{"gene":"SEC31A","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2006,"finding":"ALG-2, a Ca2+-binding protein, binds directly to the Pro-rich region of Sec31A in a Ca2+-dependent manner and is recruited to ER exit sites (ERES) via this interaction; depletion of Sec31A abolishes ALG-2 localization at ERES, and depletion of ALG-2 substantially reduces membrane-associated Sec31A at ERES, establishing a mutual stabilization mechanism.","method":"Co-immunoprecipitation, Ca2+-dependent binding assays, RNA interference knockdown, immunofluorescence colocalization, Ca2+ chelator treatment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal depletion experiments with defined localization phenotypes, replicated in companion paper (PMID:17196169)","pmids":["16957052"],"is_preprint":false},{"year":2006,"finding":"ALG-2 directly binds Sec31A (outer COPII coat component) in a Ca2+-dependent manner, as demonstrated by GST pull-down and biotin-labeled ALG-2 overlay assay; Ca2+ ionophore treatment enriches ALG-2 at Sec31A-positive membrane compartments, while BAPTA-AM disperses ALG-2 and reduces perinuclear Sec31A.","method":"GST pull-down, biotin-labeled ALG-2 overlay assay, Ca2+ ionophore/chelator treatment, immunofluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding assay with functional cellular validation; replicates PMID:16957052","pmids":["17196169"],"is_preprint":false},{"year":2010,"finding":"The ALG-2 binding site (ABS) within the Pro-rich region of Sec31A (amino acids 839–851) is necessary and sufficient for direct ALG-2 binding; deletion of the ABS reduces the high-affinity population of Sec31A at ERES as measured by FRAP, establishing the ABS as a key determinant of Sec31A retention kinetics at ERES.","method":"Biotin-labeled ALG-2 overlay assay, site-directed deletion mutagenesis, FRAP live-cell imaging, stable GFP/RFP fusion cell lines","journal":"Bioscience, biotechnology, and biochemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with FRAP functional readout and direct binding assay","pmids":["20834162"],"is_preprint":false},{"year":2013,"finding":"ALG-2/Ca2+ attenuates COPII vesicle budding in vitro through interaction with the ALG-2 binding domain in the Pro-rich region of Sec31A; ALG-2 increases recruitment of Sec23/24 and Sec13/31A to liposomes and mediates Sec13/31A binding to Sec23, stabilizing the Sec23/Sec31A complex. Ca2+-binding at EF-hand 1 of ALG-2 is required for both Sec31A binding and budding inhibition.","method":"In vitro COPII budding reconstitution assay, liposome recruitment assay, EF-hand mutagenesis of ALG-2, biochemical co-assembly assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro budding assay with mutagenesis and liposome recruitment, multiple orthogonal methods","pmids":["24069399"],"is_preprint":false},{"year":2014,"finding":"Annexin A11 (AnxA11) physically associates with Sec31A through ALG-2 as an adaptor; depletion of AnxA11 or ALG-2 decreases the stably membrane-associated pool of Sec31A at ERES, causes scattering of juxtanuclear ERES to the cell periphery, and accelerates ER-to-Golgi transport of transmembrane cargoes.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy, synchronous cargo transport assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional transport phenotype from multiple knockdowns","pmids":["25540196"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the ALG-2–Sec31A peptide complex reveals that the Sec31A PXPGF (type 2) motif binds to a third hydrophobic pocket (Pocket 3) of ALG-2, distinct from the Pocket 1 used by ALIX; Phe85 mutation in ALG-2 abolishes Sec31A binding without affecting ALIX binding, defining a novel target recognition mechanism.","method":"X-ray crystallography, site-directed mutagenesis of ALG-2 (Phe85Ala, Tyr180Ala), co-binding assays with Sec31A and ALIX peptides","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis validation of binding specificity","pmids":["25667979"],"is_preprint":false},{"year":2018,"finding":"Sec31A is O-GlcNAcylated on serine 964 by OGT; this modification accelerates COPII vesicle formation by controlling Sec31A's binding affinity to ALG-2, thereby regulating ER-to-Golgi anterograde vesicle transport.","method":"Mass spectrometry identification of O-GlcNAc site, site-directed mutagenesis (S964), COPII vesicle formation assay, binding affinity assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 1 method (mutagenesis + in vitro assay) but single lab with moderate mechanistic follow-up detail","pmids":["29913562"],"is_preprint":false},{"year":2018,"finding":"USP8 deubiquitinates Sec31A via an interaction mediated by the adaptor protein STAM1; USP8 overexpression inhibits large COPII carrier formation, while USP8 knockdown promotes large COPII carrier formation, accelerates procollagen IV ER-to-Golgi trafficking, and increases collagen IV secretion, establishing USP8 as the deubiquitinase opposing Cul3-mediated Sec31A mono-ubiquitination.","method":"Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, overexpression, immunofluorescence, collagen secretion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional knockdown/overexpression phenotypes, single lab","pmids":["29604273"],"is_preprint":false},{"year":2018,"finding":"Homozygous nonsense mutation in SEC31A causes nonsense-mediated decay of its transcript; SEC31A-null cells show reduced viability through upregulation of ER stress pathways, and Drosophila knockdown of the SEC31A orthologue produces defective brains and early lethality, establishing SEC31A as essential for COPII-mediated ER-to-Golgi transport and cell survival.","method":"CRISPR/Cas9 knockout in SH-SY5Y and HEK293T cells, qRT-PCR, immunoblotting, cell viability assays, Drosophila null mutant analysis","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined ER-stress phenotype, replicated across human cell lines and Drosophila model","pmids":["30464055"],"is_preprint":false},{"year":2024,"finding":"SEC31A interacts with ATG9a on autophagosomal seed vesicles, mediating the recruitment of COPII vesicles as a membrane source for autophagosome formation; interference with Sec31A inhibits autophagosome formation and osteogenesis in vitro and in vivo.","method":"Co-immunoprecipitation, siRNA knockdown, in vivo mouse bone tissue analysis, autophagosome counting by fluorescence microscopy","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional KD phenotype in vitro and in vivo, single lab","pmids":["39361436"],"is_preprint":false},{"year":2025,"finding":"SEC31A interacts with the insulin receptor in pancreatic alpha cells, suggesting a link between ER stress adaptation and insulin signaling; loss of Sec31A enhances survival of stressed alpha cells, with distinct responses in alpha versus beta cells.","method":"Genome-wide CRISPR screen, functional studies in mouse alpha cell lines and human islet clusters, co-immunoprecipitation of SEC31A with insulin receptor","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen plus Co-IP, but insulin receptor interaction is a single pulldown with limited mechanistic follow-up","pmids":["41093834"],"is_preprint":false},{"year":2025,"finding":"ULK1 phosphorylates SEC31A downstream of AMPK signaling in response to glucose starvation, driving SEC24C-dependent COPII reorganization and selective impairment of ER-to-Golgi export of specific cargoes such as E-cadherin, independent of autophagy.","method":"Phosphoproteomics, kinase assays, genetic epistasis (AMPK/ULK1 inhibition/activation), quantitative cell surface proteomics, live-cell imaging of COPII","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods but preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.10.31.685804"],"is_preprint":true},{"year":2025,"finding":"The C-terminal helical domain of Sec31A interacts with the adaptor protein p125A (Sec23ip); this interaction is essential for Sec31A assembly at ERES and promotes COPII outer layer (Sec13/31) assembly on donor membranes apposed to acceptor membranes, supporting tunnel-based collagen traffic.","method":"Cell-free reconstitution on membranes, p125A chimera expression, Sec31A C-terminal domain truncation, transcriptome and secretome analysis, fibrillar collagen trafficking assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 method (cell-free reconstitution) but preprint only","pmids":["bio_10.1101_2025.05.07.652703"],"is_preprint":true},{"year":2025,"finding":"Tissue-specific alternative splicing of an uncharacterized exon in SEC31A is regulated by the RNA-binding protein RBM47; inclusion of this exon increases lipid (chylomicron) transport, connecting SEC31A alternative splicing to secretion of large cargo in digestive tissues.","method":"RNA-seq across human tissues, RBM47 knockdown/overexpression, lipid transport assays, in silico correlation of splicing with RBP expression","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 — functional splicing validation with transport assay; single lab","pmids":["40436629"],"is_preprint":false},{"year":2006,"finding":"A chromosomal translocation t(2;4)(p23;q21) fuses SEC31L1 (SEC31A) exon 23 in-frame to ALK exon 20, generating a SEC31A-ALK fusion oncoprotein in inflammatory myofibroblastic tumor, with diffuse cytoplasmic ALK immunostaining indicating constitutive kinase activity driven by SEC31A's oligomerization domains.","method":"G-band karyotyping, FISH, 5'-RACE, RT-PCR, sequence analysis, genomic PCR","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 — molecular characterization of fusion gene, no in vitro kinase reconstitution in this paper","pmids":["16161041"],"is_preprint":false},{"year":2011,"finding":"SEC31A-JAK2 fusion gene generated by t(4;9)(q21;p24) acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors; it transforms cells in vitro and induces T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model, with oncogenicity dependent on constitutive JAK/STAT pathway activation.","method":"RT-PCR, FISH, in vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor treatment, kinase activity assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vitro transformation plus in vivo murine model with pathway inhibitor validation, multiple orthogonal methods","pmids":["21325169"],"is_preprint":false},{"year":2010,"finding":"SEC31A-ALK fusion (from ALK-positive large B-cell lymphoma) transforms IL3-dependent Ba/F3 cells to growth factor independence, and the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3, and STAT5.","method":"Ba/F3 transformation assay, ALK inhibitor treatment, Western blot for downstream signaling effectors","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 — cell transformation assay with pharmacological inhibitor and signaling pathway readout, single lab","pmids":["20207848"],"is_preprint":false}],"current_model":"SEC31A is the mammalian outer-coat component of the COPII complex at ER exit sites (ERES), where it forms a Sec13/31A cage that drives vesicle budding; its Pro-rich region contains a Ca2+-dependent ALG-2 binding site (ABS, residues 839–851; PXPGF type 2 motif binding ALG-2 Pocket 3) that recruits ALG-2, which in turn stabilizes Sec31A at ERES via annexin A11 as an additional adaptor; Sec31A is O-GlcNAcylated on S964 (promoting COPII vesicle formation) and mono-ubiquitinated by Cul3 (promoting large COPII carrier formation for procollagen), with USP8/STAM1 acting as the opposing deubiquitinase; its C-terminal helical domain interacts with p125A to couple outer COPII assembly with donor–acceptor membrane apposition for tunnel-based collagen traffic; ULK1 phosphorylates Sec31A downstream of AMPK during glucose starvation to drive SEC24C-dependent COPII reorganization; Sec31A also interacts with ATG9a to supply COPII vesicle membrane to autophagosomes; loss of SEC31A causes ER stress and cell death, and chromosomal rearrangements generate oncogenic SEC31A-ALK and SEC31A-JAK2 fusion kinases in hematological and solid tumors."},"narrative":{"teleology":[{"year":2006,"claim":"The question of how Ca²⁺ signaling intersects with COPII coat dynamics was answered by demonstrating that ALG-2 binds Sec31A's Pro-rich region in a Ca²⁺-dependent manner and that the two proteins mutually stabilize each other at ERES.","evidence":"Reciprocal siRNA knockdowns with immunofluorescence colocalization and Ca²⁺ chelator/ionophore treatments in mammalian cells; confirmed by independent GST pull-down and biotin-labeled ALG-2 overlay","pmids":["16957052","17196169"],"confidence":"High","gaps":["Structural basis of the ALG-2–Sec31A interaction not yet resolved","Whether ALG-2 binding promotes or inhibits vesicle budding was unknown","No downstream cargo-transport phenotype shown"]},{"year":2006,"claim":"The identification of a SEC31A–ALK fusion gene from a t(2;4) translocation in inflammatory myofibroblastic tumor established that SEC31A's oligomerization domains can drive constitutive kinase activation when fused to a receptor tyrosine kinase.","evidence":"Karyotyping, FISH, 5'-RACE, RT-PCR, and sequence analysis of patient tumor","pmids":["16161041"],"confidence":"Medium","gaps":["No in vitro kinase reconstitution or transformation assay performed in this study","Frequency and clinical spectrum of SEC31A–ALK fusions not established","Whether the COPII-coat function of SEC31A is disrupted in fusion-bearing cells was not tested"]},{"year":2010,"claim":"Mapping the ALG-2 binding site to residues 839–851 and showing via FRAP that this motif controls the high-affinity pool of Sec31A at ERES defined the minimal determinant governing outer-coat residence time.","evidence":"Deletion mutagenesis of the ABS combined with FRAP live-cell imaging and biotin-labeled ALG-2 overlay","pmids":["20834162"],"confidence":"High","gaps":["Structural resolution of the PXPGF motif–ALG-2 interface not yet available","Whether modulating Sec31A residence time affects specific cargo classes was untested"]},{"year":2010,"claim":"Demonstration that SEC31A–ALK transforms Ba/F3 cells to growth-factor independence and is sensitive to ALK inhibitors confirmed oncogenic functionality of the fusion and identified targetable downstream effectors (ERK1/2, AKT, STAT3/5).","evidence":"Ba/F3 transformation assay with TAE-684 ALK inhibitor treatment and Western blot of signaling effectors","pmids":["20207848"],"confidence":"Medium","gaps":["In vivo tumorigenic potential of SEC31A–ALK not demonstrated","Only one cell-based model used"]},{"year":2011,"claim":"The SEC31A–JAK2 fusion was shown to be a constitutively active kinase that transforms cells in vitro and induces T-lymphoblastic lymphoma or myeloid disease in vivo, confirming SEC31A as a recurrent fusion partner in oncogenic kinase translocations.","evidence":"In vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor sensitivity, kinase activity assay","pmids":["21325169"],"confidence":"High","gaps":["Whether SEC31A-driven oligomerization is universally required for kinase activation in all fusion contexts was not tested","No patient treatment outcome data"]},{"year":2013,"claim":"Reconstituted COPII budding assays resolved that ALG-2/Ca²⁺ attenuates vesicle budding by stabilizing the Sec23/Sec31A complex on donor membranes, answering the open question of whether ALG-2 promotes or inhibits budding.","evidence":"In vitro COPII budding reconstitution with liposome recruitment and EF-hand mutagenesis of ALG-2","pmids":["24069399"],"confidence":"High","gaps":["Physiological stimuli that trigger this inhibitory regulation in cells were unidentified","Effect on large versus small COPII carriers not distinguished"]},{"year":2014,"claim":"Discovery that annexin A11 bridges ALG-2 to Sec31A and that its depletion scatters ERES and accelerates transport identified a third component of the Sec31A retention complex and explained spatial organization of ERES.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown of AnxA11 and ALG-2, synchronous cargo transport assay","pmids":["25540196"],"confidence":"High","gaps":["How annexin A11's membrane-binding properties contribute to ERES tethering was not addressed","Whether this tripartite complex differs across cell types was unknown"]},{"year":2015,"claim":"Crystal structure of the ALG-2–Sec31A peptide complex revealed that the PXPGF motif binds a novel Pocket 3 distinct from the ALIX-binding Pocket 1, explaining how ALG-2 discriminates between COPII and ESCRT clients.","evidence":"X-ray crystallography with site-directed mutagenesis (Phe85Ala) and competitive binding assays","pmids":["25667979"],"confidence":"High","gaps":["Full-length Sec31A–ALG-2 complex structure unavailable","Whether other COPII subunits contact ALG-2 simultaneously was untested"]},{"year":2018,"claim":"Identification of O-GlcNAcylation at S964 and the opposing deubiquitinase USP8/STAM1 axis established that Sec31A is a convergence point for nutrient-sensitive post-translational modifications that tune COPII carrier size and budding rate.","evidence":"Mass spectrometry, site-directed mutagenesis of S964, COPII vesicle formation assay (O-GlcNAc); Co-IP, deubiquitination assay, knockdown/overexpression with collagen secretion readout (USP8)","pmids":["29913562","29604273"],"confidence":"Medium","gaps":["Interplay between O-GlcNAcylation and ubiquitination on the same Sec31A molecule not examined","Identity of the E3 ligase site for mono-ubiquitination confirmed only as Cul3 in prior literature, not re-mapped here","Single-lab findings for each modification"]},{"year":2018,"claim":"Knockout of SEC31A in human cells and Drosophila demonstrated that the gene is essential for viability, with loss triggering ER stress pathways and cell death, establishing a non-redundant requirement for Sec31A in COPII function.","evidence":"CRISPR/Cas9 knockout in SH-SY5Y and HEK293T cells, qRT-PCR, cell viability assays; Drosophila null mutant analysis showing brain defects and early lethality","pmids":["30464055"],"confidence":"High","gaps":["Whether SEC31B partially compensates in specific tissues was not tested","Specific cargo classes most affected by SEC31A loss were not catalogued"]},{"year":2024,"claim":"The finding that SEC31A interacts with ATG9a on autophagosomal seed vesicles and that its depletion impairs autophagosome formation extended Sec31A's role beyond canonical ER-to-Golgi transport to autophagy membrane supply.","evidence":"Co-immunoprecipitation, siRNA knockdown, autophagosome counting, in vivo mouse osteogenesis analysis","pmids":["39361436"],"confidence":"Medium","gaps":["Whether COPII vesicle identity is maintained during autophagosome membrane donation is unknown","Contribution of other COPII subunits to ATG9a interaction not tested","Single-lab finding"]},{"year":2025,"claim":"Tissue-specific alternative splicing of a SEC31A exon, regulated by RBM47, was shown to promote large-cargo (chylomicron) transport, revealing a splicing-based mechanism for tuning COPII carrier capacity in digestive tissues.","evidence":"RNA-seq across human tissues, RBM47 knockdown/overexpression, lipid transport assays","pmids":["40436629"],"confidence":"Medium","gaps":["Which domain of Sec31A the alternative exon encodes and how it alters cage geometry is unknown","Functional validation in primary intestinal cells not shown"]},{"year":null,"claim":"Key unresolved questions include the full structural basis of the assembled Sec13/31A cage on native COPII carriers, how the multiple post-translational modifications (O-GlcNAcylation, ubiquitination, phosphorylation) are integrated on individual Sec31A molecules during physiological transitions, and the precise mechanism by which Sec31A contributes membrane to autophagosomes versus canonical secretory vesicles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-EM or cryo-ET structure of mammalian Sec13/31A cage on native membranes","Combinatorial PTM code on Sec31A not mapped","Relative contributions of SEC31A versus SEC31B across tissues remain undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,14]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,4,6,7,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,15,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3,8]}],"complexes":["COPII (Sec13/31A outer coat)","ALG-2/AnxA11/Sec31A regulatory complex"],"partners":["ALG-2","ANXA11","SEC13","SEC23A","USP8","STAM1","ATG9A","SEC23IP"],"other_free_text":[]},"mechanistic_narrative":"SEC31A is the outer-coat subunit of the COPII complex that drives vesicle budding from ER exit sites (ERES), forming a Sec13/31A cage essential for ER-to-Golgi anterograde transport and cell viability [PMID:30464055]. Its Pro-rich region (residues 839–851) provides a Ca²⁺-dependent binding site for ALG-2, which—together with annexin A11—stabilizes Sec31A at ERES and modulates budding kinetics; this interaction is structurally mediated through a PXPGF motif engaging ALG-2 Pocket 3 [PMID:16957052, PMID:25667979, PMID:25540196]. Sec31A activity is tuned by O-GlcNAcylation at S964 (promoting vesicle formation), Cul3-dependent mono-ubiquitination (promoting large COPII carriers for procollagen), opposing deubiquitination by USP8/STAM1, tissue-specific alternative splicing regulating large-cargo (chylomicron) secretion, and interaction with p125A to couple outer-coat assembly with collagen tunnel traffic [PMID:29913562, PMID:29604273, PMID:40436629]. Chromosomal rearrangements generate oncogenic SEC31A–ALK and SEC31A–JAK2 fusion kinases that constitutively activate downstream signaling and drive hematological and solid tumors [PMID:21325169, PMID:20207848]."},"prefetch_data":{"uniprot":{"accession":"O94979","full_name":"Protein transport protein Sec31A","aliases":["ABP125","ABP130","SEC31-like protein 1","SEC31-related protein A","Web1-like protein"],"length_aa":1220,"mass_kda":133.0,"function":"Component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER) (PubMed:10788476). The coat has two main functions, the physical deformation of the endoplasmic reticulum membrane into vesicles and the selection of cargo molecules (By similarity)","subcellular_location":"Cytoplasm; Cytoplasmic vesicle, COPII-coated vesicle membrane; Endoplasmic reticulum membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O94979/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEC31A","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138674","cell_line_id":"CID000901","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"golgi","grade":2},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"SEC13","stoichiometry":10.0},{"gene":"PDCD6","stoichiometry":4.0},{"gene":"POLR1E","stoichiometry":0.2},{"gene":"RAB14","stoichiometry":0.2},{"gene":"SCYL1","stoichiometry":0.2},{"gene":"MSN","stoichiometry":0.2},{"gene":"NOP14","stoichiometry":0.2},{"gene":"RABGGTA","stoichiometry":0.2},{"gene":"SPTLC1","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000901","total_profiled":1310},"omim":[{"mim_id":"621301","title":"PROLINE-RICH COILED-COIL PROTEIN 1; PRRC1","url":"https://www.omim.org/entry/621301"},{"mim_id":"618651","title":"HALPERIN-BIRK SYNDROME; HLBKS","url":"https://www.omim.org/entry/618651"},{"mim_id":"616876","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 5; TMED5","url":"https://www.omim.org/entry/616876"},{"mim_id":"612854","title":"SEC16 HOMOLOG A, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16A","url":"https://www.omim.org/entry/612854"},{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEC31A"},"hgnc":{"alias_symbol":["KIAA0905","ABP125","ABP130"],"prev_symbol":["SEC31L1"]},"alphafold":{"accession":"O94979","domains":[{"cath_id":"1.25.40","chopping":"437-501_620-789","consensus_level":"medium","plddt":82.0065,"start":437,"end":789},{"cath_id":"1.20.940.10","chopping":"1113-1217","consensus_level":"high","plddt":87.5555,"start":1113,"end":1217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94979","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94979-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94979-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEC31A","jax_strain_url":"https://www.jax.org/strain/search?query=SEC31A"},"sequence":{"accession":"O94979","fasta_url":"https://rest.uniprot.org/uniprotkb/O94979.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94979/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94979"}},"corpus_meta":[{"pmid":"16161041","id":"PMC_16161041","title":"Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16161041","citation_count":86,"is_preprint":false},{"pmid":"21325169","id":"PMC_21325169","title":"JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21325169","citation_count":86,"is_preprint":false},{"pmid":"16957052","id":"PMC_16957052","title":"The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16957052","citation_count":86,"is_preprint":false},{"pmid":"17196169","id":"PMC_17196169","title":"ALG-2 directly binds Sec31A and localizes at endoplasmic reticulum exit sites in a Ca2+-dependent manner.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17196169","citation_count":76,"is_preprint":false},{"pmid":"20207848","id":"PMC_20207848","title":"ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions.","date":"2010","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/20207848","citation_count":69,"is_preprint":false},{"pmid":"25540196","id":"PMC_25540196","title":"A new role for annexin A11 in the early secretory pathway via stabilizing Sec31A protein at the endoplasmic reticulum exit sites (ERES).","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25540196","citation_count":43,"is_preprint":false},{"pmid":"24069399","id":"PMC_24069399","title":"ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24069399","citation_count":41,"is_preprint":false},{"pmid":"30464055","id":"PMC_30464055","title":"SEC31A mutation affects ER homeostasis, causing a neurological syndrome.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30464055","citation_count":38,"is_preprint":false},{"pmid":"20834162","id":"PMC_20834162","title":"The ALG-2 binding site in Sec31A influences the retention kinetics of Sec31A at the endoplasmic reticulum exit sites as revealed by live-cell time-lapse imaging.","date":"2010","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20834162","citation_count":36,"is_preprint":false},{"pmid":"25667979","id":"PMC_25667979","title":"Structural analysis of the complex between penta-EF-hand ALG-2 protein and Sec31A peptide reveals a novel target recognition mechanism of ALG-2.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25667979","citation_count":30,"is_preprint":false},{"pmid":"25715771","id":"PMC_25715771","title":"SEC31A-ALK Fusion Gene in Lung Adenocarcinoma.","date":"2015","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/25715771","citation_count":26,"is_preprint":false},{"pmid":"29913562","id":"PMC_29913562","title":"O-GlcNAcylation regulates endoplasmic reticulum exit sites through Sec31A modification in conventional secretory pathway.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29913562","citation_count":21,"is_preprint":false},{"pmid":"33340171","id":"PMC_33340171","title":"COPII genes SEC31A/B are essential for gametogenesis and interchangeable in pollen development in Arabidopsis.","date":"2021","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33340171","citation_count":20,"is_preprint":false},{"pmid":"32499446","id":"PMC_32499446","title":"High circ-SEC31A expression predicts unfavorable prognoses in non-small cell lung cancer by regulating the miR-520a-5p/GOT-2 axis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32499446","citation_count":18,"is_preprint":false},{"pmid":"29604273","id":"PMC_29604273","title":"Ubiquitin-specific protease 8 deubiquitinates Sec31A and decreases large COPII carriers and collagen IV secretion.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29604273","citation_count":10,"is_preprint":false},{"pmid":"33204164","id":"PMC_33204164","title":"CircSEC31A Promotes the Malignant Progression of Non-Small Cell Lung Cancer Through Regulating SEC31A Expression via Sponging miR-376a.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/33204164","citation_count":10,"is_preprint":false},{"pmid":"39361436","id":"PMC_39361436","title":"SEC31a-ATG9a Interaction Mediates the Recruitment of COPII Vesicles for Autophagosome Formation.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39361436","citation_count":8,"is_preprint":false},{"pmid":"35285061","id":"PMC_35285061","title":"Nonpermissive Skin Environment Impairs Nerve Regeneration in Diabetes via Sec31a.","date":"2022","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35285061","citation_count":3,"is_preprint":false},{"pmid":"38400880","id":"PMC_38400880","title":"SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis.","date":"2024","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/38400880","citation_count":2,"is_preprint":false},{"pmid":"38822175","id":"PMC_38822175","title":"Paediatric pancreatic acinar cell carcinoma with a novel SEC31A-BRAF fusion gene.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38822175","citation_count":2,"is_preprint":false},{"pmid":"41093834","id":"PMC_41093834","title":"Genome-wide CRISPR Screen Identifies Sec31A as a Key Regulator of Alpha Cell Survival.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41093834","citation_count":1,"is_preprint":false},{"pmid":"41057949","id":"PMC_41057949","title":"Cancer-associated fibroblast-derived circKLHL24 drives perineural invasion in pancreatic cancer via dual regulation of the sec31a-CXCL12 axis.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/41057949","citation_count":1,"is_preprint":false},{"pmid":"36730620","id":"PMC_36730620","title":"First-line crizotinib therapy is effective for a novel SEC31A-anaplastic lymphoma kinase fusion in a patient with stage IV lung adenocarcinoma: a case report and literature reviews.","date":"2022","source":"Anti-cancer drugs","url":"https://pubmed.ncbi.nlm.nih.gov/36730620","citation_count":1,"is_preprint":false},{"pmid":"40436629","id":"PMC_40436629","title":"Tissue-specific SEC31A alternative splicing is regulated by RBM47 and controls lipid transport.","date":"2025","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40436629","citation_count":0,"is_preprint":false},{"pmid":"40508110","id":"PMC_40508110","title":"A Report of a Child with SEC31A-Related Neurodevelopmental Disorder.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40508110","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_2025.06.17.657375","title":"Glycolipid transfer protein modulates vesicular trafficking from the endoplasmic reticulum in HeLa cells","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.17.657375","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.07.652703","title":"p125A (Sec23ip) couples COPII coat assembly with donor-acceptor membrane organization to facilitate tunnel-based traffic","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.07.652703","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14792,"output_tokens":4352,"usd":0.054828},"stage2":{"model":"claude-opus-4-6","input_tokens":7788,"output_tokens":3385,"usd":0.185347},"total_usd":0.240175,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"ALG-2, a Ca2+-binding protein, binds directly to the Pro-rich region of Sec31A in a Ca2+-dependent manner and is recruited to ER exit sites (ERES) via this interaction; depletion of Sec31A abolishes ALG-2 localization at ERES, and depletion of ALG-2 substantially reduces membrane-associated Sec31A at ERES, establishing a mutual stabilization mechanism.\",\n      \"method\": \"Co-immunoprecipitation, Ca2+-dependent binding assays, RNA interference knockdown, immunofluorescence colocalization, Ca2+ chelator treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal depletion experiments with defined localization phenotypes, replicated in companion paper (PMID:17196169)\",\n      \"pmids\": [\"16957052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ALG-2 directly binds Sec31A (outer COPII coat component) in a Ca2+-dependent manner, as demonstrated by GST pull-down and biotin-labeled ALG-2 overlay assay; Ca2+ ionophore treatment enriches ALG-2 at Sec31A-positive membrane compartments, while BAPTA-AM disperses ALG-2 and reduces perinuclear Sec31A.\",\n      \"method\": \"GST pull-down, biotin-labeled ALG-2 overlay assay, Ca2+ ionophore/chelator treatment, immunofluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assay with functional cellular validation; replicates PMID:16957052\",\n      \"pmids\": [\"17196169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The ALG-2 binding site (ABS) within the Pro-rich region of Sec31A (amino acids 839–851) is necessary and sufficient for direct ALG-2 binding; deletion of the ABS reduces the high-affinity population of Sec31A at ERES as measured by FRAP, establishing the ABS as a key determinant of Sec31A retention kinetics at ERES.\",\n      \"method\": \"Biotin-labeled ALG-2 overlay assay, site-directed deletion mutagenesis, FRAP live-cell imaging, stable GFP/RFP fusion cell lines\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with FRAP functional readout and direct binding assay\",\n      \"pmids\": [\"20834162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ALG-2/Ca2+ attenuates COPII vesicle budding in vitro through interaction with the ALG-2 binding domain in the Pro-rich region of Sec31A; ALG-2 increases recruitment of Sec23/24 and Sec13/31A to liposomes and mediates Sec13/31A binding to Sec23, stabilizing the Sec23/Sec31A complex. Ca2+-binding at EF-hand 1 of ALG-2 is required for both Sec31A binding and budding inhibition.\",\n      \"method\": \"In vitro COPII budding reconstitution assay, liposome recruitment assay, EF-hand mutagenesis of ALG-2, biochemical co-assembly assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro budding assay with mutagenesis and liposome recruitment, multiple orthogonal methods\",\n      \"pmids\": [\"24069399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Annexin A11 (AnxA11) physically associates with Sec31A through ALG-2 as an adaptor; depletion of AnxA11 or ALG-2 decreases the stably membrane-associated pool of Sec31A at ERES, causes scattering of juxtanuclear ERES to the cell periphery, and accelerates ER-to-Golgi transport of transmembrane cargoes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence microscopy, synchronous cargo transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional transport phenotype from multiple knockdowns\",\n      \"pmids\": [\"25540196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the ALG-2–Sec31A peptide complex reveals that the Sec31A PXPGF (type 2) motif binds to a third hydrophobic pocket (Pocket 3) of ALG-2, distinct from the Pocket 1 used by ALIX; Phe85 mutation in ALG-2 abolishes Sec31A binding without affecting ALIX binding, defining a novel target recognition mechanism.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis of ALG-2 (Phe85Ala, Tyr180Ala), co-binding assays with Sec31A and ALIX peptides\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis validation of binding specificity\",\n      \"pmids\": [\"25667979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec31A is O-GlcNAcylated on serine 964 by OGT; this modification accelerates COPII vesicle formation by controlling Sec31A's binding affinity to ALG-2, thereby regulating ER-to-Golgi anterograde vesicle transport.\",\n      \"method\": \"Mass spectrometry identification of O-GlcNAc site, site-directed mutagenesis (S964), COPII vesicle formation assay, binding affinity assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method (mutagenesis + in vitro assay) but single lab with moderate mechanistic follow-up detail\",\n      \"pmids\": [\"29913562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP8 deubiquitinates Sec31A via an interaction mediated by the adaptor protein STAM1; USP8 overexpression inhibits large COPII carrier formation, while USP8 knockdown promotes large COPII carrier formation, accelerates procollagen IV ER-to-Golgi trafficking, and increases collagen IV secretion, establishing USP8 as the deubiquitinase opposing Cul3-mediated Sec31A mono-ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, siRNA knockdown, overexpression, immunofluorescence, collagen secretion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional knockdown/overexpression phenotypes, single lab\",\n      \"pmids\": [\"29604273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Homozygous nonsense mutation in SEC31A causes nonsense-mediated decay of its transcript; SEC31A-null cells show reduced viability through upregulation of ER stress pathways, and Drosophila knockdown of the SEC31A orthologue produces defective brains and early lethality, establishing SEC31A as essential for COPII-mediated ER-to-Golgi transport and cell survival.\",\n      \"method\": \"CRISPR/Cas9 knockout in SH-SY5Y and HEK293T cells, qRT-PCR, immunoblotting, cell viability assays, Drosophila null mutant analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined ER-stress phenotype, replicated across human cell lines and Drosophila model\",\n      \"pmids\": [\"30464055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC31A interacts with ATG9a on autophagosomal seed vesicles, mediating the recruitment of COPII vesicles as a membrane source for autophagosome formation; interference with Sec31A inhibits autophagosome formation and osteogenesis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vivo mouse bone tissue analysis, autophagosome counting by fluorescence microscopy\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional KD phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"39361436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC31A interacts with the insulin receptor in pancreatic alpha cells, suggesting a link between ER stress adaptation and insulin signaling; loss of Sec31A enhances survival of stressed alpha cells, with distinct responses in alpha versus beta cells.\",\n      \"method\": \"Genome-wide CRISPR screen, functional studies in mouse alpha cell lines and human islet clusters, co-immunoprecipitation of SEC31A with insulin receptor\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus Co-IP, but insulin receptor interaction is a single pulldown with limited mechanistic follow-up\",\n      \"pmids\": [\"41093834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK1 phosphorylates SEC31A downstream of AMPK signaling in response to glucose starvation, driving SEC24C-dependent COPII reorganization and selective impairment of ER-to-Golgi export of specific cargoes such as E-cadherin, independent of autophagy.\",\n      \"method\": \"Phosphoproteomics, kinase assays, genetic epistasis (AMPK/ULK1 inhibition/activation), quantitative cell surface proteomics, live-cell imaging of COPII\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.31.685804\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The C-terminal helical domain of Sec31A interacts with the adaptor protein p125A (Sec23ip); this interaction is essential for Sec31A assembly at ERES and promotes COPII outer layer (Sec13/31) assembly on donor membranes apposed to acceptor membranes, supporting tunnel-based collagen traffic.\",\n      \"method\": \"Cell-free reconstitution on membranes, p125A chimera expression, Sec31A C-terminal domain truncation, transcriptome and secretome analysis, fibrillar collagen trafficking assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method (cell-free reconstitution) but preprint only\",\n      \"pmids\": [\"bio_10.1101_2025.05.07.652703\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tissue-specific alternative splicing of an uncharacterized exon in SEC31A is regulated by the RNA-binding protein RBM47; inclusion of this exon increases lipid (chylomicron) transport, connecting SEC31A alternative splicing to secretion of large cargo in digestive tissues.\",\n      \"method\": \"RNA-seq across human tissues, RBM47 knockdown/overexpression, lipid transport assays, in silico correlation of splicing with RBP expression\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional splicing validation with transport assay; single lab\",\n      \"pmids\": [\"40436629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A chromosomal translocation t(2;4)(p23;q21) fuses SEC31L1 (SEC31A) exon 23 in-frame to ALK exon 20, generating a SEC31A-ALK fusion oncoprotein in inflammatory myofibroblastic tumor, with diffuse cytoplasmic ALK immunostaining indicating constitutive kinase activity driven by SEC31A's oligomerization domains.\",\n      \"method\": \"G-band karyotyping, FISH, 5'-RACE, RT-PCR, sequence analysis, genomic PCR\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — molecular characterization of fusion gene, no in vitro kinase reconstitution in this paper\",\n      \"pmids\": [\"16161041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SEC31A-JAK2 fusion gene generated by t(4;9)(q21;p24) acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors; it transforms cells in vitro and induces T-lymphoblastic lymphoma or myeloid phenotype in a murine bone marrow transplantation model, with oncogenicity dependent on constitutive JAK/STAT pathway activation.\",\n      \"method\": \"RT-PCR, FISH, in vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor treatment, kinase activity assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro transformation plus in vivo murine model with pathway inhibitor validation, multiple orthogonal methods\",\n      \"pmids\": [\"21325169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SEC31A-ALK fusion (from ALK-positive large B-cell lymphoma) transforms IL3-dependent Ba/F3 cells to growth factor independence, and the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3, and STAT5.\",\n      \"method\": \"Ba/F3 transformation assay, ALK inhibitor treatment, Western blot for downstream signaling effectors\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell transformation assay with pharmacological inhibitor and signaling pathway readout, single lab\",\n      \"pmids\": [\"20207848\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC31A is the mammalian outer-coat component of the COPII complex at ER exit sites (ERES), where it forms a Sec13/31A cage that drives vesicle budding; its Pro-rich region contains a Ca2+-dependent ALG-2 binding site (ABS, residues 839–851; PXPGF type 2 motif binding ALG-2 Pocket 3) that recruits ALG-2, which in turn stabilizes Sec31A at ERES via annexin A11 as an additional adaptor; Sec31A is O-GlcNAcylated on S964 (promoting COPII vesicle formation) and mono-ubiquitinated by Cul3 (promoting large COPII carrier formation for procollagen), with USP8/STAM1 acting as the opposing deubiquitinase; its C-terminal helical domain interacts with p125A to couple outer COPII assembly with donor–acceptor membrane apposition for tunnel-based collagen traffic; ULK1 phosphorylates Sec31A downstream of AMPK during glucose starvation to drive SEC24C-dependent COPII reorganization; Sec31A also interacts with ATG9a to supply COPII vesicle membrane to autophagosomes; loss of SEC31A causes ER stress and cell death, and chromosomal rearrangements generate oncogenic SEC31A-ALK and SEC31A-JAK2 fusion kinases in hematological and solid tumors.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEC31A is the outer-coat subunit of the COPII complex that drives vesicle budding from ER exit sites (ERES), forming a Sec13/31A cage essential for ER-to-Golgi anterograde transport and cell viability [PMID:30464055]. Its Pro-rich region (residues 839–851) provides a Ca²⁺-dependent binding site for ALG-2, which—together with annexin A11—stabilizes Sec31A at ERES and modulates budding kinetics; this interaction is structurally mediated through a PXPGF motif engaging ALG-2 Pocket 3 [PMID:16957052, PMID:25667979, PMID:25540196]. Sec31A activity is tuned by O-GlcNAcylation at S964 (promoting vesicle formation), Cul3-dependent mono-ubiquitination (promoting large COPII carriers for procollagen), opposing deubiquitination by USP8/STAM1, tissue-specific alternative splicing regulating large-cargo (chylomicron) secretion, and interaction with p125A to couple outer-coat assembly with collagen tunnel traffic [PMID:29913562, PMID:29604273, PMID:40436629]. Chromosomal rearrangements generate oncogenic SEC31A–ALK and SEC31A–JAK2 fusion kinases that constitutively activate downstream signaling and drive hematological and solid tumors [PMID:21325169, PMID:20207848].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"The question of how Ca²⁺ signaling intersects with COPII coat dynamics was answered by demonstrating that ALG-2 binds Sec31A's Pro-rich region in a Ca²⁺-dependent manner and that the two proteins mutually stabilize each other at ERES.\",\n      \"evidence\": \"Reciprocal siRNA knockdowns with immunofluorescence colocalization and Ca²⁺ chelator/ionophore treatments in mammalian cells; confirmed by independent GST pull-down and biotin-labeled ALG-2 overlay\",\n      \"pmids\": [\"16957052\", \"17196169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ALG-2–Sec31A interaction not yet resolved\", \"Whether ALG-2 binding promotes or inhibits vesicle budding was unknown\", \"No downstream cargo-transport phenotype shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The identification of a SEC31A–ALK fusion gene from a t(2;4) translocation in inflammatory myofibroblastic tumor established that SEC31A's oligomerization domains can drive constitutive kinase activation when fused to a receptor tyrosine kinase.\",\n      \"evidence\": \"Karyotyping, FISH, 5'-RACE, RT-PCR, and sequence analysis of patient tumor\",\n      \"pmids\": [\"16161041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro kinase reconstitution or transformation assay performed in this study\", \"Frequency and clinical spectrum of SEC31A–ALK fusions not established\", \"Whether the COPII-coat function of SEC31A is disrupted in fusion-bearing cells was not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the ALG-2 binding site to residues 839–851 and showing via FRAP that this motif controls the high-affinity pool of Sec31A at ERES defined the minimal determinant governing outer-coat residence time.\",\n      \"evidence\": \"Deletion mutagenesis of the ABS combined with FRAP live-cell imaging and biotin-labeled ALG-2 overlay\",\n      \"pmids\": [\"20834162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural resolution of the PXPGF motif–ALG-2 interface not yet available\", \"Whether modulating Sec31A residence time affects specific cargo classes was untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that SEC31A–ALK transforms Ba/F3 cells to growth-factor independence and is sensitive to ALK inhibitors confirmed oncogenic functionality of the fusion and identified targetable downstream effectors (ERK1/2, AKT, STAT3/5).\",\n      \"evidence\": \"Ba/F3 transformation assay with TAE-684 ALK inhibitor treatment and Western blot of signaling effectors\",\n      \"pmids\": [\"20207848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumorigenic potential of SEC31A–ALK not demonstrated\", \"Only one cell-based model used\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The SEC31A–JAK2 fusion was shown to be a constitutively active kinase that transforms cells in vitro and induces T-lymphoblastic lymphoma or myeloid disease in vivo, confirming SEC31A as a recurrent fusion partner in oncogenic kinase translocations.\",\n      \"evidence\": \"In vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor sensitivity, kinase activity assay\",\n      \"pmids\": [\"21325169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SEC31A-driven oligomerization is universally required for kinase activation in all fusion contexts was not tested\", \"No patient treatment outcome data\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstituted COPII budding assays resolved that ALG-2/Ca²⁺ attenuates vesicle budding by stabilizing the Sec23/Sec31A complex on donor membranes, answering the open question of whether ALG-2 promotes or inhibits budding.\",\n      \"evidence\": \"In vitro COPII budding reconstitution with liposome recruitment and EF-hand mutagenesis of ALG-2\",\n      \"pmids\": [\"24069399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological stimuli that trigger this inhibitory regulation in cells were unidentified\", \"Effect on large versus small COPII carriers not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that annexin A11 bridges ALG-2 to Sec31A and that its depletion scatters ERES and accelerates transport identified a third component of the Sec31A retention complex and explained spatial organization of ERES.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown of AnxA11 and ALG-2, synchronous cargo transport assay\",\n      \"pmids\": [\"25540196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How annexin A11's membrane-binding properties contribute to ERES tethering was not addressed\", \"Whether this tripartite complex differs across cell types was unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structure of the ALG-2–Sec31A peptide complex revealed that the PXPGF motif binds a novel Pocket 3 distinct from the ALIX-binding Pocket 1, explaining how ALG-2 discriminates between COPII and ESCRT clients.\",\n      \"evidence\": \"X-ray crystallography with site-directed mutagenesis (Phe85Ala) and competitive binding assays\",\n      \"pmids\": [\"25667979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length Sec31A–ALG-2 complex structure unavailable\", \"Whether other COPII subunits contact ALG-2 simultaneously was untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of O-GlcNAcylation at S964 and the opposing deubiquitinase USP8/STAM1 axis established that Sec31A is a convergence point for nutrient-sensitive post-translational modifications that tune COPII carrier size and budding rate.\",\n      \"evidence\": \"Mass spectrometry, site-directed mutagenesis of S964, COPII vesicle formation assay (O-GlcNAc); Co-IP, deubiquitination assay, knockdown/overexpression with collagen secretion readout (USP8)\",\n      \"pmids\": [\"29913562\", \"29604273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between O-GlcNAcylation and ubiquitination on the same Sec31A molecule not examined\", \"Identity of the E3 ligase site for mono-ubiquitination confirmed only as Cul3 in prior literature, not re-mapped here\", \"Single-lab findings for each modification\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Knockout of SEC31A in human cells and Drosophila demonstrated that the gene is essential for viability, with loss triggering ER stress pathways and cell death, establishing a non-redundant requirement for Sec31A in COPII function.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in SH-SY5Y and HEK293T cells, qRT-PCR, cell viability assays; Drosophila null mutant analysis showing brain defects and early lethality\",\n      \"pmids\": [\"30464055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SEC31B partially compensates in specific tissues was not tested\", \"Specific cargo classes most affected by SEC31A loss were not catalogued\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The finding that SEC31A interacts with ATG9a on autophagosomal seed vesicles and that its depletion impairs autophagosome formation extended Sec31A's role beyond canonical ER-to-Golgi transport to autophagy membrane supply.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, autophagosome counting, in vivo mouse osteogenesis analysis\",\n      \"pmids\": [\"39361436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether COPII vesicle identity is maintained during autophagosome membrane donation is unknown\", \"Contribution of other COPII subunits to ATG9a interaction not tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tissue-specific alternative splicing of a SEC31A exon, regulated by RBM47, was shown to promote large-cargo (chylomicron) transport, revealing a splicing-based mechanism for tuning COPII carrier capacity in digestive tissues.\",\n      \"evidence\": \"RNA-seq across human tissues, RBM47 knockdown/overexpression, lipid transport assays\",\n      \"pmids\": [\"40436629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which domain of Sec31A the alternative exon encodes and how it alters cage geometry is unknown\", \"Functional validation in primary intestinal cells not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full structural basis of the assembled Sec13/31A cage on native COPII carriers, how the multiple post-translational modifications (O-GlcNAcylation, ubiquitination, phosphorylation) are integrated on individual Sec31A molecules during physiological transitions, and the precise mechanism by which Sec31A contributes membrane to autophagosomes versus canonical secretory vesicles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cryo-EM or cryo-ET structure of mammalian Sec13/31A cage on native membranes\", \"Combinatorial PTM code on Sec31A not mapped\", \"Relative contributions of SEC31A versus SEC31B across tissues remain undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 4, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 15, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3, 8]}\n    ],\n    \"complexes\": [\n      \"COPII (Sec13/31A outer coat)\",\n      \"ALG-2/AnxA11/Sec31A regulatory complex\"\n    ],\n    \"partners\": [\n      \"ALG-2\",\n      \"ANXA11\",\n      \"SEC13\",\n      \"SEC23A\",\n      \"USP8\",\n      \"STAM1\",\n      \"ATG9A\",\n      \"SEC23IP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}