \"finding\": \"SEC24A is required for efficient ER exit of PCSK9 (a soluble cargo); SEC24A-deficient mice show reduced plasma PCSK9 and elevated hepatic LDLR, with Apoe and Ldlr mutations epistatic to Sec24a loss, establishing a receptor-mediated lipoprotein clearance mechanism downstream of SEC24A-dependent PCSK9 secretion.\",\n      \"method\": \"Genetic knockout mouse model, epistasis analysis (Apoe/Ldlr double mutants), plasma cholesterol and PCSK9 measurements, hepatic LDLR quantification\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, genetic epistasis across multiple mutant combinations, replicated in vivo and in vitro\",\n      \"pmids\": [\"23580231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEC24A and SEC24B show partial overlap in cargo selectivity, including for both soluble and transmembrane cargoes, revealing heterogeneity in COPII cargo recruitment among SEC24 paralogs.\",\n      \"method\": \"Genetic analysis in SEC24A-deficient mouse; comparison of cargo secretion across paralog contexts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic data from KO mouse with functional cargo readout, single lab\",\n      \"pmids\": [\"23580231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC24A (the mammalian COPII cargo adaptor) is required for anterograde trafficking of the voltage-gated potassium channel Kv1.3; siRNA knockdown of Sec24a causes ER retention of Kv1.3 in vivo, and recombinant Kv1.3 and Sec24a proteins associate in vitro.\",\n      \"method\": \"siRNA knockdown in cells (ER retention assay), in vitro binding assay with recombinant proteins\",\n      \"journal\": \"BMC biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo knockdown phenotype plus in vitro binding, two orthogonal methods, single lab\",\n      \"pmids\": [\"26156069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEC24A is an essential mediator of thapsigargin-induced ER stress cell death in HAP1 cells, acting upstream of the UPR; this requirement is specific to thapsigargin and not to tunicamycin or brefeldin A.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 loss-of-function screen, validation with individual SEC24A knockout, cell death assays with multiple ER stressors\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen plus targeted KO validation, single lab, functional phenotype with pathway placement (upstream of UPR)\",\n      \"pmids\": [\"30588337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SEC24A selectively interacts with the HBV envelope S domain via its N-terminal half, and this interaction is required for ER export of HBV subviral envelope particles (SVPs); SEC24A and SEC23B form a specific complex co-opted by HBV that cannot be substituted by other paralogs, and HBV replication upregulates SEC24A transcription.\",\n      \"method\": \"Yeast-based proteomics (interaction discovery), siRNA silencing of Sec24 paralogs in HBV-expressing liver cells, SVP secretion assay, paralog specificity analysis, N-terminal domain interaction mapping\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomics interaction plus paralog-specific silencing and functional cargo secretion readout, single lab\",\n      \"pmids\": [\"32017353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC24A specifically regulates the physical colocalization of peripheral tubular ER with mitochondria (~44% reduction in colocalization in KO cells) and Ca2+ flux from the ER to mitochondria; SEC24A-KO cells show impaired ER Ca2+ efflux, reduced mitochondrial Ca2+ influx, increased autophagic flux (~2.5-fold), and reduced apoptosis (~10-fold) upon SERCA inhibition. This function is paralog-specific and not shared by SEC24B, SEC24C, or SEC24D.\",\n      \"method\": \"SEC24A knockout (CRISPR), organelle-specific fluorescent Ca2+ indicator dyes, mitochondria-ER colocalization imaging, autophagic flux assay, apoptosis assay, paralog-specific rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple orthogonal functional readouts (Ca2+ flux, colocalization, autophagy, apoptosis), paralog-specific rescue, single lab but multiple methods\",\n      \"pmids\": [\"33622772\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC24A is a paralog-specific COPII cargo adaptor that selectively recruits soluble cargoes (notably PCSK9) and transmembrane cargoes (Kv1.3) into COPII vesicles for ER-to-Golgi transport, and additionally plays a non-canonical role in tethering peripheral tubular ER to mitochondria to facilitate ER-to-mitochondria Ca2+ flux, thereby regulating apoptosis and autophagy downstream of SERCA inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC24A is a paralog-specific COPII cargo adaptor that selects discrete cargoes for ER-to-Golgi anterograde transport while also serving a non-canonical role at ER–mitochondria contact sites [#0, #5]. As a cargo adaptor it is required for efficient ER exit of the soluble protein PCSK9, and its loss in mice lowers plasma PCSK9 and raises hepatic LDLR through a receptor-mediated lipoprotein clearance mechanism, with Apoe and Ldlr mutations epistatic to Sec24a loss [#0]. SEC24A also mediates anterograde trafficking of the transmembrane voltage-gated potassium channel Kv1.3, with which it associates directly, while showing only partial overlap in cargo selectivity with the paralog SEC24B [#1, #2]. Beyond canonical secretion, SEC24A controls the physical colocalization of peripheral tubular ER with mitochondria and the resulting ER-to-mitochondria Ca2+ flux; its loss impairs ER Ca2+ efflux and mitochondrial Ca2+ influx, increases autophagic flux, and reduces apoptosis upon SERCA inhibition, a function not shared by SEC24B, SEC24C, or SEC24D [#5]. Consistent with this Ca2+-coupled role, SEC24A is an essential mediator of thapsigargin-induced ER stress cell death acting upstream of the UPR, specifically for the SERCA inhibitor and not for tunicamycin or brefeldin A [#3]. SEC24A is additionally co-opted by hepatitis B virus, forming a specific complex with SEC23B that exports HBV subviral envelope particles via interaction with the envelope S domain through its N-terminal half [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that SEC24A is not a redundant COPII component but selects specific soluble cargo, defining a physiological pathway from ER export of PCSK9 to lipoprotein receptor regulation.\",\n      \"evidence\": \"Knockout mouse with epistasis analysis across Apoe/Ldlr mutants, plasma PCSK9 and hepatic LDLR measurements\",\n      \"pmids\": [\"23580231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the cargo-recognition motif on PCSK9 or the binding interface on SEC24A\", \"Mechanism of paralog discrimination not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that SEC24 paralogs have overlapping but non-identical cargo repertoires, raising the question of how cargo selectivity is partitioned between SEC24A and SEC24B.\",\n      \"evidence\": \"Genetic comparison of cargo secretion across paralog contexts in the SEC24A-deficient mouse\",\n      \"pmids\": [\"23580231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Extent of overlap not quantified across the full cargo set\", \"No structural basis for shared versus distinct recognition\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SEC24A's adaptor role from soluble to transmembrane cargo by demonstrating it is required for export of the Kv1.3 channel and binds it directly.\",\n      \"evidence\": \"siRNA knockdown ER retention assay plus in vitro binding of recombinant Kv1.3 and SEC24A\",\n      \"pmids\": [\"26156069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ER-export signal on Kv1.3 not mapped\", \"Single lab, no reciprocal validation of the interaction in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed SEC24A upstream of the UPR as a selective mediator of cell death triggered by SERCA inhibition, distinguishing it from a general secretory requirement.\",\n      \"evidence\": \"Genome-wide CRISPR loss-of-function screen with targeted SEC24A knockout validation across multiple ER stressors in HAP1 cells\",\n      \"pmids\": [\"30588337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between SEC24A and thapsigargin-specific death not defined at this stage\", \"Why tunicamycin and brefeldin A responses are spared unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a virus-co-opted, paralog-specific SEC24A–SEC23B complex that exports HBV subviral particles, mapping the determinant to the SEC24A N-terminal half.\",\n      \"evidence\": \"Yeast-based interaction proteomics, paralog-specific siRNA silencing, SVP secretion assay, and N-terminal domain interaction mapping in HBV-expressing liver cells\",\n      \"pmids\": [\"32017353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural definition of the S-domain/SEC24A interface absent\", \"Whether the SEC23B pairing is HBV-specific or a general SEC24A preference unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a non-canonical SEC24A function at ER–mitochondria contacts, linking ER tubule–mitochondria tethering and Ca2+ transfer to the control of autophagy and apoptosis, and explaining the thapsigargin-specific death phenotype.\",\n      \"evidence\": \"CRISPR knockout with organelle-specific Ca2+ indicators, ER–mitochondria colocalization imaging, autophagic flux and apoptosis assays, and paralog-specific rescue\",\n      \"pmids\": [\"33622772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tethering is direct or requires intermediary contact-site proteins is unknown\", \"Relationship between the COPII cargo-adaptor function and the contact-site function not mechanistically reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC24A reconciles its canonical COPII cargo-selection activity with its membrane-tethering role at ER–mitochondria contacts, and what structural features drive its cargo and paralog specificity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SEC24A cargo or partner interfaces in the corpus\", \"Mechanism of ER–mitochondria tethering not molecularly defined\", \"Determinants distinguishing SEC24A from other paralogs not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"COPII coat\", \"SEC24A-SEC23B complex\"],\n    \"partners\": [\"PCSK9\", \"KCNA3\", \"SEC23B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}