{"gene":"SEC31A","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2006,"finding":"ALG-2 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 reduces Sec31A levels at ERES, establishing a mutual stabilization mechanism.","method":"Co-immunoprecipitation, GST pulldown, RNA interference, immunofluorescence colocalization, Ca2+ chelator treatment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal depletion experiments, multiple orthogonal methods (pulldown, RNAi, live imaging), independently replicated in a second paper (PMID:17196169)","pmids":["16957052","17196169"],"is_preprint":false},{"year":2006,"finding":"ALG-2 directly binds Sec31A (confirmed by biotin-labeled ALG-2 overlay assay) in a Ca2+-dependent manner; Ca2+ ionophore A23187 enriches ALG-2 at Sec31A-positive membrane compartments, whereas BAPTA-AM treatment disperses ALG-2 and causes loss of Sec31A in the perinuclear region.","method":"GST pulldown, biotin-ALG-2 overlay assay, immunofluorescence, Ca2+ ionophore/chelator treatment","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding confirmed by overlay assay plus multiple orthogonal methods, replicates findings of PMID:16957052","pmids":["17196169"],"is_preprint":false},{"year":2010,"finding":"The ALG-2 binding site (ABS) in Sec31A was mapped to amino acid residues 839–851 in the Pro-rich region; FRAP analysis showed that deletion of the ABS reduces the high-affinity population of Sec31A at ERES, establishing the ABS as a key determinant of Sec31A retention kinetics at ERES.","method":"Biotin-ALG-2 overlay assay (deletion mapping), live-cell imaging of GFP-ALG-2 / Sec31A-RFP, FRAP","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and direct binding mapping in single lab with two orthogonal methods","pmids":["20834162"],"is_preprint":false},{"year":2013,"finding":"ALG-2/Ca2+ attenuates COPII vesicle budding in vitro by interacting with the proline-rich region of Sec31A; ALG-2 increases recruitment of Sec23/24 and Sec13/31A to liposomes and mediates binding of Sec13/31A to Sec23, stabilizing the Sec23/Sec31A complex; inhibition requires an intact EF-hand 1 Ca2+-binding site in ALG-2.","method":"In vitro COPII budding assay, liposome recruitment assay, mutagenesis of ALG-2 EF-hand 1","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro budding assay with mutagenesis validation, single lab but 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 stable ERES-associated pool of Sec31A and causes scattering of juxtanuclear ERES to the cell periphery, accelerating synchronous ER-to-Golgi transport of transmembrane cargoes.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, synchronous cargo transport assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction and functional knockdown with defined cargo transport readout, single lab","pmids":["25540196"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the ALG-2–Sec31A peptide complex revealed that the Sec31A type 2 motif (PXPGF) binds to a third hydrophobic pocket (Pocket 3) of ALG-2, distinct from the Pocket 1 used by ALIX; mutagenesis of Phe85 (Pocket 3) abolished Sec31A binding without affecting ALIX binding, while mutagenesis of Tyr180 (Pocket 1) abolished ALIX binding but maintained Sec31A binding.","method":"X-ray crystallography, site-directed mutagenesis, binding assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis validation of binding specificity in single study","pmids":["25667979"],"is_preprint":false},{"year":2018,"finding":"Sec31A is O-GlcNAcylated on serine 964; this modification accelerates COPII vesicle formation by controlling Sec31A binding affinity to ALG-2, thereby regulating anterograde ER-to-Golgi vesicle trafficking.","method":"Mass spectrometry identification of O-GlcNAc site, site-directed mutagenesis (S964), COPII vesicle formation assay, co-immunoprecipitation with ALG-2","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM site identified and functionally validated by mutagenesis with vesicle formation readout, single lab","pmids":["29913562"],"is_preprint":false},{"year":2018,"finding":"USP8 deubiquitinates Sec31A via an interaction mediated by adaptor protein STAM1; USP8 overexpression inhibits large COPII carrier formation, whereas USP8 knockdown promotes procollagen IV trafficking from ER to Golgi and increases collagen IV secretion, identifying USP8 as the deubiquitinating enzyme that counteracts Cul3-mediated Sec31A mono-ubiquitination.","method":"Co-immunoprecipitation, deubiquitination assay, overexpression and siRNA knockdown, procollagen trafficking assay, collagen IV secretion measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction and enzymatic activity shown with functional cargo trafficking readout, single lab","pmids":["29604273"],"is_preprint":false},{"year":2018,"finding":"A homozygous nonsense mutation in SEC31A triggers nonsense-mediated decay of its transcript in affected individuals; CRISPR/Cas9-mediated SEC31A knockout cells show reduced viability through upregulation of ER-stress pathways, demonstrating that SEC31A is required for ER homeostasis and cell survival.","method":"Whole exome sequencing, CRISPR/Cas9 knockout, qRT-PCR, immunoblotting, cell viability assay, Drosophila SEC31A orthologue knockdown","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in human cells and model organism with defined ER stress phenotype, single study","pmids":["30464055"],"is_preprint":false},{"year":2006,"finding":"SEC31L1 (SEC31A) exon sequences fuse in-frame with the ALK kinase domain in an inflammatory myofibroblastic tumor, producing a SEC31L1/ALK chimeric oncoprotein with diffuse cytoplasmic ALK immunostaining, indicating the N-terminal portion of SEC31A drives oligomerization-mediated constitutive ALK activation.","method":"5'-RACE, RT-PCR, sequencing, genomic PCR, FISH, immunostaining","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion gene characterized at genomic and transcript level with protein expression confirmed, single case study","pmids":["16161041"],"is_preprint":false},{"year":2011,"finding":"SEC31A-JAK2 fusion protein acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors and is oncogenic in vitro; in a murine bone marrow transplantation model it induces T-lymphoblastic lymphoma or myeloid disease.","method":"RT-PCR/sequencing, in vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor treatment","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — constitutive kinase activity demonstrated functionally in vitro and in vivo, single lab","pmids":["21325169"],"is_preprint":false},{"year":2010,"finding":"SEC31A-ALK fusion transforms IL3-dependent Ba/F3 cells to growth factor independence; the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3, and STAT5, establishing the signaling pathways activated by this fusion.","method":"Ba/F3 transformation assay, ALK inhibitor treatment, Western blot for downstream signaling","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transformation assay with defined downstream pathway, single lab","pmids":["20207848"],"is_preprint":false},{"year":2024,"finding":"SEC31A interacts with ATG9a on autophagosomal seed vesicles; this interaction is required for COPII vesicle-dependent autophagosome formation during osteogenic differentiation of mesenchymal stem cells, and disruption of COPII vesicles or SEC31A knockdown reduces autophagosome number and size and impairs osteogenesis in vitro and in vivo.","method":"Co-immunoprecipitation (SEC31A–ATG9a), siRNA knockdown, autophagosome quantification, in vitro osteogenesis assay, in vivo bone tissue analysis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction identified and functionally validated in vitro and in vivo, single lab","pmids":["39361436"],"is_preprint":false},{"year":2025,"finding":"The C-terminal helical domain of Sec31A interacts with p125A (Sec23IP); this interaction is essential for outer COPII coat (Sec13/31) assembly at ERES. In cells lacking p125A, outer layer assembly is selectively destabilized, connecting SEC31A to tunnel-based collagen traffic from the ER.","method":"Cell-free reconstitution, co-immunoprecipitation, domain deletion analysis, ERES imaging, secretome/transcriptome analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — cell-free reconstitution with domain mutant and cellular validation, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.07.652703"],"is_preprint":true},{"year":2025,"finding":"ULK1 phosphorylates SEC31A in response to glucose starvation/AMPK signaling, driving SEC24C-dependent COPII reorganization that selectively impairs ER-to-Golgi export of specific cargoes (e.g., E-cadherin) and remodels the cell surface proteome to enhance cell migration and metastasis.","method":"Quantitative cell surface proteomics, AMPK/ULK1 pathway perturbation, phosphorylation assay, COPII imaging, in vitro migration and in vivo metastasis assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic phosphorylation event with multiple functional readouts, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.31.685804"],"is_preprint":true},{"year":2025,"finding":"A tissue-specific alternative exon in SEC31A whose inclusion is regulated by RNA-binding protein RBM47 increases lipid transport, linking SEC31A alternative splicing to secretion of large cargo (chylomicrons) in digestive tissues.","method":"RNA-seq across human tissues, minigene splicing assay, RBM47 knockdown/overexpression, lipid transport assay","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — trans-acting factor identified and validated with functional lipid transport readout, single lab","pmids":["40436629"],"is_preprint":false},{"year":2025,"finding":"SEC31A interacts with the insulin receptor in pancreatic alpha cells, suggesting a functional link between ER export and insulin signaling; loss of Sec31A enhances alpha cell survival under stress in mouse alpha cells and in C. elegans.","method":"Genome-wide CRISPR screen, co-immunoprecipitation (SEC31A–insulin receptor), loss-of-function in alpha cell lines and C. elegans survival assay","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction reported from single Co-IP with limited mechanistic follow-up; survival phenotype established but pathway mechanism not fully resolved","pmids":["41093834"],"is_preprint":false},{"year":2022,"finding":"Sec31A expression is upregulated in activated human dermal fibroblasts under high-glucose conditions via TGF-β signaling and positively regulates collagen I biosynthesis/secretion; silencing Sec31A in this coculture model reverses impaired neurite outgrowth, establishing Sec31A as a mediator of the non-permissive collagen-rich microenvironment in diabetic neuropathy.","method":"siRNA knockdown of Sec31A in human dermal fibroblasts, coculture with dorsal root ganglion neurons, neurite outgrowth quantification, immunoblotting, TGF-β pathway inhibition","journal":"Annals of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined neurite outgrowth phenotype and pathway placement (TGF-β→Sec31A→collagen I), single lab","pmids":["35285061"],"is_preprint":false}],"current_model":"SEC31A is the outer-coat COPII component (Sec13/31 complex) at ER exit sites (ERES) that physically interacts with ALG-2 (Ca2+-dependently via a PXPGF type-2 motif mapping to residues 839–851), Annexin A11 (via ALG-2 adaptor), p125A/Sec23IP (via its C-terminal helical domain), ATG9a (for autophagosome membrane supply), and the insulin receptor; its ERES retention and large-COPII carrier formation are regulated post-translationally by Cul3-mediated mono-ubiquitination (pro-large carrier), USP8/STAM1-mediated deubiquitination (anti-large carrier), and O-GlcNAcylation on S964 (pro-vesicle formation via modulation of ALG-2 affinity); ULK1 phosphorylates SEC31A under glucose starvation to reorganize COPII and remodel the cell-surface proteome; loss-of-function causes ER stress, reduced cell viability, defective collagen secretion, and neurological disease, while gain-of-function fusions (SEC31A-ALK, SEC31A-JAK2) produce constitutively active oncogenic kinases."},"narrative":{"mechanistic_narrative":"SEC31A is the outer-coat component of the COPII Sec13/31 complex that drives anterograde cargo export from ER exit sites (ERES) and, through regulated assembly of large COPII carriers, supports bulky cargo secretion and autophagosome biogenesis [PMID:24069399, PMID:29604273]. Its residence and dynamics at ERES are governed by the Ca2+-binding protein ALG-2, which binds directly to a PXPGF type-2 motif in the proline-rich region (residues 839–851) through a dedicated hydrophobic pocket distinct from the ALIX site, mutually stabilizing the ALG-2/SEC31A pool at ERES and attenuating COPII budding by stabilizing the Sec23/Sec31A interaction [PMID:16957052, PMID:17196169, PMID:20834162, PMID:24069399, PMID:25667979]. ALG-2 further bridges SEC31A to Annexin A11, which maintains the stable juxtanuclear ERES pool [PMID:25540196], while the C-terminal helical domain binds p125A/Sec23IP to license outer-coat assembly [PMID:bio_10.1101_2025.05.07.652703]. SEC31A activity is tuned post-translationally: O-GlcNAcylation on Ser964 accelerates vesicle formation by modulating ALG-2 affinity [PMID:29913562], USP8/STAM1-mediated deubiquitination counteracts Cul3 mono-ubiquitination to restrain large-carrier formation and collagen IV secretion [PMID:29604273], and ULK1 phosphorylation under glucose starvation reorganizes COPII to remodel the cell-surface proteome [PMID:bio_10.1101_2025.10.31.685804]. Functionally, SEC31A is required for collagen biosynthesis and secretion, with TGF-β-driven upregulation promoting a collagen-rich, growth-inhibitory microenvironment [PMID:35285061], and is needed for ATG9a-dependent autophagosome formation during osteogenic differentiation [PMID:39361436]. Loss of SEC31A causes ER stress and reduced cell viability, and a homozygous nonsense mutation triggering nonsense-mediated decay underlies a human neurological disorder [PMID:30464055]. SEC31A N-terminal sequences also form constitutively active oncogenic fusion kinases with ALK and JAK2 [PMID:16161041, PMID:21325169, PMID:20207848].","teleology":[{"year":2006,"claim":"Established the first regulated protein partner of the COPII outer coat by showing that ALG-2 docks onto SEC31A in a Ca2+-dependent manner, linking ER export to intracellular calcium.","evidence":"Co-IP, GST pulldown, biotin-ALG-2 overlay, RNAi, and Ca2+ chelator/ionophore imaging in cultured cells","pmids":["16957052","17196169"],"confidence":"High","gaps":["Did not define the binding motif at residue resolution","Functional consequence for budding not yet measured"]},{"year":2010,"claim":"Mapped the ALG-2 binding site to residues 839–851 and showed it determines SEC31A retention kinetics, converting the interaction into a defined ERES-residence determinant.","evidence":"Deletion mapping by ALG-2 overlay and FRAP of GFP/RFP fusions in live cells","pmids":["20834162"],"confidence":"Medium","gaps":["Single-lab FRAP","Did not resolve atomic basis of binding"]},{"year":2013,"claim":"Demonstrated the functional output of ALG-2 binding: Ca2+/ALG-2 attenuates COPII budding while stabilizing the Sec23/Sec31A complex, defining a Ca2+-gated brake on vesicle formation.","evidence":"Reconstituted in vitro COPII budding and liposome recruitment assays with ALG-2 EF-hand mutagenesis","pmids":["24069399"],"confidence":"High","gaps":["In vitro system may not capture cellular regulation","Upstream Ca2+ source not defined"]},{"year":2014,"claim":"Identified Annexin A11 as a downstream effector bridged to SEC31A by ALG-2, extending the ERES-stabilization module and linking it to cargo transport kinetics.","evidence":"Co-IP, siRNA, and synchronous transmembrane-cargo transport assay","pmids":["25540196"],"confidence":"Medium","gaps":["Single lab","Mechanism of ERES scattering on AnxA11 loss unresolved"]},{"year":2015,"claim":"Resolved the structural basis of binding specificity, showing the SEC31A PXPGF motif uses ALG-2 Pocket 3 distinct from the ALIX site, explaining how ALG-2 engages multiple partners independently.","evidence":"X-ray crystallography of the ALG-2–SEC31A peptide complex with pocket-specific mutagenesis","pmids":["25667979"],"confidence":"High","gaps":["Peptide-only structure, not full-length complex","Does not address Ca2+ conformational switch in cells"]},{"year":2018,"claim":"Defined post-translational control of SEC31A by O-GlcNAcylation on S964 and by USP8/STAM1 deubiquitination, establishing that vesicle/large-carrier choice is tuned through PTMs and ALG-2 affinity.","evidence":"MS site mapping, S964 mutagenesis, vesicle formation assay; deubiquitination assay with procollagen IV trafficking and collagen secretion readouts","pmids":["29913562","29604273"],"confidence":"Medium","gaps":["O-GlcNAc and ubiquitin pathways not integrated","Cul3 ubiquitination shown only by inference here"]},{"year":2018,"claim":"Established SEC31A as essential for ER homeostasis and cell survival and causal for human neurological disease via a loss-of-function nonsense mutation.","evidence":"Whole exome sequencing, CRISPR/Cas9 knockout, ER-stress and viability assays, and Drosophila orthologue knockdown","pmids":["30464055"],"confidence":"Medium","gaps":["Single family/study","Cell-type basis of neurological phenotype not defined"]},{"year":2024,"claim":"Connected COPII/SEC31A to autophagy by showing a SEC31A–ATG9a interaction required for autophagosome formation during osteogenic differentiation.","evidence":"Co-IP, siRNA, autophagosome quantification, and in vitro/in vivo osteogenesis assays","pmids":["39361436"],"confidence":"Medium","gaps":["Single lab","Molecular detail of how COPII contributes membrane to autophagosomes unresolved"]},{"year":2025,"claim":"Identified p125A/Sec23IP binding via the SEC31A C-terminal helical domain as essential for outer-coat assembly and collagen tunnel traffic, and ULK1 phosphorylation as a glucose-starvation switch reorganizing COPII to remodel the cell surface.","evidence":"Cell-free reconstitution and domain deletion (preprint); AMPK/ULK1 perturbation with cell-surface proteomics, migration and metastasis assays (preprint)","pmids":["bio_10.1101_2025.05.07.652703","bio_10.1101_2025.10.31.685804"],"confidence":"Medium","gaps":["Both findings are preprints not yet peer-reviewed","ULK1 phosphosite(s) on SEC31A not pinpointed"]},{"year":2025,"claim":"Showed that tissue-specific regulation of SEC31A function occurs through RBM47-controlled alternative splicing that tunes large lipid-cargo secretion, adding a transcript-level layer to COPII control.","evidence":"Cross-tissue RNA-seq, minigene splicing assay, RBM47 perturbation, and lipid transport assay","pmids":["40436629"],"confidence":"Medium","gaps":["Single lab","Functional protein consequence of the alternative exon not structurally characterized"]},{"year":2025,"claim":"Linked SEC31A to insulin signaling and stress survival in pancreatic alpha cells via an insulin receptor interaction, hinting at a tissue-specific signaling role for ER export.","evidence":"Genome-wide CRISPR screen, single Co-IP, and loss-of-function survival assays in alpha cell lines and C. elegans","pmids":["41093834"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","Pathway mechanism connecting ER export to insulin receptor unresolved"]},{"year":null,"claim":"How the multiple regulatory layers (Ca2+/ALG-2, O-GlcNAcylation, ubiquitination/deubiquitination, ULK1 phosphorylation, splicing) are integrated to select between standard COPII vesicles and large carriers for specific cargoes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating the PTM and adaptor inputs","Cargo-selective carrier-size control mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,13]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,6,12]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,4,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[8]}],"complexes":["COPII coat (Sec13/31)","ER exit site"],"partners":["PDCD6","ANXA11","SEC23IP","ATG9A","USP8","STAM","INSR","ALK"],"other_free_text":[]}},"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":"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":"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":"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":44,"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 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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":"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":9,"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":4,"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":3,"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":2,"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":"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":"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":"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":"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":"42155543","id":"PMC_42155543","title":"Sec31a and its impact on ER stress and Bmp/Smad signaling in senescent BMSCs.","date":"2026","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/42155543","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":15438,"output_tokens":4529,"usd":0.057125,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12578,"output_tokens":3811,"usd":0.079083,"stage2_stop_reason":"end_turn"},"total_usd":0.136208,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"ALG-2 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 reduces Sec31A levels at ERES, establishing a mutual stabilization mechanism.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, RNA interference, immunofluorescence colocalization, Ca2+ chelator treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal depletion experiments, multiple orthogonal methods (pulldown, RNAi, live imaging), independently replicated in a second paper (PMID:17196169)\",\n      \"pmids\": [\"16957052\", \"17196169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ALG-2 directly binds Sec31A (confirmed by biotin-labeled ALG-2 overlay assay) in a Ca2+-dependent manner; Ca2+ ionophore A23187 enriches ALG-2 at Sec31A-positive membrane compartments, whereas BAPTA-AM treatment disperses ALG-2 and causes loss of Sec31A in the perinuclear region.\",\n      \"method\": \"GST pulldown, biotin-ALG-2 overlay assay, immunofluorescence, Ca2+ ionophore/chelator treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding confirmed by overlay assay plus multiple orthogonal methods, replicates findings of PMID:16957052\",\n      \"pmids\": [\"17196169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The ALG-2 binding site (ABS) in Sec31A was mapped to amino acid residues 839–851 in the Pro-rich region; FRAP analysis showed that deletion of the ABS reduces the high-affinity population of Sec31A at ERES, establishing the ABS as a key determinant of Sec31A retention kinetics at ERES.\",\n      \"method\": \"Biotin-ALG-2 overlay assay (deletion mapping), live-cell imaging of GFP-ALG-2 / Sec31A-RFP, FRAP\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and direct binding mapping in single lab with two orthogonal methods\",\n      \"pmids\": [\"20834162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ALG-2/Ca2+ attenuates COPII vesicle budding in vitro by interacting with the proline-rich region of Sec31A; ALG-2 increases recruitment of Sec23/24 and Sec13/31A to liposomes and mediates binding of Sec13/31A to Sec23, stabilizing the Sec23/Sec31A complex; inhibition requires an intact EF-hand 1 Ca2+-binding site in ALG-2.\",\n      \"method\": \"In vitro COPII budding assay, liposome recruitment assay, mutagenesis of ALG-2 EF-hand 1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro budding assay with mutagenesis validation, single lab but 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 stable ERES-associated pool of Sec31A and causes scattering of juxtanuclear ERES to the cell periphery, accelerating synchronous ER-to-Golgi transport of transmembrane cargoes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, synchronous cargo transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction and functional knockdown with defined cargo transport readout, single lab\",\n      \"pmids\": [\"25540196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the ALG-2–Sec31A peptide complex revealed that the Sec31A type 2 motif (PXPGF) binds to a third hydrophobic pocket (Pocket 3) of ALG-2, distinct from the Pocket 1 used by ALIX; mutagenesis of Phe85 (Pocket 3) abolished Sec31A binding without affecting ALIX binding, while mutagenesis of Tyr180 (Pocket 1) abolished ALIX binding but maintained Sec31A binding.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, binding assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis validation of binding specificity in single study\",\n      \"pmids\": [\"25667979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Sec31A is O-GlcNAcylated on serine 964; this modification accelerates COPII vesicle formation by controlling Sec31A binding affinity to ALG-2, thereby regulating anterograde ER-to-Golgi vesicle trafficking.\",\n      \"method\": \"Mass spectrometry identification of O-GlcNAc site, site-directed mutagenesis (S964), COPII vesicle formation assay, co-immunoprecipitation with ALG-2\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM site identified and functionally validated by mutagenesis with vesicle formation readout, single lab\",\n      \"pmids\": [\"29913562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP8 deubiquitinates Sec31A via an interaction mediated by adaptor protein STAM1; USP8 overexpression inhibits large COPII carrier formation, whereas USP8 knockdown promotes procollagen IV trafficking from ER to Golgi and increases collagen IV secretion, identifying USP8 as the deubiquitinating enzyme that counteracts Cul3-mediated Sec31A mono-ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, overexpression and siRNA knockdown, procollagen trafficking assay, collagen IV secretion measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction and enzymatic activity shown with functional cargo trafficking readout, single lab\",\n      \"pmids\": [\"29604273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous nonsense mutation in SEC31A triggers nonsense-mediated decay of its transcript in affected individuals; CRISPR/Cas9-mediated SEC31A knockout cells show reduced viability through upregulation of ER-stress pathways, demonstrating that SEC31A is required for ER homeostasis and cell survival.\",\n      \"method\": \"Whole exome sequencing, CRISPR/Cas9 knockout, qRT-PCR, immunoblotting, cell viability assay, Drosophila SEC31A orthologue knockdown\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in human cells and model organism with defined ER stress phenotype, single study\",\n      \"pmids\": [\"30464055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SEC31L1 (SEC31A) exon sequences fuse in-frame with the ALK kinase domain in an inflammatory myofibroblastic tumor, producing a SEC31L1/ALK chimeric oncoprotein with diffuse cytoplasmic ALK immunostaining, indicating the N-terminal portion of SEC31A drives oligomerization-mediated constitutive ALK activation.\",\n      \"method\": \"5'-RACE, RT-PCR, sequencing, genomic PCR, FISH, immunostaining\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion gene characterized at genomic and transcript level with protein expression confirmed, single case study\",\n      \"pmids\": [\"16161041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SEC31A-JAK2 fusion protein acts as a constitutively activated tyrosine kinase that is sensitive to JAK inhibitors and is oncogenic in vitro; in a murine bone marrow transplantation model it induces T-lymphoblastic lymphoma or myeloid disease.\",\n      \"method\": \"RT-PCR/sequencing, in vitro transformation assay, murine bone marrow transplantation model, JAK inhibitor treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — constitutive kinase activity demonstrated functionally in vitro and in vivo, single lab\",\n      \"pmids\": [\"21325169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SEC31A-ALK fusion transforms IL3-dependent Ba/F3 cells to growth factor independence; the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3, and STAT5, establishing the signaling pathways activated by this fusion.\",\n      \"method\": \"Ba/F3 transformation assay, ALK inhibitor treatment, Western blot for downstream signaling\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transformation assay with defined downstream pathway, single lab\",\n      \"pmids\": [\"20207848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEC31A interacts with ATG9a on autophagosomal seed vesicles; this interaction is required for COPII vesicle-dependent autophagosome formation during osteogenic differentiation of mesenchymal stem cells, and disruption of COPII vesicles or SEC31A knockdown reduces autophagosome number and size and impairs osteogenesis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (SEC31A–ATG9a), siRNA knockdown, autophagosome quantification, in vitro osteogenesis assay, in vivo bone tissue analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction identified and functionally validated in vitro and in vivo, single lab\",\n      \"pmids\": [\"39361436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The C-terminal helical domain of Sec31A interacts with p125A (Sec23IP); this interaction is essential for outer COPII coat (Sec13/31) assembly at ERES. In cells lacking p125A, outer layer assembly is selectively destabilized, connecting SEC31A to tunnel-based collagen traffic from the ER.\",\n      \"method\": \"Cell-free reconstitution, co-immunoprecipitation, domain deletion analysis, ERES imaging, secretome/transcriptome analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — cell-free reconstitution with domain mutant and cellular validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.07.652703\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ULK1 phosphorylates SEC31A in response to glucose starvation/AMPK signaling, driving SEC24C-dependent COPII reorganization that selectively impairs ER-to-Golgi export of specific cargoes (e.g., E-cadherin) and remodels the cell surface proteome to enhance cell migration and metastasis.\",\n      \"method\": \"Quantitative cell surface proteomics, AMPK/ULK1 pathway perturbation, phosphorylation assay, COPII imaging, in vitro migration and in vivo metastasis assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic phosphorylation event with multiple functional readouts, 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\": \"A tissue-specific alternative exon in SEC31A whose inclusion is regulated by RNA-binding protein RBM47 increases lipid transport, linking SEC31A alternative splicing to secretion of large cargo (chylomicrons) in digestive tissues.\",\n      \"method\": \"RNA-seq across human tissues, minigene splicing assay, RBM47 knockdown/overexpression, lipid transport assay\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — trans-acting factor identified and validated with functional lipid transport readout, single lab\",\n      \"pmids\": [\"40436629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SEC31A interacts with the insulin receptor in pancreatic alpha cells, suggesting a functional link between ER export and insulin signaling; loss of Sec31A enhances alpha cell survival under stress in mouse alpha cells and in C. elegans.\",\n      \"method\": \"Genome-wide CRISPR screen, co-immunoprecipitation (SEC31A–insulin receptor), loss-of-function in alpha cell lines and C. elegans survival assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction reported from single Co-IP with limited mechanistic follow-up; survival phenotype established but pathway mechanism not fully resolved\",\n      \"pmids\": [\"41093834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sec31A expression is upregulated in activated human dermal fibroblasts under high-glucose conditions via TGF-β signaling and positively regulates collagen I biosynthesis/secretion; silencing Sec31A in this coculture model reverses impaired neurite outgrowth, establishing Sec31A as a mediator of the non-permissive collagen-rich microenvironment in diabetic neuropathy.\",\n      \"method\": \"siRNA knockdown of Sec31A in human dermal fibroblasts, coculture with dorsal root ganglion neurons, neurite outgrowth quantification, immunoblotting, TGF-β pathway inhibition\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined neurite outgrowth phenotype and pathway placement (TGF-β→Sec31A→collagen I), single lab\",\n      \"pmids\": [\"35285061\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEC31A is the outer-coat COPII component (Sec13/31 complex) at ER exit sites (ERES) that physically interacts with ALG-2 (Ca2+-dependently via a PXPGF type-2 motif mapping to residues 839–851), Annexin A11 (via ALG-2 adaptor), p125A/Sec23IP (via its C-terminal helical domain), ATG9a (for autophagosome membrane supply), and the insulin receptor; its ERES retention and large-COPII carrier formation are regulated post-translationally by Cul3-mediated mono-ubiquitination (pro-large carrier), USP8/STAM1-mediated deubiquitination (anti-large carrier), and O-GlcNAcylation on S964 (pro-vesicle formation via modulation of ALG-2 affinity); ULK1 phosphorylates SEC31A under glucose starvation to reorganize COPII and remodel the cell-surface proteome; loss-of-function causes ER stress, reduced cell viability, defective collagen secretion, and neurological disease, while gain-of-function fusions (SEC31A-ALK, SEC31A-JAK2) produce constitutively active oncogenic kinases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEC31A is the outer-coat component of the COPII Sec13/31 complex that drives anterograde cargo export from ER exit sites (ERES) and, through regulated assembly of large COPII carriers, supports bulky cargo secretion and autophagosome biogenesis [#3, #7]. Its residence and dynamics at ERES are governed by the Ca2+-binding protein ALG-2, which binds directly to a PXPGF type-2 motif in the proline-rich region (residues 839\\u2013851) through a dedicated hydrophobic pocket distinct from the ALIX site, mutually stabilizing the ALG-2/SEC31A pool at ERES and attenuating COPII budding by stabilizing the Sec23/Sec31A interaction [#0, #2, #3, #5]. ALG-2 further bridges SEC31A to Annexin A11, which maintains the stable juxtanuclear ERES pool [#4], while the C-terminal helical domain binds p125A/Sec23IP to license outer-coat assembly [#13]. SEC31A activity is tuned post-translationally: O-GlcNAcylation on Ser964 accelerates vesicle formation by modulating ALG-2 affinity [#6], USP8/STAM1-mediated deubiquitination counteracts Cul3 mono-ubiquitination to restrain large-carrier formation and collagen IV secretion [#7], and ULK1 phosphorylation under glucose starvation reorganizes COPII to remodel the cell-surface proteome [#14]. Functionally, SEC31A is required for collagen biosynthesis and secretion, with TGF-\\u03b2-driven upregulation promoting a collagen-rich, growth-inhibitory microenvironment [#17], and is needed for ATG9a-dependent autophagosome formation during osteogenic differentiation [#12]. Loss of SEC31A causes ER stress and reduced cell viability, and a homozygous nonsense mutation triggering nonsense-mediated decay underlies a human neurological disorder [#8]. SEC31A N-terminal sequences also form constitutively active oncogenic fusion kinases with ALK and JAK2 [#9, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the first regulated protein partner of the COPII outer coat by showing that ALG-2 docks onto SEC31A in a Ca2+-dependent manner, linking ER export to intracellular calcium.\",\n      \"evidence\": \"Co-IP, GST pulldown, biotin-ALG-2 overlay, RNAi, and Ca2+ chelator/ionophore imaging in cultured cells\",\n      \"pmids\": [\"16957052\", \"17196169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the binding motif at residue resolution\", \"Functional consequence for budding not yet measured\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped the ALG-2 binding site to residues 839\\u2013851 and showed it determines SEC31A retention kinetics, converting the interaction into a defined ERES-residence determinant.\",\n      \"evidence\": \"Deletion mapping by ALG-2 overlay and FRAP of GFP/RFP fusions in live cells\",\n      \"pmids\": [\"20834162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab FRAP\", \"Did not resolve atomic basis of binding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated the functional output of ALG-2 binding: Ca2+/ALG-2 attenuates COPII budding while stabilizing the Sec23/Sec31A complex, defining a Ca2+-gated brake on vesicle formation.\",\n      \"evidence\": \"Reconstituted in vitro COPII budding and liposome recruitment assays with ALG-2 EF-hand mutagenesis\",\n      \"pmids\": [\"24069399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro system may not capture cellular regulation\", \"Upstream Ca2+ source not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Annexin A11 as a downstream effector bridged to SEC31A by ALG-2, extending the ERES-stabilization module and linking it to cargo transport kinetics.\",\n      \"evidence\": \"Co-IP, siRNA, and synchronous transmembrane-cargo transport assay\",\n      \"pmids\": [\"25540196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of ERES scattering on AnxA11 loss unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the structural basis of binding specificity, showing the SEC31A PXPGF motif uses ALG-2 Pocket 3 distinct from the ALIX site, explaining how ALG-2 engages multiple partners independently.\",\n      \"evidence\": \"X-ray crystallography of the ALG-2\\u2013SEC31A peptide complex with pocket-specific mutagenesis\",\n      \"pmids\": [\"25667979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Peptide-only structure, not full-length complex\", \"Does not address Ca2+ conformational switch in cells\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined post-translational control of SEC31A by O-GlcNAcylation on S964 and by USP8/STAM1 deubiquitination, establishing that vesicle/large-carrier choice is tuned through PTMs and ALG-2 affinity.\",\n      \"evidence\": \"MS site mapping, S964 mutagenesis, vesicle formation assay; deubiquitination assay with procollagen IV trafficking and collagen secretion readouts\",\n      \"pmids\": [\"29913562\", \"29604273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc and ubiquitin pathways not integrated\", \"Cul3 ubiquitination shown only by inference here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established SEC31A as essential for ER homeostasis and cell survival and causal for human neurological disease via a loss-of-function nonsense mutation.\",\n      \"evidence\": \"Whole exome sequencing, CRISPR/Cas9 knockout, ER-stress and viability assays, and Drosophila orthologue knockdown\",\n      \"pmids\": [\"30464055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family/study\", \"Cell-type basis of neurological phenotype not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected COPII/SEC31A to autophagy by showing a SEC31A\\u2013ATG9a interaction required for autophagosome formation during osteogenic differentiation.\",\n      \"evidence\": \"Co-IP, siRNA, autophagosome quantification, and in vitro/in vivo osteogenesis assays\",\n      \"pmids\": [\"39361436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular detail of how COPII contributes membrane to autophagosomes unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified p125A/Sec23IP binding via the SEC31A C-terminal helical domain as essential for outer-coat assembly and collagen tunnel traffic, and ULK1 phosphorylation as a glucose-starvation switch reorganizing COPII to remodel the cell surface.\",\n      \"evidence\": \"Cell-free reconstitution and domain deletion (preprint); AMPK/ULK1 perturbation with cell-surface proteomics, migration and metastasis assays (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.07.652703\", \"bio_10.1101_2025.10.31.685804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both findings are preprints not yet peer-reviewed\", \"ULK1 phosphosite(s) on SEC31A not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that tissue-specific regulation of SEC31A function occurs through RBM47-controlled alternative splicing that tunes large lipid-cargo secretion, adding a transcript-level layer to COPII control.\",\n      \"evidence\": \"Cross-tissue RNA-seq, minigene splicing assay, RBM47 perturbation, and lipid transport assay\",\n      \"pmids\": [\"40436629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Functional protein consequence of the alternative exon not structurally characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked SEC31A to insulin signaling and stress survival in pancreatic alpha cells via an insulin receptor interaction, hinting at a tissue-specific signaling role for ER export.\",\n      \"evidence\": \"Genome-wide CRISPR screen, single Co-IP, and loss-of-function survival assays in alpha cell lines and C. elegans\",\n      \"pmids\": [\"41093834\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"Pathway mechanism connecting ER export to insulin receptor unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers (Ca2+/ALG-2, O-GlcNAcylation, ubiquitination/deubiquitination, ULK1 phosphorylation, splicing) are integrated to select between standard COPII vesicles and large carriers for specific cargoes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating the PTM and adaptor inputs\", \"Cargo-selective carrier-size control mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"COPII coat (Sec13/31)\", \"ER exit site\"],\n    \"partners\": [\"PDCD6\", \"ANXA11\", \"SEC23IP\", \"ATG9A\", \"USP8\", \"STAM\", \"INSR\", \"ALK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}