{"gene":"SAR1A","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2012,"finding":"Human SAR1A (and SAR1B) lower the mechanical rigidity of membranes to which they bind in vitro, consistent with their role in sculpting highly curved COPII vesicles. At high concentrations, however, SAR1A increases bending rigidity and shows decreased protein mobility, implying that protein clustering governs membrane mechanical properties.","method":"Optical trap-based in vitro membrane deformation assay measuring bending rigidity","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro reconstitution assay, but single lab with no independent replication reported","pmids":["22974979"],"is_preprint":false},{"year":2015,"finding":"SAR1A GTPase dysfunction is the initiating event in ethanol-induced Golgi fragmentation in hepatocytes: loss of SAR1A activity impairs COPII vesicle formation, preventing ER-to-Golgi delivery of PDIA3 (protein disulfide isomerase A3), which in turn blocks giantin dimerization required for compact Golgi architecture. SAR1A gene silencing alone recapitulates this phenotype, arresting PDIA3 in the ER and causing large-scale Golgi fragmentation.","method":"siRNA knockdown of SAR1A in HepG2 cells and primary hepatocytes; immunofluorescence and Western blotting; ethanol-fed rat model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, validated in cell line and animal model, multiple orthogonal readouts, single lab","pmids":["26607390"],"is_preprint":false},{"year":2018,"finding":"Dominant-negative SAR1A mutants (T39N or H79G) reduce cell-surface expression of the cardiac sodium channel Nav1.5 and decrease peak sodium current density, establishing SAR1A as a regulator of Nav1.5 ER exit and trafficking. Simultaneous siRNA knockdown of SAR1A and SAR1B reduces current density, while single knockdown of either alone has minimal effect. Co-immunoprecipitation demonstrated that SAR1A physically interacts with MOG1, and SAR1A/SAR1B are required for MOG1-mediated increases in Nav1.5 surface expression.","method":"Dominant-negative overexpression, siRNA knockdown, patch-clamp electrophysiology (INa density), co-immunoprecipitation; HEK/Nav1.5 cells and neonatal rat cardiomyocytes","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, dominant-negative mutagenesis, electrophysiological readout, two orthogonal methods, single lab","pmids":["30251687"],"is_preprint":false},{"year":2018,"finding":"The C-terminal region of Sec23A and Sec23B (effector proteins of SAR1A) specifically binds the active, GTP-bound form of SAR1A. A pull-down assay using recombinant C-terminal Sec23B shows that GTP-bound SAR1A increases during neuronal process elongation and oligodendroglial morphological differentiation. The GEF PREB (prolactin regulatory element binding protein) increases binding to the nucleotide-free (activated) form of SAR1A during morphological differentiation.","method":"Affinity precipitation (pull-down) using recombinant C-terminal Sec23B; differentiation of N1E-115 neuronal and FBD-102b oligodendroglial cell lines","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant pull-down assay with GTP-state specificity validated in two cell lines, single lab","pmids":["30078678"],"is_preprint":false},{"year":2022,"finding":"TGF-β1 upregulates SAR1A expression in hypertrophic scar fibroblasts through a TAK1/JNK/p38 signaling axis (not the Smad3 or ERK pathway). siRNA knockdown of SAR1A suppresses procollagen-I secretion (but not collagen-1A mRNA expression), placing SAR1A downstream of TGF-β1/TAK1 signaling specifically in the post-translational secretory step.","method":"siRNA knockdown, kinase inhibitor pharmacology (TAK1, JNK, p38, Smad3, ERK inhibitors), Western blotting for procollagen-I secretion","journal":"Open medicine (Warsaw, Poland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via kinase inhibitors plus siRNA KD with defined secretion phenotype, single lab, multiple pathway inhibitors used","pmids":["36188194"],"is_preprint":false},{"year":2022,"finding":"SAR1A knockdown in osteosarcoma cells impairs invasion and migration, reduces lamellipodia formation, suppresses epithelial-mesenchymal transition markers, and decreases YAP activity downstream of RhoA. Knockdown also enhances ER stress, reactive oxygen species, and autophagic flux, and reduces lung metastases in vivo, placing SAR1A upstream of the RhoA/YAP axis and ER homeostasis in osteosarcoma metastasis.","method":"siRNA knockdown, wound healing and Transwell invasion assays, phalloidin staining, Western blotting, immunofluorescence, in vivo lung metastasis model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal phenotypic readouts in vitro and in vivo, single lab","pmids":["36047971"],"is_preprint":false},{"year":2024,"finding":"Genetic inactivation of Sar1a in mice causes lethality during mid-embryogenesis, demonstrating an essential in vivo role for SAR1A in COPII-mediated ER-to-Golgi trafficking. Replacement of the Sar1b coding sequence with Sar1a at the endogenous Sar1b locus rescues the perinatal lethality of Sar1b-null mice and produces phenotypically normal adults, establishing near-complete functional overlap between SAR1A and SAR1B in vivo.","method":"Conditional and constitutive gene knockout in mice; knock-in of Sar1a coding sequence at Sar1b locus; adenovirus-mediated overexpression rescue; phenotypic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via multiple engineered mouse alleles, rescue experiments, replicated in peer-reviewed publication and preprint","pmids":["38687799","38463989"],"is_preprint":false},{"year":2024,"finding":"SAR1A overexpression in CHO cells reduces intracellular antibody accumulation (especially in the ER) and increases specific antibody production rate, demonstrating that SAR1A enhances COPII vesicle-mediated ER-to-Golgi transport. Overexpression also lowered antibody glycan galactosylation and induced stronger unfolded protein response at end of culture.","method":"Stable overexpression in CHO cells, chase assay with translation inhibitor, immunofluorescence imaging, LC-MS glycosylation profiling, UPR gene expression analysis","journal":"Journal of bioscience and bioengineering","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple orthogonal readouts (chase assay, imaging, MS), single lab","pmids":["38806389"],"is_preprint":false},{"year":2025,"finding":"SAR1A requires K27-linked oligo-ubiquitination to assemble the STING-COPII transport complex, which mediates STING trafficking from the ER to the Golgi apparatus. USP1 (a deubiquitinase) removes this ubiquitination from SAR1A, thereby blocking STING trafficking and type I interferon production. Pharmacological inhibition of USP1 (with ML323) sustains SAR1A ubiquitination, promotes COPII complex formation, and enhances STING-dependent innate immune signaling.","method":"Chemical screening, ubiquitination assays, USP1 inhibitor (ML323) treatment, Co-IP of STING-COPII complex, STING trafficking assays, IFN production measurements in tumor microenvironment models","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, pharmacological and genetic manipulation, multiple functional readouts, single lab","pmids":["39976106"],"is_preprint":false},{"year":2025,"finding":"GLTP knockout alters the intracellular localization of SAR1A and of its activating GEF Sec12 at ER exit sites, suggesting that the GLTP/VAPA interaction modulates SAR1A activation state and COPII vesicle formation from the ER.","method":"GLTP knockout HeLa cells; immunofluorescence localization of SAR1A and Sec12; GLTP VAPA-binding mutant expression","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data from single lab preprint, indirect evidence of SAR1A regulation without direct functional rescue","pmids":["bio_10.1101_2025.06.17.657375"],"is_preprint":true}],"current_model":"SAR1A is a small GTPase that initiates COPII coat assembly at ER exit sites by recruiting coat proteins to the ER membrane, driving vesicular transport of secretory cargo (including Nav1.5, procollagen-I, and STING) from the ER to the Golgi; its activity is controlled by GTP/GDP cycling regulated by the GEF PREB and by K27-linked oligo-ubiquitination (removed by USP1), and it physically interacts with Sec23 effectors and MOG1, with loss of SAR1A causing Golgi fragmentation, impaired cargo secretion, and embryonic lethality in mice, while SAR1A and SAR1B are functionally interchangeable in vivo."},"narrative":{"mechanistic_narrative":"SAR1A is a small GTPase that initiates COPII coat assembly at ER exit sites to drive vesicular export of secretory cargo from the ER to the Golgi, and its genetic inactivation is lethal in mid-embryogenesis in mice, establishing an essential role in ER-to-Golgi trafficking [PMID:38687799, PMID:38463989]. SAR1A cycles between GTP- and GDP-bound states: its active, GTP-bound form is specifically engaged by the C-terminal region of the Sec23 effectors, with the GEF PREB promoting binding to the nucleotide-free activated form during cellular differentiation [PMID:30078678]. Membrane binding by SAR1A lowers bilayer bending rigidity in a manner consistent with sculpting highly curved COPII vesicles, while protein clustering at high density reverses this effect [PMID:22974979]. Through this coat-assembly activity SAR1A enables ER exit of diverse cargo, including the cardiac sodium channel Nav1.5 (via physical interaction with MOG1) [PMID:30251687], procollagen-I downstream of TGF-β1/TAK1/JNK/p38 signaling [PMID:36188194], the disulfide isomerase PDIA3 whose delivery maintains compact Golgi architecture [PMID:26607390], and secreted antibody in CHO cells [PMID:38806389]. SAR1A function is gated by K27-linked oligo-ubiquitination, which is required to assemble a STING-COPII transport complex driving STING trafficking and type I interferon production; the deubiquitinase USP1 removes this modification to block the pathway [PMID:39976106]. Loss of SAR1A causes Golgi fragmentation, impaired cargo secretion, and, in osteosarcoma, suppressed invasion and metastasis with elevated ER stress through a RhoA/YAP axis [PMID:26607390, PMID:36047971]. SAR1A and SAR1B are functionally interchangeable in vivo, as Sar1a knocked into the Sar1b locus rescues Sar1b-null lethality [PMID:38687799, PMID:38463989].","teleology":[{"year":2012,"claim":"Established the biophysical basis for how SAR1A could sculpt COPII vesicles, by showing it directly alters membrane mechanics rather than acting only as a scaffold.","evidence":"Optical trap-based in vitro membrane deformation assay measuring bending rigidity of SAR1A-bound bilayers","pmids":["22974979"],"confidence":"Medium","gaps":["No independent replication of the rigidity measurements","Does not connect membrane mechanics to coat assembly or cargo selection in cells"]},{"year":2015,"claim":"Showed that SAR1A loss alone is sufficient to disrupt Golgi architecture by blocking ER export of a specific cargo, linking COPII initiation to organelle integrity.","evidence":"siRNA knockdown in HepG2 cells and primary hepatocytes with ethanol-fed rat model; IF and Western blotting tracing PDIA3 and giantin","pmids":["26607390"],"confidence":"Medium","gaps":["Single lab; mechanism of SAR1A inactivation by ethanol not resolved","Whether PDIA3 is a direct or indirect cargo dependency not established"]},{"year":2018,"claim":"Defined the nucleotide-state logic of SAR1A activation, demonstrating GTP-bound SAR1A is selectively read by Sec23 effectors and that PREB acts as the activating GEF during differentiation.","evidence":"Recombinant C-terminal Sec23B pull-down with GTP-state specificity in differentiating neuronal and oligodendroglial cell lines","pmids":["30078678"],"confidence":"Medium","gaps":["Direct GEF activity of PREB on SAR1A not reconstituted biochemically","Cargo specificity during differentiation not identified"]},{"year":2018,"claim":"Identified SAR1A as a regulator of ion channel trafficking, connecting COPII export to cardiac sodium current via a physical MOG1 interaction.","evidence":"Dominant-negative mutants, dual SAR1A/SAR1B siRNA, patch-clamp, and co-IP in HEK/Nav1.5 cells and rat cardiomyocytes","pmids":["30251687"],"confidence":"Medium","gaps":["Functional redundancy with SAR1B obscures isoform-specific contribution","Whether MOG1 acts as a cargo adaptor or regulator of SAR1A not resolved"]},{"year":2022,"claim":"Placed SAR1A downstream of a defined signaling cascade in fibrosis, showing TGF-β1 raises SAR1A via TAK1/JNK/p38 to enable procollagen-I secretion at a post-translational step.","evidence":"siRNA knockdown plus kinase inhibitor epistasis and Western blotting in hypertrophic scar fibroblasts","pmids":["36188194"],"confidence":"Medium","gaps":["Transcriptional mechanism linking TAK1/JNK/p38 to SAR1A expression not defined","Single lab; no in vivo fibrosis validation"]},{"year":2022,"claim":"Connected SAR1A secretory function to cancer cell behavior, linking its loss to suppressed migration/EMT, ER stress, and reduced metastasis through a RhoA/YAP axis.","evidence":"siRNA knockdown with migration/invasion assays, phalloidin staining, and an in vivo lung metastasis model in osteosarcoma","pmids":["36047971"],"confidence":"Medium","gaps":["Mechanistic link between COPII function and RhoA/YAP activity not established","Single lab"]},{"year":2024,"claim":"Proved SAR1A is essential in vivo and that SAR1A and SAR1B are functionally interchangeable, resolving the question of isoform specificity at the organismal level.","evidence":"Multiple engineered mouse alleles including Sar1a knockout and Sar1a-into-Sar1b-locus knock-in with rescue analysis","pmids":["38687799","38463989"],"confidence":"High","gaps":["Does not explain why two isoforms are maintained if interchangeable","Tissue-specific roles in adult animals not dissected"]},{"year":2024,"claim":"Demonstrated that increasing SAR1A is rate-enhancing for ER-to-Golgi cargo flux, by showing overexpression relieves ER cargo accumulation and boosts secretion.","evidence":"Stable overexpression in CHO cells with chase assay, imaging, LC-MS glycan profiling, and UPR readouts","pmids":["38806389"],"confidence":"Medium","gaps":["Altered glycosylation and UPR induction indicate trade-offs not mechanistically explained","Single lab; specific to recombinant antibody cargo"]},{"year":2025,"claim":"Revealed post-translational gating of SAR1A by ubiquitination, showing K27-linked oligo-ubiquitination is required to build a STING-COPII complex and that USP1 reverses it to suppress innate immune signaling.","evidence":"Ubiquitination assays, USP1 inhibitor (ML323), co-IP of STING-COPII complex, and IFN/trafficking readouts in tumor microenvironment models","pmids":["39976106"],"confidence":"Medium","gaps":["E3 ligase adding the K27 ubiquitin not identified","How ubiquitination mechanistically licenses complex assembly not resolved"]},{"year":2025,"claim":"Implicated a lipid-transfer pathway in positioning SAR1A and its GEF Sec12 at ER exit sites, suggesting upstream control of SAR1A activation.","evidence":"GLTP knockout and VAPA-binding mutant in HeLa cells with IF localization of SAR1A and Sec12 (preprint)","pmids":["bio_10.1101_2025.06.17.657375"],"confidence":"Low","gaps":["Localization-only evidence without direct functional rescue","Preprint, not peer-reviewed; effect on COPII output not measured directly"]},{"year":null,"claim":"The full set of cargo-selection determinants and the E3 ligase/regulatory inputs that govern SAR1A activation in different tissues remain to be defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["E3 ligase responsible for K27 oligo-ubiquitination unknown","How distinct cargoes (Nav1.5, procollagen-I, STING, PDIA3) are selected by the same coat machinery unresolved","Reconstitution of PREB/Sec12 GEF activity on SAR1A lacking"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,7,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,8]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,6,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":["COPII coat","STING-COPII transport complex"],"partners":["SEC23A","SEC23B","PREB","MOG1","SAR1B","STING1","USP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR31","full_name":"Small COPII coat GTPase SAR1A","aliases":["COPII-associated small GTPase","Secretion-associated Ras-related GTPase 1A"],"length_aa":198,"mass_kda":22.4,"function":"Small GTPase that cycles between an active GTP-bound and an inactive GDP-bound state and mainly functions in vesicle-mediated endoplasmic reticulum (ER) to Golgi transport. The active GTP-bound form inserts into the endoplasmic reticulum membrane where it recruits the remainder of the coat protein complex II/COPII. The coat protein complex II assembling and polymerizing on endoplasmic reticulum membrane is responsible for both the sorting of cargos and the deformation and budding of membranes into vesicles destined to the Golgi (PubMed:23433038, PubMed:32358066, PubMed:36369712). The GTPase activity of SAR1 by controlling the timing of COPII budding regulates the size of the formed vesicles and is important for cargo selection depending on their size (PubMed:32358066). Together with SEC16A, forms the organized scaffold defining endoplasmic reticulum exit sites (ERES), some specific domains of the endoplasmic reticulum where COPII vesicles form (PubMed:17005010). In addition to its role in vesicle trafficking, can also function as a leucine sensor regulating TORC1 signaling and more indirectly cellular metabolism, growth and survival. In absence of leucine, interacts with the GATOR2 complex via MIOS and inhibits TORC1 signaling. The binding of leucine abrogates the interaction with GATOR2 and the inhibition of the TORC1 signaling. This function is completely independent of the GTPase activity of SAR1B (PubMed:34290409)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus, Golgi stack membrane; Cytoplasm, cytosol; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NR31/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SAR1A","classification":"Not Classified","n_dependent_lines":62,"n_total_lines":1208,"dependency_fraction":0.05132450331125828},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000079332","cell_line_id":"CID000904","localizations":[{"compartment":"golgi","grade":3},{"compartment":"mitochondria","grade":2},{"compartment":"er","grade":1}],"interactors":[{"gene":"BIN1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2},{"gene":"YIPF5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000904","total_profiled":1310},"omim":[{"mim_id":"621301","title":"PROLINE-RICH COILED-COIL PROTEIN 1; PRRC1","url":"https://www.omim.org/entry/621301"},{"mim_id":"612854","title":"SEC16 HOMOLOG A, ENDOPLASMIC RETICULUM EXPORT FACTOR; SEC16A","url":"https://www.omim.org/entry/612854"},{"mim_id":"610512","title":"SEC23 HOMOLOG B, COAT COMPLEX II COMPONENT; SEC23B","url":"https://www.omim.org/entry/610512"},{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"},{"mim_id":"607691","title":"SECRETION-ASSOCIATED RAS-RELATED GTPase 1A; SAR1A","url":"https://www.omim.org/entry/607691"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SAR1A"},"hgnc":{"alias_symbol":["SAR1","Sara"],"prev_symbol":["SARA1"]},"alphafold":{"accession":"Q9NR31","domains":[{"cath_id":"3.40.50.300","chopping":"1-198","consensus_level":"medium","plddt":86.1148,"start":1,"end":198}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR31","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR31-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR31-F1-predicted_aligned_error_v6.png","plddt_mean":86.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAR1A","jax_strain_url":"https://www.jax.org/strain/search?query=SAR1A"},"sequence":{"accession":"Q9NR31","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR31.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR31/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR31"}},"corpus_meta":[{"pmid":"18318767","id":"PMC_18318767","title":"Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia.","date":"2008","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/18318767","citation_count":42,"is_preprint":false},{"pmid":"32011035","id":"PMC_32011035","title":"Novel ASAP1-USP6, FAT1-USP6, SAR1A-USP6, and TNC-USP6 fusions in primary aneurysmal bone cyst.","date":"2020","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32011035","citation_count":34,"is_preprint":false},{"pmid":"22974979","id":"PMC_22974979","title":"Modulation of membrane rigidity by the human vesicle trafficking proteins Sar1A and Sar1B.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22974979","citation_count":30,"is_preprint":false},{"pmid":"26607390","id":"PMC_26607390","title":"Downregulation of the small GTPase SAR1A: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26607390","citation_count":23,"is_preprint":false},{"pmid":"30251687","id":"PMC_30251687","title":"Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Nav1.5.","date":"2018","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/30251687","citation_count":22,"is_preprint":false},{"pmid":"32884349","id":"PMC_32884349","title":"Circ-SAR1A Promotes Renal Cell Carcinoma Progression Through miR-382/YBX1 Axis.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32884349","citation_count":21,"is_preprint":false},{"pmid":"36047971","id":"PMC_36047971","title":"SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36047971","citation_count":14,"is_preprint":false},{"pmid":"38687799","id":"PMC_38687799","title":"Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/38687799","citation_count":14,"is_preprint":false},{"pmid":"35334496","id":"PMC_35334496","title":"Circ_SAR1A regulates the malignant behavior of lung cancer cells via the miR-21-5p/TXNIP axis.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35334496","citation_count":11,"is_preprint":false},{"pmid":"30078678","id":"PMC_30078678","title":"Pull down assay for GTP-bound form of Sar1a reveals its activation during morphological differentiation.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30078678","citation_count":11,"is_preprint":false},{"pmid":"39976106","id":"PMC_39976106","title":"Targeting USP1 Potentiates Radiation-Induced Type I IFN-Dependent Antitumor Immunity by Enhancing Oligo-Ubiquitinated SAR1A-Mediated STING Trafficking and Activation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39976106","citation_count":10,"is_preprint":false},{"pmid":"36188194","id":"PMC_36188194","title":"TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36188194","citation_count":7,"is_preprint":false},{"pmid":"38806389","id":"PMC_38806389","title":"Sar1A overexpression in Chinese hamster ovary cells and its effects on antibody productivity and secretion.","date":"2024","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/38806389","citation_count":6,"is_preprint":false},{"pmid":"39595043","id":"PMC_39595043","title":"SAR1A Induces Cell Growth and Epithelial-Mesenchymal Transition Through the PI3K/AKT/mTOR Pathway in Head and Neck Squamous Cell Carcinoma: An In Vitro and In Vivo Study.","date":"2024","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/39595043","citation_count":2,"is_preprint":false},{"pmid":"28499394","id":"PMC_28499394","title":"SAR1a promoter polymorphisms are not associated with fetal hemoglobin in patients with sickle cell disease from Cameroon.","date":"2017","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/28499394","citation_count":2,"is_preprint":false},{"pmid":"38463989","id":"PMC_38463989","title":"Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38463989","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.17.657375","title":"Glycolipid transfer protein modulates vesicular trafficking from the endoplasmic reticulum in HeLa cells","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.17.657375","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10826,"output_tokens":2918,"usd":0.038124,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10234,"output_tokens":3633,"usd":0.070998,"stage2_stop_reason":"end_turn"},"total_usd":0.109122,"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\": 2012,\n      \"finding\": \"Human SAR1A (and SAR1B) lower the mechanical rigidity of membranes to which they bind in vitro, consistent with their role in sculpting highly curved COPII vesicles. At high concentrations, however, SAR1A increases bending rigidity and shows decreased protein mobility, implying that protein clustering governs membrane mechanical properties.\",\n      \"method\": \"Optical trap-based in vitro membrane deformation assay measuring bending rigidity\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro reconstitution assay, but single lab with no independent replication reported\",\n      \"pmids\": [\"22974979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SAR1A GTPase dysfunction is the initiating event in ethanol-induced Golgi fragmentation in hepatocytes: loss of SAR1A activity impairs COPII vesicle formation, preventing ER-to-Golgi delivery of PDIA3 (protein disulfide isomerase A3), which in turn blocks giantin dimerization required for compact Golgi architecture. SAR1A gene silencing alone recapitulates this phenotype, arresting PDIA3 in the ER and causing large-scale Golgi fragmentation.\",\n      \"method\": \"siRNA knockdown of SAR1A in HepG2 cells and primary hepatocytes; immunofluorescence and Western blotting; ethanol-fed rat model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, validated in cell line and animal model, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"26607390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dominant-negative SAR1A mutants (T39N or H79G) reduce cell-surface expression of the cardiac sodium channel Nav1.5 and decrease peak sodium current density, establishing SAR1A as a regulator of Nav1.5 ER exit and trafficking. Simultaneous siRNA knockdown of SAR1A and SAR1B reduces current density, while single knockdown of either alone has minimal effect. Co-immunoprecipitation demonstrated that SAR1A physically interacts with MOG1, and SAR1A/SAR1B are required for MOG1-mediated increases in Nav1.5 surface expression.\",\n      \"method\": \"Dominant-negative overexpression, siRNA knockdown, patch-clamp electrophysiology (INa density), co-immunoprecipitation; HEK/Nav1.5 cells and neonatal rat cardiomyocytes\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, dominant-negative mutagenesis, electrophysiological readout, two orthogonal methods, single lab\",\n      \"pmids\": [\"30251687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The C-terminal region of Sec23A and Sec23B (effector proteins of SAR1A) specifically binds the active, GTP-bound form of SAR1A. A pull-down assay using recombinant C-terminal Sec23B shows that GTP-bound SAR1A increases during neuronal process elongation and oligodendroglial morphological differentiation. The GEF PREB (prolactin regulatory element binding protein) increases binding to the nucleotide-free (activated) form of SAR1A during morphological differentiation.\",\n      \"method\": \"Affinity precipitation (pull-down) using recombinant C-terminal Sec23B; differentiation of N1E-115 neuronal and FBD-102b oligodendroglial cell lines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant pull-down assay with GTP-state specificity validated in two cell lines, single lab\",\n      \"pmids\": [\"30078678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGF-β1 upregulates SAR1A expression in hypertrophic scar fibroblasts through a TAK1/JNK/p38 signaling axis (not the Smad3 or ERK pathway). siRNA knockdown of SAR1A suppresses procollagen-I secretion (but not collagen-1A mRNA expression), placing SAR1A downstream of TGF-β1/TAK1 signaling specifically in the post-translational secretory step.\",\n      \"method\": \"siRNA knockdown, kinase inhibitor pharmacology (TAK1, JNK, p38, Smad3, ERK inhibitors), Western blotting for procollagen-I secretion\",\n      \"journal\": \"Open medicine (Warsaw, Poland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via kinase inhibitors plus siRNA KD with defined secretion phenotype, single lab, multiple pathway inhibitors used\",\n      \"pmids\": [\"36188194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SAR1A knockdown in osteosarcoma cells impairs invasion and migration, reduces lamellipodia formation, suppresses epithelial-mesenchymal transition markers, and decreases YAP activity downstream of RhoA. Knockdown also enhances ER stress, reactive oxygen species, and autophagic flux, and reduces lung metastases in vivo, placing SAR1A upstream of the RhoA/YAP axis and ER homeostasis in osteosarcoma metastasis.\",\n      \"method\": \"siRNA knockdown, wound healing and Transwell invasion assays, phalloidin staining, Western blotting, immunofluorescence, in vivo lung metastasis model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal phenotypic readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"36047971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic inactivation of Sar1a in mice causes lethality during mid-embryogenesis, demonstrating an essential in vivo role for SAR1A in COPII-mediated ER-to-Golgi trafficking. Replacement of the Sar1b coding sequence with Sar1a at the endogenous Sar1b locus rescues the perinatal lethality of Sar1b-null mice and produces phenotypically normal adults, establishing near-complete functional overlap between SAR1A and SAR1B in vivo.\",\n      \"method\": \"Conditional and constitutive gene knockout in mice; knock-in of Sar1a coding sequence at Sar1b locus; adenovirus-mediated overexpression rescue; phenotypic analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via multiple engineered mouse alleles, rescue experiments, replicated in peer-reviewed publication and preprint\",\n      \"pmids\": [\"38687799\", \"38463989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SAR1A overexpression in CHO cells reduces intracellular antibody accumulation (especially in the ER) and increases specific antibody production rate, demonstrating that SAR1A enhances COPII vesicle-mediated ER-to-Golgi transport. Overexpression also lowered antibody glycan galactosylation and induced stronger unfolded protein response at end of culture.\",\n      \"method\": \"Stable overexpression in CHO cells, chase assay with translation inhibitor, immunofluorescence imaging, LC-MS glycosylation profiling, UPR gene expression analysis\",\n      \"journal\": \"Journal of bioscience and bioengineering\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple orthogonal readouts (chase assay, imaging, MS), single lab\",\n      \"pmids\": [\"38806389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SAR1A requires K27-linked oligo-ubiquitination to assemble the STING-COPII transport complex, which mediates STING trafficking from the ER to the Golgi apparatus. USP1 (a deubiquitinase) removes this ubiquitination from SAR1A, thereby blocking STING trafficking and type I interferon production. Pharmacological inhibition of USP1 (with ML323) sustains SAR1A ubiquitination, promotes COPII complex formation, and enhances STING-dependent innate immune signaling.\",\n      \"method\": \"Chemical screening, ubiquitination assays, USP1 inhibitor (ML323) treatment, Co-IP of STING-COPII complex, STING trafficking assays, IFN production measurements in tumor microenvironment models\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, pharmacological and genetic manipulation, multiple functional readouts, single lab\",\n      \"pmids\": [\"39976106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GLTP knockout alters the intracellular localization of SAR1A and of its activating GEF Sec12 at ER exit sites, suggesting that the GLTP/VAPA interaction modulates SAR1A activation state and COPII vesicle formation from the ER.\",\n      \"method\": \"GLTP knockout HeLa cells; immunofluorescence localization of SAR1A and Sec12; GLTP VAPA-binding mutant expression\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data from single lab preprint, indirect evidence of SAR1A regulation without direct functional rescue\",\n      \"pmids\": [\"bio_10.1101_2025.06.17.657375\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SAR1A is a small GTPase that initiates COPII coat assembly at ER exit sites by recruiting coat proteins to the ER membrane, driving vesicular transport of secretory cargo (including Nav1.5, procollagen-I, and STING) from the ER to the Golgi; its activity is controlled by GTP/GDP cycling regulated by the GEF PREB and by K27-linked oligo-ubiquitination (removed by USP1), and it physically interacts with Sec23 effectors and MOG1, with loss of SAR1A causing Golgi fragmentation, impaired cargo secretion, and embryonic lethality in mice, while SAR1A and SAR1B are functionally interchangeable in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAR1A is a small GTPase that initiates COPII coat assembly at ER exit sites to drive vesicular export of secretory cargo from the ER to the Golgi, and its genetic inactivation is lethal in mid-embryogenesis in mice, establishing an essential role in ER-to-Golgi trafficking [#6]. SAR1A cycles between GTP- and GDP-bound states: its active, GTP-bound form is specifically engaged by the C-terminal region of the Sec23 effectors, with the GEF PREB promoting binding to the nucleotide-free activated form during cellular differentiation [#3]. Membrane binding by SAR1A lowers bilayer bending rigidity in a manner consistent with sculpting highly curved COPII vesicles, while protein clustering at high density reverses this effect [#0]. Through this coat-assembly activity SAR1A enables ER exit of diverse cargo, including the cardiac sodium channel Nav1.5 (via physical interaction with MOG1) [#2], procollagen-I downstream of TGF-\\u03b21/TAK1/JNK/p38 signaling [#4], the disulfide isomerase PDIA3 whose delivery maintains compact Golgi architecture [#1], and secreted antibody in CHO cells [#7]. SAR1A function is gated by K27-linked oligo-ubiquitination, which is required to assemble a STING-COPII transport complex driving STING trafficking and type I interferon production; the deubiquitinase USP1 removes this modification to block the pathway [#8]. Loss of SAR1A causes Golgi fragmentation, impaired cargo secretion, and, in osteosarcoma, suppressed invasion and metastasis with elevated ER stress through a RhoA/YAP axis [#1, #5]. SAR1A and SAR1B are functionally interchangeable in vivo, as Sar1a knocked into the Sar1b locus rescues Sar1b-null lethality [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the biophysical basis for how SAR1A could sculpt COPII vesicles, by showing it directly alters membrane mechanics rather than acting only as a scaffold.\",\n      \"evidence\": \"Optical trap-based in vitro membrane deformation assay measuring bending rigidity of SAR1A-bound bilayers\",\n      \"pmids\": [\"22974979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication of the rigidity measurements\", \"Does not connect membrane mechanics to coat assembly or cargo selection in cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that SAR1A loss alone is sufficient to disrupt Golgi architecture by blocking ER export of a specific cargo, linking COPII initiation to organelle integrity.\",\n      \"evidence\": \"siRNA knockdown in HepG2 cells and primary hepatocytes with ethanol-fed rat model; IF and Western blotting tracing PDIA3 and giantin\",\n      \"pmids\": [\"26607390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; mechanism of SAR1A inactivation by ethanol not resolved\", \"Whether PDIA3 is a direct or indirect cargo dependency not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the nucleotide-state logic of SAR1A activation, demonstrating GTP-bound SAR1A is selectively read by Sec23 effectors and that PREB acts as the activating GEF during differentiation.\",\n      \"evidence\": \"Recombinant C-terminal Sec23B pull-down with GTP-state specificity in differentiating neuronal and oligodendroglial cell lines\",\n      \"pmids\": [\"30078678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF activity of PREB on SAR1A not reconstituted biochemically\", \"Cargo specificity during differentiation not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified SAR1A as a regulator of ion channel trafficking, connecting COPII export to cardiac sodium current via a physical MOG1 interaction.\",\n      \"evidence\": \"Dominant-negative mutants, dual SAR1A/SAR1B siRNA, patch-clamp, and co-IP in HEK/Nav1.5 cells and rat cardiomyocytes\",\n      \"pmids\": [\"30251687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional redundancy with SAR1B obscures isoform-specific contribution\", \"Whether MOG1 acts as a cargo adaptor or regulator of SAR1A not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SAR1A downstream of a defined signaling cascade in fibrosis, showing TGF-\\u03b21 raises SAR1A via TAK1/JNK/p38 to enable procollagen-I secretion at a post-translational step.\",\n      \"evidence\": \"siRNA knockdown plus kinase inhibitor epistasis and Western blotting in hypertrophic scar fibroblasts\",\n      \"pmids\": [\"36188194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mechanism linking TAK1/JNK/p38 to SAR1A expression not defined\", \"Single lab; no in vivo fibrosis validation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SAR1A secretory function to cancer cell behavior, linking its loss to suppressed migration/EMT, ER stress, and reduced metastasis through a RhoA/YAP axis.\",\n      \"evidence\": \"siRNA knockdown with migration/invasion assays, phalloidin staining, and an in vivo lung metastasis model in osteosarcoma\",\n      \"pmids\": [\"36047971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between COPII function and RhoA/YAP activity not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proved SAR1A is essential in vivo and that SAR1A and SAR1B are functionally interchangeable, resolving the question of isoform specificity at the organismal level.\",\n      \"evidence\": \"Multiple engineered mouse alleles including Sar1a knockout and Sar1a-into-Sar1b-locus knock-in with rescue analysis\",\n      \"pmids\": [\"38687799\", \"38463989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not explain why two isoforms are maintained if interchangeable\", \"Tissue-specific roles in adult animals not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that increasing SAR1A is rate-enhancing for ER-to-Golgi cargo flux, by showing overexpression relieves ER cargo accumulation and boosts secretion.\",\n      \"evidence\": \"Stable overexpression in CHO cells with chase assay, imaging, LC-MS glycan profiling, and UPR readouts\",\n      \"pmids\": [\"38806389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Altered glycosylation and UPR induction indicate trade-offs not mechanistically explained\", \"Single lab; specific to recombinant antibody cargo\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed post-translational gating of SAR1A by ubiquitination, showing K27-linked oligo-ubiquitination is required to build a STING-COPII complex and that USP1 reverses it to suppress innate immune signaling.\",\n      \"evidence\": \"Ubiquitination assays, USP1 inhibitor (ML323), co-IP of STING-COPII complex, and IFN/trafficking readouts in tumor microenvironment models\",\n      \"pmids\": [\"39976106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase adding the K27 ubiquitin not identified\", \"How ubiquitination mechanistically licenses complex assembly not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated a lipid-transfer pathway in positioning SAR1A and its GEF Sec12 at ER exit sites, suggesting upstream control of SAR1A activation.\",\n      \"evidence\": \"GLTP knockout and VAPA-binding mutant in HeLa cells with IF localization of SAR1A and Sec12 (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.17.657375\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization-only evidence without direct functional rescue\", \"Preprint, not peer-reviewed; effect on COPII output not measured directly\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full set of cargo-selection determinants and the E3 ligase/regulatory inputs that govern SAR1A activation in different tissues remain to be defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for K27 oligo-ubiquitination unknown\", \"How distinct cargoes (Nav1.5, procollagen-I, STING, PDIA3) are selected by the same coat machinery unresolved\", \"Reconstitution of PREB/Sec12 GEF activity on SAR1A lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GTPase activity\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GTPase activity\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 7, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"COPII coat\", \"STING-COPII transport complex\"],\n    \"partners\": [\"SEC23A\", \"SEC23B\", \"PREB\", \"MOG1\", \"SAR1B\", \"STING1\", \"USP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}