{"gene":"SEC24C","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1999,"finding":"SEC24C (KIAA0079) is a mammalian homologue of yeast Sec24p: it co-elutes with mammalian Sec23p on gel filtration, its C-terminal region binds the N-terminal region of Sec23p in vitro, and overexpression causes a defect in protein export from the ER.","method":"Gel filtration co-elution, in vitro binding assay, overexpression ER-export assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus functional overexpression assay, single lab, two orthogonal methods","pmids":["10214955"],"is_preprint":false},{"year":2009,"finding":"SEC24C is required for docking of the prechylomicron transport vesicle (PCTV) with the Golgi; immunodepletion of SEC24C from cytosol nearly completely abolished PCTV-Golgi docking activity, which was restored by adding back recombinant SEC24C.","method":"Immunodepletion of cytosolic SEC24C, reconstitution with recombinant SEC24C, PCTV-Golgi docking assay","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution with recombinant protein in a defined functional assay, single lab with two orthogonal approaches (depletion + rescue)","pmids":["19965600"],"is_preprint":false},{"year":2011,"finding":"SERT exclusively requires SEC24C (not SEC24A, B, or D) for ER export: mass spectrometry showed SERT C-terminal peptide recruits SEC24C-containing COPII complexes from brain lysates; siRNA depletion of SEC24C (but not other isoforms) trapped SERT in the ER; a dominant-negative SEC24C-D796V/D797N reduced SERT surface levels; and a SERT-607RI608-AA mutant lacking the SEC24C-binding motif was insensitive to SEC24C knockdown.","method":"Mass spectrometry pulldown from brain lysates, isoform-selective siRNA knockdown, dominant-negative SEC24C overexpression, surface biotinylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent orthogonal methods (MS pulldown, siRNA, dominant-negative mutagenesis) in a single study, replicated across endogenous and transfected systems","pmids":["21454670"],"is_preprint":false},{"year":2012,"finding":"The triple Arg (3R) motif in the third intracellular loop of α2B-adrenergic receptor mediates direct interaction with Sec24C/D and is required for ER export; mutation or deletion of the 3R motif reduced co-immunoprecipitation with Sec24C/D and impaired cell surface transport.","method":"Co-immunoprecipitation, mutagenesis, surface expression assay, CD8 chimera transfer assay","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with mutagenesis and chimera transfer, single lab","pmids":["22404651"],"is_preprint":false},{"year":2013,"finding":"A single residue at position +2 downstream of the ER export motif (RI) in SERT determines SEC24C vs. SEC24D isoform specificity: hydrophilic residues (Lys, Asn, Gln) recruit SEC24C, whereas hydrophobic residues (Tyr, Val) recruit SEC24D. Substituting Lys610 with Tyr switched SERT from SEC24C- to SEC24D-dependence.","method":"siRNA depletion of individual SEC24 isoforms, dominant-negative SEC24C/D overexpression, mutagenesis of SERT and other SLC6 transporters, surface biotinylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis combined with siRNA and dominant-negative approaches, validated across multiple SLC6 family members in the same study","pmids":["23288844"],"is_preprint":false},{"year":2013,"finding":"A novel ER export signal motif ΦXΦXΦ (hydrophobic-X-hydrophobic-X-hydrophobic) in the N-terminus of bovine AE1 anion exchanger selectively interacts with SEC24C (via the Sec23A-Sec24C complex); mutation of the SEC24C IxM cargo-binding site (895LIL897→AAA) caused ER retention of ΦXΦXΦ-containing chimeric proteins.","method":"Synthetic peptide pulldown with Sec23A-Sec24C complex, chimeric protein mutagenesis, cell surface expression assay, N-glycan processing analysis, co-transfection with SEC24C-AAA dominant negative","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro pulldown plus mutagenesis of both cargo and Sec24C binding site, multiple chimeric constructs tested","pmids":["23658022"],"is_preprint":false},{"year":2014,"finding":"SEC24C-dependent ER export determines axonal targeting of SERT in dorsal raphe neurons: disruption of the SEC24C-binding motif (RI→AA) or overexpression of dominant-negative SEC24C-D796V/D797N redirected SERT from axons to the somatodendritic compartment, while VMAT2 axonal targeting was unaffected by either dominant-negative SEC24C or SEC24D.","method":"Dominant-negative SEC24C/D overexpression in cultured neurons, fluorescence imaging of endogenous and heterologous SERT distribution, mutagenesis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative approach validated with multiple SERT mutants and isoform selectivity controls in primary neurons","pmids":["24790205"],"is_preprint":false},{"year":2014,"finding":"SEC24C is essential for early mammalian embryonic development; homozygous Sec24c null mice die at ~E7.5, whereas tissue-specific deletion in hepatocytes, pancreatic cells, smooth muscle cells, and intestinal epithelial cells produces no phenotype, indicating functional compensation by other SEC24 paralogs in those tissues.","method":"Conventional and conditional knockout mice, embryonic phenotype analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function in multiple tissue-specific KO lines with defined developmental phenotype","pmids":["24876386"],"is_preprint":false},{"year":2016,"finding":"SEC24C directly interacts with Syntaxin5 in its 'open' conformation and is required for ER export of the preassembled Q-SNARE complex (Syntaxin5, GS27, Bet1); mutation of the IxM cargo-binding site in SEC24C drastically reduced incorporation of all three Q-SNAREs into COPII vesicles, while R-SNARE Sec22b is recruited by other isoforms.","method":"Co-immunoprecipitation, dominant-negative/mutation of IxM site in SEC24C, immunoisolation of COPII vesicles, confocal co-localization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with mutagenesis and immunoisolated vesicle analysis, multiple orthogonal approaches in single study","pmids":["27413010"],"is_preprint":false},{"year":2017,"finding":"Claudin-1 interacts with SEC24C through its C-terminal YV motif for ER export and cell surface delivery; this interaction is required for HCV entry, as blocking COPII transport reduces claudin-1 surface levels.","method":"Co-immunoprecipitation, mutagenesis of YV motif, surface expression assay, HCV entry assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with mutagenesis and functional viral entry readout, single lab","pmids":["28679754"],"is_preprint":false},{"year":2018,"finding":"SEC24C is essential for postmitotic neuron survival: conditional KO of Sec24c in neural progenitors caused perinatal mortality, microcephaly, unfolded protein response activation, and apoptosis of cortical neurons; this neuronal cell death was rescued by knock-in expression of SEC24D in place of SEC24C.","method":"Conditional Sec24c KO mice, SEC24D knock-in rescue, iPSC-derived neuron KD, UPR marker analysis, TUNEL apoptosis assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse genetic models (cKO + rescue knock-in) plus human iPSC-derived neurons, replicated with orthogonal cell-autonomous validation","pmids":["29939162"],"is_preprint":false},{"year":2018,"finding":"Amino acid transporter SLC6A14 (ATB0,+) exclusively co-precipitates with SEC24C (not with SEC24A, B, or D) for ER export; a dominant-negative SEC24C mutant reduced ATB0,+ plasma membrane expression and increased its proteolytic degradation; a Lys at position +2 of the RI export motif is required for SEC24C binding.","method":"Co-immunoprecipitation, proximity ligation assay, dominant-negative SEC24C, surface biotinylation, immunofluorescence co-localization","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed by proximity ligation assay plus functional dominant-negative experiment, single lab","pmids":["30445147"],"is_preprint":false},{"year":2021,"finding":"SEC24C is an HIV-1 host dependency factor: it directly and specifically interacts with hexameric HIV-1 capsid lattices via an FG-motif (residues 228-242); a 2.3-Å crystal structure showed the FG-motif binds a pocket comprising two adjoining capsid subunits; deletion of SEC24C reduced core stability, reverse transcription, nuclear import, and infectivity; live-cell microscopy showed SEC24C co-trafficked with HIV-1 cores in the cytoplasm during ingress.","method":"Crystal structure at 2.3-Å resolution, biochemical binding assays, Sec24C gene deletion and complementation in Jurkat cells, siRNA knockdown in HeLa cells, live-cell microscopy, reverse transcription and nuclear import assays","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure combined with multiple orthogonal functional assays (KO complementation, siRNA, live imaging, biochemical binding), replicated across cell types","pmids":["33649557"],"is_preprint":false},{"year":2021,"finding":"AKT kinase phosphorylates SEC24C, and AKT inhibition decreases SEC24C phosphoserine levels (detected by proximity ligation assay and 2D electrophoresis), which correlates with transient increase of SLC6A14 transporter at the plasma membrane, suggesting AKT-mediated phosphorylation of SEC24C regulates ER export of SLC6A14.","method":"2D electrophoresis, proximity ligation assay with phospho-specific antibodies, AKT inhibitor (MK-2206) treatment, surface biotinylation","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence of phosphorylation via 2D gel and PLA (no direct kinase assay or phosphosite mutagenesis), single lab, single method per endpoint","pmids":["34359969"],"is_preprint":false},{"year":2021,"finding":"Murine SEC24D can functionally substitute for SEC24C during embryonic development: Sec24cc-d/c-d knock-in mice (C-terminal 90% of SEC24C replaced by SEC24D sequence) survive to term whereas Sec24c null mice die at E7.5, indicating the early embryonic requirement for SEC24C reflects tissue/stage-specific expression rather than unique cargo specificity.","method":"Dual recombinase-mediated cassette exchange knock-in mice, embryonic lethality rescue analysis, pathological evaluation","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic rescue experiment in mice with defined developmental phenotype endpoint, well-controlled knock-in design","pmids":["34702932"],"is_preprint":false},{"year":2024,"finding":"SEC24C and p24-family members TMP21 and TMED9 facilitate clearance of misfolded alpha-1-antitrypsin Z (ATZ) from the ER to lysosomes via ERLAD: ATZ co-immunoprecipitates with TMP21, TMED9, SEC24C, FAM134B, and calnexin; live-cell imaging showed ATZ and p24-family members co-trafficking to lysosomes; depletion of SEC24C inhibited lysosomal trafficking of ATZ and increased intracellular ATZ levels; p24-family members co-immunoprecipitate with both ATZ and SEC24C, placing SEC24C at ER-exit sites for ERLAD.","method":"Co-immunoprecipitation, live-cell imaging, chemical inhibitors of ER exit/autophagy, siRNA depletion, overexpression of p24 proteins","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, live imaging, siRNA depletion, chemical inhibitors, overexpression rescue) in a single study","pmids":["38294851"],"is_preprint":false},{"year":2024,"finding":"SEC24C interacts with PERK (EIF2AK3) and activates downstream UPR-related apoptosis; under normal conditions SEC24C is nuclear-localized but translocates to the ER upon ER stress, and SEC24C overexpression augments bortezomib-induced apoptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, subcellular fractionation/localization, overexpression + drug treatment apoptosis assay","journal":"Bioscience trends","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP experiment and localization data, single lab, limited mechanistic validation of PERK interaction","pmids":["39085101"],"is_preprint":false},{"year":2025,"finding":"SEC24C is dynamically regulated by O-GlcNAcylation (present in interphase) and phosphorylation (enriched in specific cell cycle phases); O-GlcNAc is rapidly removed upon mitotic entry and its removal influences the timing of SEC24C dispersal from juxtanuclear ER exit sites to a diffuse cytosolic pool; novel phosphosites were identified that regulate SEC24C stability and localization during mitosis.","method":"Mass spectrometry phosphoproteomics, O-GlcNAc modification analysis, cell cycle synchronization, live-cell imaging of SEC24C localization, mutagenesis of phosphosites","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified PTMs with functional imaging validation of localization phenotype, mutagenesis of sites, single lab","pmids":["40617351"],"is_preprint":false},{"year":2025,"finding":"Tanshinone IIA inhibits STING transport from the ER to the Golgi by weakening the interaction between STING and SEC24C, thereby preventing cGAS-STING pathway activation.","method":"Co-immunoprecipitation of STING and SEC24C with/without Tanshinone IIA, STING localization assay, downstream signaling readouts","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment measuring interaction reduction, single lab, no direct mutagenesis of the STING-SEC24C interface","pmids":["40252465"],"is_preprint":false},{"year":2025,"finding":"Kremen1 (dependence receptor) induces autophagic cell death requiring SEC24C: biotin proximity labeling identified SEC24C as a critical effector; Kremen1 is in proximity with SEC24C and ATG9A after vesicular trafficking, and SEC24C is brought into proximity with ATG8, ERGIC, and ATG9A, increasing autophagosome formation leading to cell death.","method":"Biotin proximity labeling (BioID/TurboID), genetic silencing of autophagy effectors, pharmacological inhibition of autophagy, proximity ligation assay","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling without direct biochemical reconstitution, mechanistic link to SEC24C is correlative, single lab","pmids":["41807954"],"is_preprint":false},{"year":2025,"finding":"Acute glucose starvation impairs ER-to-Golgi export of specific cargoes (e.g., E-cadherin) in a SEC24C-dependent manner; AMPK and ULK1 signaling (independent of autophagy) orchestrate this process, with ULK1-mediated phosphorylation of SEC31A driving SEC24C-dependent COPII reorganization.","method":"SEC24C knockout cells, quantitative cell surface proteomics, nutrient deprivation experiments, ULK1 kinase assay, AMPK/ULK1 inhibitor experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with quantitative proteomics and kinase pathway dissection, multiple methods, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"SEC24C is a cargo-selective adaptor subunit of the COPII vesicle coat that directly recognizes specific ER export signals (RI, 3R, ΦXΦXΦ, IxM, YV motifs) on transmembrane cargo proteins—including neurotransmitter transporters (SERT, GlyT-1a, ATB0,+), GPCRs (α2B-AR), SNAREs (Syntaxin5/Q-SNARE complex), claudin-1, and STING—to package them into COPII vesicles at ER exit sites; it is also required for PCTV-Golgi docking, facilitates ERLAD-mediated lysosomal clearance of misfolded ATZ via a p24-adaptor complex, and is subject to cell-cycle-regulated O-GlcNAcylation and phosphorylation that control its dispersal from ER exit sites during mitosis; in neurons, SEC24C-mediated ER export is uniquely essential for postmitotic neuronal homeostasis and axonal targeting of cargoes, and SEC24C's FG-motif is exploited by HIV-1 capsid for cytoplasmic trafficking during viral infection."},"narrative":{"mechanistic_narrative":"SEC24C is a cargo-selective adaptor subunit of the COPII vesicle coat that packages specific transmembrane cargo into vesicles at ER exit sites; it co-elutes and directly binds the SEC23 component of the inner coat [PMID:10214955]. Through distinct cargo-binding pockets, SEC24C reads short ER-export motifs on client proteins: an RI motif whose +2 residue dictates SEC24C-versus-SEC24D selectivity in SLC6 neurotransmitter transporters such as SERT and the amino acid transporter SLC6A14/ATB0,+ [PMID:21454670, PMID:23288844, PMID:30445147], a triple-arginine (3R) motif in the α2B-adrenergic receptor [PMID:22404651], a ΦXΦXΦ motif engaged by the SEC24C IxM pocket [PMID:23658022], and a C-terminal YV motif in claudin-1 [PMID:28679754]. The same IxM cargo-binding site captures the open-conformation Q-SNARE syntaxin5 together with GS27 and Bet1, coupling SNARE assembly to ER export [PMID:27413010]. Beyond conventional anterograde transport, SEC24C is required for prechylomicron transport vesicle docking with the Golgi [PMID:19965600] and, acting with the p24 proteins TMP21 and TMED9, routes misfolded alpha-1-antitrypsin Z from the ER to lysosomes via ERLAD [PMID:38294851]. Its activity is developmentally and physiologically essential: Sec24c-null mice die at E7.5, an early requirement attributable to expression timing rather than unique cargo specificity since SEC24D knock-in rescues both embryonic and neuronal phenotypes [PMID:24876386, PMID:34702932], yet postmitotic cortical neurons depend on SEC24C-mediated ER export for survival and for axonal targeting of cargoes such as SERT [PMID:24790205, PMID:29939162]. SEC24C is regulated by cell-cycle-coupled O-GlcNAcylation and phosphorylation that govern its dispersal from ER exit sites during mitosis [PMID:40617351], and its FG-motif is bound at atomic resolution by the HIV-1 capsid lattice to support cytoplasmic core trafficking and infectivity [PMID:33649557].","teleology":[{"year":1999,"claim":"Established SEC24C as a mammalian COPII inner-coat component by showing it partners with the SEC23 subunit and functions in ER export.","evidence":"Gel filtration co-elution and in vitro binding with Sec23p plus an overexpression ER-export defect assay","pmids":["10214955"],"confidence":"Medium","gaps":["No cargo specificity defined","No structural basis of SEC23 binding","Endogenous function inferred only from overexpression"]},{"year":2009,"claim":"Extended SEC24C function beyond canonical vesicle formation to docking of a specialized lipid-cargo carrier with the Golgi.","evidence":"Immunodepletion of cytosolic SEC24C with recombinant protein rescue in a PCTV-Golgi docking assay","pmids":["19965600"],"confidence":"High","gaps":["Molecular partner mediating docking not identified","Relationship to canonical COPII coating unclear"]},{"year":2011,"claim":"Demonstrated isoform-exclusive cargo selection by showing SERT requires SEC24C specifically, defining SEC24C as a dedicated ER-export adaptor for select cargoes.","evidence":"MS pulldown from brain lysates, isoform-selective siRNA, dominant-negative SEC24C, and cargo motif (RI) mutagenesis with surface biotinylation","pmids":["21454670"],"confidence":"High","gaps":["Structural basis of motif recognition not resolved","Generality across cargo families not yet tested"]},{"year":2012,"claim":"Identified a distinct 3R recognition mode, showing SEC24C/D recognize multiple motif classes on diverse cargo including a GPCR.","evidence":"Co-IP, mutagenesis, and CD8 chimera transfer with surface expression for α2B-adrenergic receptor","pmids":["22404651"],"confidence":"Medium","gaps":["SEC24C versus SEC24D contributions not separated","Direct binding pocket not mapped"]},{"year":2013,"claim":"Resolved how a single residue dictates SEC24C-versus-SEC24D isoform choice, giving a residue-level code for paralog selectivity.","evidence":"Isoform siRNA, dominant-negative constructs, and +2-position mutagenesis across SLC6 transporters with surface biotinylation","pmids":["23288844"],"confidence":"High","gaps":["Structural explanation of +2 selectivity absent","In vivo consequences of switching not addressed"]},{"year":2013,"claim":"Mapped a SEC24C cargo-binding site (IxM) and a new ΦXΦXΦ motif, localizing motif recognition to a defined region of the adaptor.","evidence":"Peptide pulldown with Sec23A-Sec24C complex and SEC24C IxM-site (LIL→AAA) mutagenesis with chimeric cargo","pmids":["23658022"],"confidence":"High","gaps":["No co-crystal of motif in the IxM pocket","Affinities and competition among motifs unquantified"]},{"year":2014,"claim":"Showed SEC24C-dependent ER export sets neuronal cargo polarity, linking adaptor selectivity to axonal targeting.","evidence":"Dominant-negative SEC24C/D and RI-motif mutagenesis with imaging of SERT distribution in primary dorsal raphe neurons","pmids":["24790205"],"confidence":"High","gaps":["Mechanism connecting ER export to polarized sorting unresolved","Endogenous loss-of-function not tested here"]},{"year":2014,"claim":"Defined the organismal requirement for SEC24C, revealing essential embryonic function with tissue-restricted paralog compensation.","evidence":"Conventional and conditional Sec24c knockout mice with developmental phenotyping","pmids":["24876386"],"confidence":"High","gaps":["Cargoes responsible for E7.5 lethality unknown","Basis of tissue-specific compensation not defined"]},{"year":2016,"claim":"Connected SEC24C to fusion-machinery export by showing it packages the assembled Q-SNARE complex via its IxM site.","evidence":"Co-IP, IxM-site mutagenesis, and immunoisolation of COPII vesicles with confocal co-localization","pmids":["27413010"],"confidence":"High","gaps":["Conformational selectivity for open syntaxin5 not structurally explained","Coordination with R-SNARE-recruiting isoforms unclear"]},{"year":2017,"claim":"Showed a YV motif recruits SEC24C for claudin-1 surface delivery, with consequences for viral entry.","evidence":"Co-IP, YV-motif mutagenesis, surface expression, and HCV entry assay","pmids":["28679754"],"confidence":"Medium","gaps":["Direct binding versus indirect association not distinguished","Single-lab functional readout"]},{"year":2018,"claim":"Established that postmitotic neurons uniquely depend on SEC24C, and that the dependency reflects shared adaptor activity rescuable by SEC24D.","evidence":"Conditional Sec24c KO mice, SEC24D knock-in rescue, iPSC-derived neuron knockdown, UPR and apoptosis assays","pmids":["29939162"],"confidence":"High","gaps":["Neuron-essential cargoes not identified","Trigger of UPR upon SEC24C loss undefined"]},{"year":2021,"claim":"Provided atomic-resolution insight into a non-canonical role, showing HIV-1 capsid hijacks the SEC24C FG-motif for cytoplasmic core trafficking.","evidence":"2.3-Å crystal structure, binding assays, SEC24C deletion/complementation, siRNA, and live-cell imaging of HIV-1 cores","pmids":["33649557"],"confidence":"High","gaps":["How capsid binding intersects with normal COPII function unclear","Physiological ligand of the FG-motif unknown"]},{"year":2021,"claim":"Demonstrated paralog interchangeability in vivo, attributing the embryonic SEC24C requirement to expression timing rather than unique cargo specificity.","evidence":"C-terminal SEC24C→SEC24D knock-in mice with embryonic lethality rescue analysis","pmids":["34702932"],"confidence":"High","gaps":["Cargo-specific differences in adult tissues not excluded","Mechanism of stage-specific expression not addressed"]},{"year":2021,"claim":"Raised AKT-dependent phosphorylation as a regulatory input controlling SEC24C-mediated transporter export.","evidence":"2D electrophoresis and phospho-PLA after AKT inhibition with SLC6A14 surface biotinylation","pmids":["34359969"],"confidence":"Low","gaps":["No direct kinase assay or phosphosite mutagenesis","Correlative link to transporter surface levels"]},{"year":2024,"claim":"Placed SEC24C in ERLAD-mediated quality control, routing misfolded ATZ to lysosomes via a p24-adaptor complex.","evidence":"Co-IP, live-cell imaging, siRNA depletion, chemical inhibitors, and p24 overexpression","pmids":["38294851"],"confidence":"High","gaps":["Whether SEC24C acts through canonical COPII vesicles in ERLAD unclear","Selectivity for misfolded cargo undefined"]},{"year":2024,"claim":"Proposed an ER-stress signaling role via PERK interaction and stress-induced relocalization promoting apoptosis.","evidence":"Co-IP, subcellular fractionation, and overexpression with drug-induced apoptosis in hepatocellular carcinoma cells","pmids":["39085101"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","Nuclear localization claim conflicts with canonical ERES function and needs orthogonal confirmation"]},{"year":2025,"claim":"Revealed cell-cycle-coupled PTM control, with O-GlcNAcylation and phosphorylation timing SEC24C dispersal from ER exit sites during mitosis.","evidence":"Phosphoproteomics, O-GlcNAc analysis, cell-cycle synchronization, phosphosite mutagenesis, and live-cell imaging","pmids":["40617351"],"confidence":"Medium","gaps":["Enzymes adding/removing the modifications not all defined","Functional impact on cargo export during mitosis not directly measured"]},{"year":2025,"claim":"Linked SEC24C to a small-molecule-modulated innate-immunity step by weakening STING-SEC24C interaction to block ER-to-Golgi STING transport.","evidence":"Co-IP of STING and SEC24C with/without Tanshinone IIA and STING localization plus signaling readouts","pmids":["40252465"],"confidence":"Low","gaps":["No mutagenesis of the STING-SEC24C interface","Direct versus indirect interaction not resolved"]},{"year":2025,"claim":"Implicated SEC24C as an effector in Kremen1-induced autophagic cell death through proximity to autophagy machinery.","evidence":"Biotin proximity labeling, autophagy effector silencing, pharmacological autophagy inhibition, and PLA","pmids":["41807954"],"confidence":"Low","gaps":["Correlative proximity without biochemical reconstitution","Direct SEC24C role versus bystander effect unresolved"]},{"year":2025,"claim":"Connected nutrient-sensing kinases to COPII reorganization, with AMPK/ULK1 driving SEC24C-dependent export of cargoes such as E-cadherin under glucose starvation.","evidence":"SEC24C KO cells, quantitative cell-surface proteomics, ULK1 kinase assay, and AMPK/ULK1 inhibition (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Direct SEC24C phosphorylation versus SEC31A-mediated effect not separated"]},{"year":null,"claim":"How SEC24C integrates its many recognized motifs, PTMs, and stress signals into a unified set of structural and regulatory rules for cargo capture remains open.","evidence":"No single study reconciles motif recognition, PTM control, and non-canonical roles into one mechanistic framework","pmids":[],"confidence":"Low","gaps":["No co-structure of a physiological cargo motif in the IxM/RI pockets","PTM regulation of cargo selectivity not directly demonstrated","Cargo basis of neuron- and embryo-essential functions unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,3,5,8,9,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,5,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,5,15,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[12,17]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,5,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,6,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15]}],"complexes":["COPII coat","Sec23-Sec24 inner coat"],"partners":["SEC23A","STX5","GS27","BET1","TMED9","TMP21","EIF2AK3","SLC6A4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P53992","full_name":"Protein transport protein Sec24C","aliases":["SEC24-related protein C"],"length_aa":1094,"mass_kda":118.3,"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:10214955, PubMed:17499046, PubMed:18843296, PubMed:20427317). Plays a central role in cargo selection within the COPII complex and together with SEC24D may have a different specificity compared to SEC24A and SEC24B (PubMed:17499046, PubMed:18843296, PubMed:20427317). May more specifically package GPI-anchored proteins through the cargo receptor TMED10 (PubMed:20427317). May also be specific for IxM motif-containing cargos like the SNAREs GOSR2 and STX5 (PubMed:18843296)","subcellular_location":"Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P53992/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC24C","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000176986","cell_line_id":"CID000899","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2}],"interactors":[{"gene":"SEC23A","stoichiometry":10.0},{"gene":"SCYL1","stoichiometry":0.2},{"gene":"MSN","stoichiometry":0.2},{"gene":"SEC23B","stoichiometry":0.2},{"gene":"YIF1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000899","total_profiled":1310},"omim":[{"mim_id":"619642","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 2; TMED2","url":"https://www.omim.org/entry/619642"},{"mim_id":"612854","title":"SEC16 HOMOLOG A, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16A","url":"https://www.omim.org/entry/612854"},{"mim_id":"607186","title":"SEC24-RELATED GENE FAMILY, MEMBER D; SEC24D","url":"https://www.omim.org/entry/607186"},{"mim_id":"607185","title":"SEC24-RELATED GENE FAMILY, MEMBER C; SEC24C","url":"https://www.omim.org/entry/607185"},{"mim_id":"607184","title":"SEC24-RELATED GENE FAMILY, MEMBER B; SEC24B","url":"https://www.omim.org/entry/607184"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC24C"},"hgnc":{"alias_symbol":["KIAA0079"],"prev_symbol":[]},"alphafold":{"accession":"P53992","domains":[{"cath_id":"2.60.40.1670","chopping":"325-419_484-498_746-829","consensus_level":"medium","plddt":96.4915,"start":325,"end":829},{"cath_id":"2.30.30.380","chopping":"420-483","consensus_level":"medium","plddt":96.4469,"start":420,"end":483},{"cath_id":"3.40.50.410","chopping":"502-745","consensus_level":"high","plddt":96.6047,"start":502,"end":745},{"cath_id":"1.20.120.730","chopping":"843-947_1070-1094","consensus_level":"medium","plddt":95.3425,"start":843,"end":1094},{"cath_id":"3.40.20.10","chopping":"949-1066","consensus_level":"medium","plddt":93.4023,"start":949,"end":1066}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P53992","model_url":"https://alphafold.ebi.ac.uk/files/AF-P53992-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P53992-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC24C","jax_strain_url":"https://www.jax.org/strain/search?query=SEC24C"},"sequence":{"accession":"P53992","fasta_url":"https://rest.uniprot.org/uniprotkb/P53992.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P53992/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P53992"}},"corpus_meta":[{"pmid":"21454670","id":"PMC_21454670","title":"The serotonin transporter is an exclusive client of the coat protein complex II (COPII) component SEC24C.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21454670","citation_count":69,"is_preprint":false},{"pmid":"33649557","id":"PMC_33649557","title":"Sec24C is an HIV-1 host dependency factor crucial for virus replication.","date":"2021","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33649557","citation_count":66,"is_preprint":false},{"pmid":"22404651","id":"PMC_22404651","title":"A triple arg motif mediates α(2B)-adrenergic receptor interaction with Sec24C/D and export.","date":"2012","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/22404651","citation_count":54,"is_preprint":false},{"pmid":"23288844","id":"PMC_23288844","title":"Switching the clientele: a lysine residing in the C terminus of the serotonin transporter specifies its preference for the coat protein complex II 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Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24790205","citation_count":27,"is_preprint":false},{"pmid":"35510797","id":"PMC_35510797","title":"Sec24C mediates a Golgi-independent trafficking pathway that is required for tonoplast localisation of ABCC1 and ABCC2.","date":"2022","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/35510797","citation_count":23,"is_preprint":false},{"pmid":"23658022","id":"PMC_23658022","title":"A new class of endoplasmic reticulum export signal PhiXPhiXPhi for transmembrane proteins and its selective interaction with Sec24C.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23658022","citation_count":20,"is_preprint":false},{"pmid":"28679754","id":"PMC_28679754","title":"Sec24C-Dependent Transport of Claudin-1 Regulates Hepatitis C Virus Entry.","date":"2017","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/28679754","citation_count":19,"is_preprint":false},{"pmid":"30445147","id":"PMC_30445147","title":"Trafficking of the amino acid transporter B0,+ (SLC6A14) to the plasma membrane involves an exclusive interaction with SEC24C for its exit from the endoplasmic reticulum.","date":"2018","source":"Biochimica et biophysica acta. 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alpha1-antitrypsin Z from the endoplasmic reticulum to lysosomes.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/38294851","citation_count":8,"is_preprint":false},{"pmid":"34359969","id":"PMC_34359969","title":"Trafficking to the Cell Surface of Amino Acid Transporter SLC6A14 Upregulated in Cancer Is Controlled by Phosphorylation of SEC24C Protein by AKT Kinase.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34359969","citation_count":6,"is_preprint":false},{"pmid":"40131364","id":"PMC_40131364","title":"SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis.","date":"2025","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/40131364","citation_count":4,"is_preprint":false},{"pmid":"39085101","id":"PMC_39085101","title":"SEC24C suppresses the propagation and chemoresistance of hepatocellular carcinoma by promoting unfolded protein response-related apoptosis.","date":"2024","source":"Bioscience trends","url":"https://pubmed.ncbi.nlm.nih.gov/39085101","citation_count":3,"is_preprint":false},{"pmid":"40617351","id":"PMC_40617351","title":"Dynamic regulation of Sec24C by phosphorylation and O-GlcNAcylation during cell cycle progression.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40617351","citation_count":2,"is_preprint":false},{"pmid":"40252465","id":"PMC_40252465","title":"Tanshinone IIA alleviates myocarditis in Trex1-D18N lupus-like mice by inhibiting the interaction between STING and SEC24C.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40252465","citation_count":2,"is_preprint":false},{"pmid":"39676447","id":"PMC_39676447","title":"Sec24C Participates in Cuticular Wax Transport by Facilitating Plasma Membrane Localization of ABCG5.","date":"2024","source":"Plant, cell & environment","url":"https://pubmed.ncbi.nlm.nih.gov/39676447","citation_count":2,"is_preprint":false},{"pmid":"41807954","id":"PMC_41807954","title":"Kremen1 dependence receptor induces SEC24C and ATG9A-dependent cell death.","date":"2026","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41807954","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.31.685804","title":"ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling","date":"2025-11-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.31.685804","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.15.633131","title":"Kremen1 dependence receptor induces SEC24C and ATG9A-dependent autophagic cell death","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633131","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.25.625199","title":"Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir","date":"2024-11-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.625199","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15410,"output_tokens":5475,"usd":0.064177,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13962,"output_tokens":5495,"usd":0.103593,"stage2_stop_reason":"end_turn"},"total_usd":0.16777,"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\": 1999,\n      \"finding\": \"SEC24C (KIAA0079) is a mammalian homologue of yeast Sec24p: it co-elutes with mammalian Sec23p on gel filtration, its C-terminal region binds the N-terminal region of Sec23p in vitro, and overexpression causes a defect in protein export from the ER.\",\n      \"method\": \"Gel filtration co-elution, in vitro binding assay, overexpression ER-export assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus functional overexpression assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"10214955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SEC24C is required for docking of the prechylomicron transport vesicle (PCTV) with the Golgi; immunodepletion of SEC24C from cytosol nearly completely abolished PCTV-Golgi docking activity, which was restored by adding back recombinant SEC24C.\",\n      \"method\": \"Immunodepletion of cytosolic SEC24C, reconstitution with recombinant SEC24C, PCTV-Golgi docking assay\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution with recombinant protein in a defined functional assay, single lab with two orthogonal approaches (depletion + rescue)\",\n      \"pmids\": [\"19965600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SERT exclusively requires SEC24C (not SEC24A, B, or D) for ER export: mass spectrometry showed SERT C-terminal peptide recruits SEC24C-containing COPII complexes from brain lysates; siRNA depletion of SEC24C (but not other isoforms) trapped SERT in the ER; a dominant-negative SEC24C-D796V/D797N reduced SERT surface levels; and a SERT-607RI608-AA mutant lacking the SEC24C-binding motif was insensitive to SEC24C knockdown.\",\n      \"method\": \"Mass spectrometry pulldown from brain lysates, isoform-selective siRNA knockdown, dominant-negative SEC24C overexpression, surface biotinylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent orthogonal methods (MS pulldown, siRNA, dominant-negative mutagenesis) in a single study, replicated across endogenous and transfected systems\",\n      \"pmids\": [\"21454670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The triple Arg (3R) motif in the third intracellular loop of α2B-adrenergic receptor mediates direct interaction with Sec24C/D and is required for ER export; mutation or deletion of the 3R motif reduced co-immunoprecipitation with Sec24C/D and impaired cell surface transport.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, surface expression assay, CD8 chimera transfer assay\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with mutagenesis and chimera transfer, single lab\",\n      \"pmids\": [\"22404651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A single residue at position +2 downstream of the ER export motif (RI) in SERT determines SEC24C vs. SEC24D isoform specificity: hydrophilic residues (Lys, Asn, Gln) recruit SEC24C, whereas hydrophobic residues (Tyr, Val) recruit SEC24D. Substituting Lys610 with Tyr switched SERT from SEC24C- to SEC24D-dependence.\",\n      \"method\": \"siRNA depletion of individual SEC24 isoforms, dominant-negative SEC24C/D overexpression, mutagenesis of SERT and other SLC6 transporters, surface biotinylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis combined with siRNA and dominant-negative approaches, validated across multiple SLC6 family members in the same study\",\n      \"pmids\": [\"23288844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel ER export signal motif ΦXΦXΦ (hydrophobic-X-hydrophobic-X-hydrophobic) in the N-terminus of bovine AE1 anion exchanger selectively interacts with SEC24C (via the Sec23A-Sec24C complex); mutation of the SEC24C IxM cargo-binding site (895LIL897→AAA) caused ER retention of ΦXΦXΦ-containing chimeric proteins.\",\n      \"method\": \"Synthetic peptide pulldown with Sec23A-Sec24C complex, chimeric protein mutagenesis, cell surface expression assay, N-glycan processing analysis, co-transfection with SEC24C-AAA dominant negative\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro pulldown plus mutagenesis of both cargo and Sec24C binding site, multiple chimeric constructs tested\",\n      \"pmids\": [\"23658022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEC24C-dependent ER export determines axonal targeting of SERT in dorsal raphe neurons: disruption of the SEC24C-binding motif (RI→AA) or overexpression of dominant-negative SEC24C-D796V/D797N redirected SERT from axons to the somatodendritic compartment, while VMAT2 axonal targeting was unaffected by either dominant-negative SEC24C or SEC24D.\",\n      \"method\": \"Dominant-negative SEC24C/D overexpression in cultured neurons, fluorescence imaging of endogenous and heterologous SERT distribution, mutagenesis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative approach validated with multiple SERT mutants and isoform selectivity controls in primary neurons\",\n      \"pmids\": [\"24790205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SEC24C is essential for early mammalian embryonic development; homozygous Sec24c null mice die at ~E7.5, whereas tissue-specific deletion in hepatocytes, pancreatic cells, smooth muscle cells, and intestinal epithelial cells produces no phenotype, indicating functional compensation by other SEC24 paralogs in those tissues.\",\n      \"method\": \"Conventional and conditional knockout mice, embryonic phenotype analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function in multiple tissue-specific KO lines with defined developmental phenotype\",\n      \"pmids\": [\"24876386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEC24C directly interacts with Syntaxin5 in its 'open' conformation and is required for ER export of the preassembled Q-SNARE complex (Syntaxin5, GS27, Bet1); mutation of the IxM cargo-binding site in SEC24C drastically reduced incorporation of all three Q-SNAREs into COPII vesicles, while R-SNARE Sec22b is recruited by other isoforms.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative/mutation of IxM site in SEC24C, immunoisolation of COPII vesicles, confocal co-localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with mutagenesis and immunoisolated vesicle analysis, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"27413010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Claudin-1 interacts with SEC24C through its C-terminal YV motif for ER export and cell surface delivery; this interaction is required for HCV entry, as blocking COPII transport reduces claudin-1 surface levels.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of YV motif, surface expression assay, HCV entry assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with mutagenesis and functional viral entry readout, single lab\",\n      \"pmids\": [\"28679754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEC24C is essential for postmitotic neuron survival: conditional KO of Sec24c in neural progenitors caused perinatal mortality, microcephaly, unfolded protein response activation, and apoptosis of cortical neurons; this neuronal cell death was rescued by knock-in expression of SEC24D in place of SEC24C.\",\n      \"method\": \"Conditional Sec24c KO mice, SEC24D knock-in rescue, iPSC-derived neuron KD, UPR marker analysis, TUNEL apoptosis assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse genetic models (cKO + rescue knock-in) plus human iPSC-derived neurons, replicated with orthogonal cell-autonomous validation\",\n      \"pmids\": [\"29939162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Amino acid transporter SLC6A14 (ATB0,+) exclusively co-precipitates with SEC24C (not with SEC24A, B, or D) for ER export; a dominant-negative SEC24C mutant reduced ATB0,+ plasma membrane expression and increased its proteolytic degradation; a Lys at position +2 of the RI export motif is required for SEC24C binding.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, dominant-negative SEC24C, surface biotinylation, immunofluorescence co-localization\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed by proximity ligation assay plus functional dominant-negative experiment, single lab\",\n      \"pmids\": [\"30445147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SEC24C is an HIV-1 host dependency factor: it directly and specifically interacts with hexameric HIV-1 capsid lattices via an FG-motif (residues 228-242); a 2.3-Å crystal structure showed the FG-motif binds a pocket comprising two adjoining capsid subunits; deletion of SEC24C reduced core stability, reverse transcription, nuclear import, and infectivity; live-cell microscopy showed SEC24C co-trafficked with HIV-1 cores in the cytoplasm during ingress.\",\n      \"method\": \"Crystal structure at 2.3-Å resolution, biochemical binding assays, Sec24C gene deletion and complementation in Jurkat cells, siRNA knockdown in HeLa cells, live-cell microscopy, reverse transcription and nuclear import assays\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure combined with multiple orthogonal functional assays (KO complementation, siRNA, live imaging, biochemical binding), replicated across cell types\",\n      \"pmids\": [\"33649557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKT kinase phosphorylates SEC24C, and AKT inhibition decreases SEC24C phosphoserine levels (detected by proximity ligation assay and 2D electrophoresis), which correlates with transient increase of SLC6A14 transporter at the plasma membrane, suggesting AKT-mediated phosphorylation of SEC24C regulates ER export of SLC6A14.\",\n      \"method\": \"2D electrophoresis, proximity ligation assay with phospho-specific antibodies, AKT inhibitor (MK-2206) treatment, surface biotinylation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence of phosphorylation via 2D gel and PLA (no direct kinase assay or phosphosite mutagenesis), single lab, single method per endpoint\",\n      \"pmids\": [\"34359969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Murine SEC24D can functionally substitute for SEC24C during embryonic development: Sec24cc-d/c-d knock-in mice (C-terminal 90% of SEC24C replaced by SEC24D sequence) survive to term whereas Sec24c null mice die at E7.5, indicating the early embryonic requirement for SEC24C reflects tissue/stage-specific expression rather than unique cargo specificity.\",\n      \"method\": \"Dual recombinase-mediated cassette exchange knock-in mice, embryonic lethality rescue analysis, pathological evaluation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic rescue experiment in mice with defined developmental phenotype endpoint, well-controlled knock-in design\",\n      \"pmids\": [\"34702932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC24C and p24-family members TMP21 and TMED9 facilitate clearance of misfolded alpha-1-antitrypsin Z (ATZ) from the ER to lysosomes via ERLAD: ATZ co-immunoprecipitates with TMP21, TMED9, SEC24C, FAM134B, and calnexin; live-cell imaging showed ATZ and p24-family members co-trafficking to lysosomes; depletion of SEC24C inhibited lysosomal trafficking of ATZ and increased intracellular ATZ levels; p24-family members co-immunoprecipitate with both ATZ and SEC24C, placing SEC24C at ER-exit sites for ERLAD.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, chemical inhibitors of ER exit/autophagy, siRNA depletion, overexpression of p24 proteins\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, live imaging, siRNA depletion, chemical inhibitors, overexpression rescue) in a single study\",\n      \"pmids\": [\"38294851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC24C interacts with PERK (EIF2AK3) and activates downstream UPR-related apoptosis; under normal conditions SEC24C is nuclear-localized but translocates to the ER upon ER stress, and SEC24C overexpression augments bortezomib-induced apoptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, overexpression + drug treatment apoptosis assay\",\n      \"journal\": \"Bioscience trends\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment and localization data, single lab, limited mechanistic validation of PERK interaction\",\n      \"pmids\": [\"39085101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC24C is dynamically regulated by O-GlcNAcylation (present in interphase) and phosphorylation (enriched in specific cell cycle phases); O-GlcNAc is rapidly removed upon mitotic entry and its removal influences the timing of SEC24C dispersal from juxtanuclear ER exit sites to a diffuse cytosolic pool; novel phosphosites were identified that regulate SEC24C stability and localization during mitosis.\",\n      \"method\": \"Mass spectrometry phosphoproteomics, O-GlcNAc modification analysis, cell cycle synchronization, live-cell imaging of SEC24C localization, mutagenesis of phosphosites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified PTMs with functional imaging validation of localization phenotype, mutagenesis of sites, single lab\",\n      \"pmids\": [\"40617351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tanshinone IIA inhibits STING transport from the ER to the Golgi by weakening the interaction between STING and SEC24C, thereby preventing cGAS-STING pathway activation.\",\n      \"method\": \"Co-immunoprecipitation of STING and SEC24C with/without Tanshinone IIA, STING localization assay, downstream signaling readouts\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment measuring interaction reduction, single lab, no direct mutagenesis of the STING-SEC24C interface\",\n      \"pmids\": [\"40252465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Kremen1 (dependence receptor) induces autophagic cell death requiring SEC24C: biotin proximity labeling identified SEC24C as a critical effector; Kremen1 is in proximity with SEC24C and ATG9A after vesicular trafficking, and SEC24C is brought into proximity with ATG8, ERGIC, and ATG9A, increasing autophagosome formation leading to cell death.\",\n      \"method\": \"Biotin proximity labeling (BioID/TurboID), genetic silencing of autophagy effectors, pharmacological inhibition of autophagy, proximity ligation assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling without direct biochemical reconstitution, mechanistic link to SEC24C is correlative, single lab\",\n      \"pmids\": [\"41807954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Acute glucose starvation impairs ER-to-Golgi export of specific cargoes (e.g., E-cadherin) in a SEC24C-dependent manner; AMPK and ULK1 signaling (independent of autophagy) orchestrate this process, with ULK1-mediated phosphorylation of SEC31A driving SEC24C-dependent COPII reorganization.\",\n      \"method\": \"SEC24C knockout cells, quantitative cell surface proteomics, nutrient deprivation experiments, ULK1 kinase assay, AMPK/ULK1 inhibitor experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with quantitative proteomics and kinase pathway dissection, multiple methods, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SEC24C is a cargo-selective adaptor subunit of the COPII vesicle coat that directly recognizes specific ER export signals (RI, 3R, ΦXΦXΦ, IxM, YV motifs) on transmembrane cargo proteins—including neurotransmitter transporters (SERT, GlyT-1a, ATB0,+), GPCRs (α2B-AR), SNAREs (Syntaxin5/Q-SNARE complex), claudin-1, and STING—to package them into COPII vesicles at ER exit sites; it is also required for PCTV-Golgi docking, facilitates ERLAD-mediated lysosomal clearance of misfolded ATZ via a p24-adaptor complex, and is subject to cell-cycle-regulated O-GlcNAcylation and phosphorylation that control its dispersal from ER exit sites during mitosis; in neurons, SEC24C-mediated ER export is uniquely essential for postmitotic neuronal homeostasis and axonal targeting of cargoes, and SEC24C's FG-motif is exploited by HIV-1 capsid for cytoplasmic trafficking during viral infection.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC24C is a cargo-selective adaptor subunit of the COPII vesicle coat that packages specific transmembrane cargo into vesicles at ER exit sites; it co-elutes and directly binds the SEC23 component of the inner coat [#0]. Through distinct cargo-binding pockets, SEC24C reads short ER-export motifs on client proteins: an RI motif whose +2 residue dictates SEC24C-versus-SEC24D selectivity in SLC6 neurotransmitter transporters such as SERT and the amino acid transporter SLC6A14/ATB0,+ [#2, #4, #11], a triple-arginine (3R) motif in the \\u03b12B-adrenergic receptor [#3], a \\u03a6X\\u03a6X\\u03a6 motif engaged by the SEC24C IxM pocket [#5], and a C-terminal YV motif in claudin-1 [#9]. The same IxM cargo-binding site captures the open-conformation Q-SNARE syntaxin5 together with GS27 and Bet1, coupling SNARE assembly to ER export [#8]. Beyond conventional anterograde transport, SEC24C is required for prechylomicron transport vesicle docking with the Golgi [#1] and, acting with the p24 proteins TMP21 and TMED9, routes misfolded alpha-1-antitrypsin Z from the ER to lysosomes via ERLAD [#15]. Its activity is developmentally and physiologically essential: Sec24c-null mice die at E7.5, an early requirement attributable to expression timing rather than unique cargo specificity since SEC24D knock-in rescues both embryonic and neuronal phenotypes [#7, #14], yet postmitotic cortical neurons depend on SEC24C-mediated ER export for survival and for axonal targeting of cargoes such as SERT [#6, #10]. SEC24C is regulated by cell-cycle-coupled O-GlcNAcylation and phosphorylation that govern its dispersal from ER exit sites during mitosis [#17], and its FG-motif is bound at atomic resolution by the HIV-1 capsid lattice to support cytoplasmic core trafficking and infectivity [#12].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established SEC24C as a mammalian COPII inner-coat component by showing it partners with the SEC23 subunit and functions in ER export.\",\n      \"evidence\": \"Gel filtration co-elution and in vitro binding with Sec23p plus an overexpression ER-export defect assay\",\n      \"pmids\": [\"10214955\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo specificity defined\", \"No structural basis of SEC23 binding\", \"Endogenous function inferred only from overexpression\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended SEC24C function beyond canonical vesicle formation to docking of a specialized lipid-cargo carrier with the Golgi.\",\n      \"evidence\": \"Immunodepletion of cytosolic SEC24C with recombinant protein rescue in a PCTV-Golgi docking assay\",\n      \"pmids\": [\"19965600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partner mediating docking not identified\", \"Relationship to canonical COPII coating unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated isoform-exclusive cargo selection by showing SERT requires SEC24C specifically, defining SEC24C as a dedicated ER-export adaptor for select cargoes.\",\n      \"evidence\": \"MS pulldown from brain lysates, isoform-selective siRNA, dominant-negative SEC24C, and cargo motif (RI) mutagenesis with surface biotinylation\",\n      \"pmids\": [\"21454670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of motif recognition not resolved\", \"Generality across cargo families not yet tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a distinct 3R recognition mode, showing SEC24C/D recognize multiple motif classes on diverse cargo including a GPCR.\",\n      \"evidence\": \"Co-IP, mutagenesis, and CD8 chimera transfer with surface expression for \\u03b12B-adrenergic receptor\",\n      \"pmids\": [\"22404651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SEC24C versus SEC24D contributions not separated\", \"Direct binding pocket not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how a single residue dictates SEC24C-versus-SEC24D isoform choice, giving a residue-level code for paralog selectivity.\",\n      \"evidence\": \"Isoform siRNA, dominant-negative constructs, and +2-position mutagenesis across SLC6 transporters with surface biotinylation\",\n      \"pmids\": [\"23288844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural explanation of +2 selectivity absent\", \"In vivo consequences of switching not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped a SEC24C cargo-binding site (IxM) and a new \\u03a6X\\u03a6X\\u03a6 motif, localizing motif recognition to a defined region of the adaptor.\",\n      \"evidence\": \"Peptide pulldown with Sec23A-Sec24C complex and SEC24C IxM-site (LIL\\u2192AAA) mutagenesis with chimeric cargo\",\n      \"pmids\": [\"23658022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal of motif in the IxM pocket\", \"Affinities and competition among motifs unquantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed SEC24C-dependent ER export sets neuronal cargo polarity, linking adaptor selectivity to axonal targeting.\",\n      \"evidence\": \"Dominant-negative SEC24C/D and RI-motif mutagenesis with imaging of SERT distribution in primary dorsal raphe neurons\",\n      \"pmids\": [\"24790205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting ER export to polarized sorting unresolved\", \"Endogenous loss-of-function not tested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the organismal requirement for SEC24C, revealing essential embryonic function with tissue-restricted paralog compensation.\",\n      \"evidence\": \"Conventional and conditional Sec24c knockout mice with developmental phenotyping\",\n      \"pmids\": [\"24876386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargoes responsible for E7.5 lethality unknown\", \"Basis of tissue-specific compensation not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SEC24C to fusion-machinery export by showing it packages the assembled Q-SNARE complex via its IxM site.\",\n      \"evidence\": \"Co-IP, IxM-site mutagenesis, and immunoisolation of COPII vesicles with confocal co-localization\",\n      \"pmids\": [\"27413010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational selectivity for open syntaxin5 not structurally explained\", \"Coordination with R-SNARE-recruiting isoforms unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed a YV motif recruits SEC24C for claudin-1 surface delivery, with consequences for viral entry.\",\n      \"evidence\": \"Co-IP, YV-motif mutagenesis, surface expression, and HCV entry assay\",\n      \"pmids\": [\"28679754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding versus indirect association not distinguished\", \"Single-lab functional readout\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that postmitotic neurons uniquely depend on SEC24C, and that the dependency reflects shared adaptor activity rescuable by SEC24D.\",\n      \"evidence\": \"Conditional Sec24c KO mice, SEC24D knock-in rescue, iPSC-derived neuron knockdown, UPR and apoptosis assays\",\n      \"pmids\": [\"29939162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuron-essential cargoes not identified\", \"Trigger of UPR upon SEC24C loss undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided atomic-resolution insight into a non-canonical role, showing HIV-1 capsid hijacks the SEC24C FG-motif for cytoplasmic core trafficking.\",\n      \"evidence\": \"2.3-\\u00c5 crystal structure, binding assays, SEC24C deletion/complementation, siRNA, and live-cell imaging of HIV-1 cores\",\n      \"pmids\": [\"33649557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How capsid binding intersects with normal COPII function unclear\", \"Physiological ligand of the FG-motif unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated paralog interchangeability in vivo, attributing the embryonic SEC24C requirement to expression timing rather than unique cargo specificity.\",\n      \"evidence\": \"C-terminal SEC24C\\u2192SEC24D knock-in mice with embryonic lethality rescue analysis\",\n      \"pmids\": [\"34702932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-specific differences in adult tissues not excluded\", \"Mechanism of stage-specific expression not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Raised AKT-dependent phosphorylation as a regulatory input controlling SEC24C-mediated transporter export.\",\n      \"evidence\": \"2D electrophoresis and phospho-PLA after AKT inhibition with SLC6A14 surface biotinylation\",\n      \"pmids\": [\"34359969\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct kinase assay or phosphosite mutagenesis\", \"Correlative link to transporter surface levels\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SEC24C in ERLAD-mediated quality control, routing misfolded ATZ to lysosomes via a p24-adaptor complex.\",\n      \"evidence\": \"Co-IP, live-cell imaging, siRNA depletion, chemical inhibitors, and p24 overexpression\",\n      \"pmids\": [\"38294851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SEC24C acts through canonical COPII vesicles in ERLAD unclear\", \"Selectivity for misfolded cargo undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed an ER-stress signaling role via PERK interaction and stress-induced relocalization promoting apoptosis.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, and overexpression with drug-induced apoptosis in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39085101\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Nuclear localization claim conflicts with canonical ERES function and needs orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed cell-cycle-coupled PTM control, with O-GlcNAcylation and phosphorylation timing SEC24C dispersal from ER exit sites during mitosis.\",\n      \"evidence\": \"Phosphoproteomics, O-GlcNAc analysis, cell-cycle synchronization, phosphosite mutagenesis, and live-cell imaging\",\n      \"pmids\": [\"40617351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymes adding/removing the modifications not all defined\", \"Functional impact on cargo export during mitosis not directly measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SEC24C to a small-molecule-modulated innate-immunity step by weakening STING-SEC24C interaction to block ER-to-Golgi STING transport.\",\n      \"evidence\": \"Co-IP of STING and SEC24C with/without Tanshinone IIA and STING localization plus signaling readouts\",\n      \"pmids\": [\"40252465\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mutagenesis of the STING-SEC24C interface\", \"Direct versus indirect interaction not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SEC24C as an effector in Kremen1-induced autophagic cell death through proximity to autophagy machinery.\",\n      \"evidence\": \"Biotin proximity labeling, autophagy effector silencing, pharmacological autophagy inhibition, and PLA\",\n      \"pmids\": [\"41807954\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative proximity without biochemical reconstitution\", \"Direct SEC24C role versus bystander effect unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected nutrient-sensing kinases to COPII reorganization, with AMPK/ULK1 driving SEC24C-dependent export of cargoes such as E-cadherin under glucose starvation.\",\n      \"evidence\": \"SEC24C KO cells, quantitative cell-surface proteomics, ULK1 kinase assay, and AMPK/ULK1 inhibition (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Direct SEC24C phosphorylation versus SEC31A-mediated effect not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SEC24C integrates its many recognized motifs, PTMs, and stress signals into a unified set of structural and regulatory rules for cargo capture remains open.\",\n      \"evidence\": \"No single study reconciles motif recognition, PTM control, and non-canonical roles into one mechanistic framework\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-structure of a physiological cargo motif in the IxM/RI pockets\", \"PTM regulation of cargo selectivity not directly demonstrated\", \"Cargo basis of neuron- and embryo-essential functions unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 3, 5, 8, 9, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 5, 15, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 5, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 6, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\"COPII coat\", \"Sec23-Sec24 inner coat\"],\n    \"partners\": [\"SEC23A\", \"STX5\", \"GS27\", \"BET1\", \"TMED9\", \"TMP21\", \"EIF2AK3\", \"SLC6A4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}