{"gene":"SAR1B","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2021,"finding":"SAR1B functions as an intracellular leucine sensor: under leucine deficiency, SAR1B physically binds to and inhibits GATOR2 (an mTORC1 activator), thereby suppressing mTORC1 signaling; upon leucine sufficiency, SAR1B binds leucine directly, undergoes a conformational change, and dissociates from GATOR2, permitting mTORC1 activation.","method":"Biochemical binding assays, co-immunoprecipitation, conformational change analysis, and genetic knockdown/knockout experiments in cells and mouse tumor models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assays with conformational change validation, epistasis through GATOR2, and in vivo genetic models; published in Nature with multiple orthogonal methods","pmids":["34290409"],"is_preprint":false},{"year":2012,"finding":"In native intestinal cytosol, SAR1B forms a 75-kDa multiprotein complex with FABP1, Sec13, and small VCP/p97-interactive protein. Phosphorylation of SAR1B by PKCζ (requiring ATP) disassembles this complex, freeing FABP1 to bind to intestinal endoplasmic reticulum and generate the pre-chylomicron transport vesicle (PCTV). Without PKCζ or ATP, the complex remains intact and FABP1 cannot bind ER.","method":"Gel filtration chromatography, anti-FABP1 antibody pulldown, LC-MS/MS, MALDI-TOF identification of complex members, native PAGE, in vitro phosphorylation assay with PKCζ, ER binding and PCTV budding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of complex assembly/disassembly, direct identification of complex components by MS, phosphorylation-dependent functional readout (PCTV budding), multiple orthogonal methods in single study","pmids":["22303004"],"is_preprint":false},{"year":2004,"finding":"SAR1B (Sar1b) is an essential component of the COPII vesicle coat machinery responsible for transporting chylomicrons from the endoplasmic reticulum to the Golgi apparatus in enterocytes; mutations in SAR1B result in retention of chylomicron-like particles in membrane-bound compartments.","method":"Crystallographic analysis of Sar1-Sec23/24 complex (reviewed); genetic disease association with functional inference from chylomicron retention disease patients","journal":"Current opinion in lipidology","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — structural data (crystal structure of Sar1-Sec23/24 complex) combined with disease genetics establishing pathway position, but this is a review synthesizing prior work","pmids":["15017362"],"is_preprint":false},{"year":2011,"finding":"Overexpression of SAR1B in Caco-2/15 cells increases COPII complex assembly (elevated Sec12, Sec23/Sec24, and p125/Sec23-interacting protein by co-immunoprecipitation), enhances chylomicron production, augments triacylglycerol/cholesteryl ester/phospholipid esterification and secretion, stimulates monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity, enhances apolipoprotein B-48 synthesis, and elevates microsomal triglyceride transfer protein (MTP) activity. Additionally, Sec23/Sec24 interact with SREBP cleavage-activating protein and SREBP-1c, facilitating nuclear transfer of SREBP-1c for lipid metabolism gene activation.","method":"Overexpression in Caco-2/15 cells, co-immunoprecipitation, enzyme activity assays (MGAT/DGAT, MTP), Western blot, lipid secretion measurements","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying COPII complex interactions, multiple functional readouts (lipid synthesis, enzyme activity), single lab but orthogonal methods","pmids":["21836065"],"is_preprint":false},{"year":2012,"finding":"Human SAR1B (and SAR1A) proteins lower the mechanical rigidity of membranes to which they bind in vitro (measured by optical trap assay), consistent with a role in membrane deformation during vesicle formation. At high concentrations, membrane rigidity increases and protein mobility decreases, suggesting a clustering-dependent regulation of membrane mechanical properties distinct from yeast Sar1.","method":"Optical trap-based in vitro membrane deformation assay measuring bending rigidity; protein mobility measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution assay measuring membrane mechanical properties, single lab, single method","pmids":["22974979"],"is_preprint":false},{"year":2017,"finding":"Complete knockout of SAR1B (via zinc finger nuclease) in Caco-2/15 cells reduces triglyceride secretion (~40%), apolipoprotein B-48 secretion (~57%), and chylomicron output (~34.5%). A compensatory upregulation of SAR1A partially substitutes. Double knockout of SAR1A and SAR1B leads to near-complete inhibition of triglyceride, apoB-48, and chylomicron secretion, demonstrating functional redundancy. SAR1B loss also impairs HDL biogenesis and cholesterol efflux to apoA-I, associated with reduced ABCA1 expression.","method":"Zinc finger nuclease-mediated gene knockout in Caco-2/15 cells, double knockout engineering, radiolabeled cholesterol transport assays, Western blot, lipoprotein secretion measurements","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, double-KO epistasis establishing functional redundancy with SAR1A, multiple lipid transport readouts, single lab","pmids":["28982670"],"is_preprint":false},{"year":2018,"finding":"SAR1A and SAR1B regulate ER exit and cell-surface trafficking of the cardiac sodium channel Nav1.5. Dominant-negative SAR1B mutants (T39N or H79G) reduce Nav1.5 surface expression and peak sodium current density. Simultaneous knockdown of both SAR1A and SAR1B, but not single knockdown alone, reduces Nav1.5 current density. SAR1A and SAR1B co-immunoprecipitate with MOG1, and SAR1B/A are required for MOG1-mediated increases in Nav1.5 surface trafficking.","method":"Overexpression of dominant-negative mutants, siRNA knockdown, co-immunoprecipitation, electrophysiology (patch clamp), cell surface biotinylation in HEK/Nav1.5 cells and neonatal rat cardiomyocytes","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying SAR1B-MOG1 interaction, dominant-negative and knockdown with electrophysiological readout, multiple methods, single lab","pmids":["30251687"],"is_preprint":false},{"year":2019,"finding":"SAR1B deletion in Caco-2/15 cells disrupts lipid homeostasis by enhancing mitochondrial fatty acid β-oxidation and diminishing lipogenesis, mediated through PPARα and PGC1α transcription factors. SAR1B knockout cells also spontaneously exhibit inflammatory and oxidative stress characteristics via NF-κB and NRF2 pathway activation.","method":"CRISPR-Cas9 knockout of SAR1A, SAR1B, and SAR1A/B in Caco-2/15 cells; measurement of fatty acid β-oxidation, lipogenesis, ROS, inflammatory markers; Western blot and gene expression analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined metabolic phenotypes, transcription factor pathway placement, multiple orthogonal readouts, single lab","pmids":["31409740"],"is_preprint":false},{"year":2021,"finding":"Genetic deletion or mutation of Sar1b in mice (CRISPR-Cas9) causes late-gestation lethality in homozygotes. Heterozygous mice show reduced plasma triglycerides, total cholesterol, and HDL-cholesterol; reduced chylomicron secretion after gastric lipid gavage; decreased intestinal apolipoprotein B and MTP expression; accumulation of mucosal lipids; increased fecal lipid excretion; and altered fatty acid β-oxidation and lipogenesis.","method":"CRISPR-Cas9 mouse gene deletion and mutation, lipid gavage challenge, plasma and fecal lipid measurements, histology, Western blot, gene expression analysis","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mammalian genetic model with defined lipid transport phenotype, multiple quantitative readouts, single lab","pmids":["33964306"],"is_preprint":false},{"year":2024,"finding":"SAR1A and SAR1B are functionally interchangeable in vivo: mice engineered to express the Sar1a coding sequence at the endogenous Sar1b locus survive normally and are phenotypically normal, demonstrating near-complete functional overlap. Hepatocyte-specific deletion of Sar1b causes hypocholesterolemia that is rescued equally by adenoviral overexpression of either SAR1A or SAR1B.","method":"Knock-in mice (Sar1a coding sequence at Sar1b locus), hepatocyte-specific Sar1b conditional KO, adenoviral rescue experiments, plasma cholesterol measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic knock-in and conditional KO with functional rescue establishing functional redundancy, multiple in vivo genetic models, published in PNAS","pmids":["38687799"],"is_preprint":false},{"year":2020,"finding":"Knockdown of Sar1b in developing mouse neocortex inhibits radial migration of newborn cortical neurons without affecting progenitor proliferation or mitotic exit; neurons stalled in white matter fail to develop axons across the corpus callosum midline and are subsequently lost. The CMRD-associated human mutant hSAR1B(D137N) also impairs cortical neuron positioning, suggesting a dominant-negative effect. This demonstrates a cell-autonomous function of SAR1B in cortical development independent of intestinal lipid absorption.","method":"In utero electroporation-mediated Sar1b knockdown and dominant-negative mutant expression in mouse neocortex, immunofluorescence, neuronal position and axon morphology analysis","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular migration phenotype and dominant-negative mutant validation in vivo, single lab, two approaches (knockdown + disease mutant)","pmids":["33002559"],"is_preprint":false},{"year":2015,"finding":"SAR1B overexpression in Caco-2/15 cells promotes cholesterol transport and metabolism: it reduces cellular cholesterol content while elevating cholesterol secretion in chylomicrons when cells are incubated with oleic acid-containing micelles. Overexpression also decreases the phosphorylated/non-phosphorylated HMG-CoA reductase ratio (indicating elevated enzymatic activity) and reduces expression of intestinal cholesterol transporters NPC1L1 and SR-BI and metabolic regulators PCSK9 and LDLR.","method":"Overexpression in Caco-2/15 cells, cholesterol transport assays, Western blot for lipid metabolism regulators, enzyme activity measurements","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression with downstream expression changes but limited direct mechanistic linkage; indirect readouts","pmids":["25826777"],"is_preprint":false},{"year":2015,"finding":"In a zebrafish Sar1b knockdown model, Sar1b deficiency causes dietary lipid accumulation in enterocytes; Sar1b is required for growth of exocrine pancreas and liver; and Sar1b deficiency causes defects in procollagen II secretion and abnormal differentiation of craniofacial cartilage, as well as loss of select neuroD-positive neurons.","method":"Antisense oligonucleotide morpholino knockdown in zebrafish, transgenic reporter expression, histology, immunostaining for procollagen II and neuroD","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with multiple specific phenotypic readouts (lipid accumulation, procollagen secretion, neuronal differentiation), zebrafish as vertebrate model","pmids":["25559265"],"is_preprint":false}],"current_model":"SAR1B is a small GTPase that initiates COPII vesicle coat assembly at the ER membrane, driving anterograde transport of cargo including chylomicrons and Nav1.5 from the ER to the Golgi; in enterocytes, PKCζ-mediated phosphorylation of SAR1B releases it from a cytosolic FABP1-containing complex to enable pre-chylomicron transport vesicle budding; beyond its trafficking role, SAR1B acts as an intracellular leucine sensor that directly binds leucine, undergoes a conformational change, and dissociates from the mTORC1 activator GATOR2 to permit mTORC1 activation, coupling amino acid sensing to cell growth signaling; SAR1B also has cell-autonomous functions in cortical neuron migration and is functionally redundant with its paralog SAR1A in vivo."},"narrative":{"mechanistic_narrative":"SAR1B is a small GTPase that nucleates COPII vesicle coat assembly at the endoplasmic reticulum to drive ER-to-Golgi anterograde transport, and it also functions as an intracellular amino acid sensor that couples nutrient status to growth signaling [PMID:34290409, PMID:15017362]. In its trafficking role, SAR1B recruits and organizes the COPII machinery—Sec12, Sec23/Sec24, and the Sec23-interacting protein p125—and lowers membrane bending rigidity to promote vesicle budding [PMID:21836065, PMID:22974979]. In enterocytes this activity is required for chylomicron export: SAR1B resides in a cytosolic complex with FABP1, Sec13, and a VCP/p97-interactive protein, and PKCζ-mediated, ATP-dependent phosphorylation disassembles the complex to free FABP1 for ER binding and pre-chylomicron transport vesicle budding [PMID:22303004]. Loss of SAR1B reduces triglyceride, apoB-48, and chylomicron secretion, impairs HDL biogenesis, and reprograms lipid homeostasis toward mitochondrial β-oxidation through PPARα/PGC1α with concomitant NF-κB and NRF2 activation; SAR1A compensates for these defects and the two paralogs are functionally interchangeable in vivo [PMID:28982670, PMID:31409740, PMID:38687799]. Beyond lipid handling, SAR1B governs ER exit of the cardiac sodium channel Nav1.5 in concert with MOG1 [PMID:30251687] and is required cell-autonomously for radial migration of cortical neurons [PMID:33002559]. As a leucine sensor, SAR1B binds and inhibits the mTORC1 activator GATOR2 under leucine deficiency, and upon direct leucine binding it undergoes a conformational change, dissociates from GATOR2, and permits mTORC1 activation [PMID:34290409]. Mutations in SAR1B cause chylomicron retention disease, reflecting failed ER export of chylomicron-like particles [PMID:15017362, PMID:33002559].","teleology":[{"year":2004,"claim":"Established SAR1B's pathway position by linking it to the COPII coat and to a human lipid-malabsorption disorder, defining its role in ER-to-Golgi chylomicron export.","evidence":"Crystallographic analysis of the Sar1-Sec23/24 complex combined with chylomicron retention disease genetics","pmids":["15017362"],"confidence":"Medium","gaps":["Review synthesis rather than primary mechanistic experiment","Does not resolve SAR1B-specific versus SAR1A-specific contributions","No direct cellular loss-of-function data"]},{"year":2011,"claim":"Showed SAR1B gain-of-function amplifies COPII assembly and the entire enterocyte lipid-handling program, positioning it upstream of chylomicron synthesis and secretion.","evidence":"Overexpression in Caco-2/15 cells with co-IP of COPII components and lipid enzyme/secretion assays","pmids":["21836065"],"confidence":"Medium","gaps":["Overexpression may not reflect physiological stoichiometry","Single lab","Causal link between COPII assembly and SREBP-1c nuclear transfer not directly tested"]},{"year":2012,"claim":"Resolved how SAR1B is gated for chylomicron vesicle budding, defining a phosphorylation switch that disassembles a cytosolic holding complex to license FABP1-driven PCTV formation.","evidence":"Gel filtration, MS identification of complex members, in vitro PKCζ phosphorylation, and PCTV budding assays in intestinal cytosol","pmids":["22303004"],"confidence":"High","gaps":["Phosphorylation site on SAR1B not mapped","Relationship to GTPase cycle unresolved","In vivo relevance of the cytosolic complex not tested"]},{"year":2012,"claim":"Provided a biophysical mechanism for budding by showing SAR1B directly lowers membrane bending rigidity, with concentration-dependent clustering effects.","evidence":"Optical trap-based in vitro membrane deformation and protein mobility assay","pmids":["22974979"],"confidence":"Medium","gaps":["Single in vitro method","Physiological concentration regime unclear","Functional consequence of clustering not tested in cells"]},{"year":2015,"claim":"Extended SAR1B requirement beyond intestine in a whole-vertebrate context, implicating it in secretion of procollagen and in pancreas, liver, and neuronal development.","evidence":"Morpholino knockdown in zebrafish with histology and procollagen II/neuroD immunostaining","pmids":["25559265"],"confidence":"Medium","gaps":["Morpholino off-target effects not fully excluded","No genetic rescue","Mechanism of tissue-specific cargo dependence unknown"]},{"year":2017,"claim":"Defined the cellular loss-of-function phenotype and established functional redundancy with SAR1A through double-knockout epistasis.","evidence":"ZFN single and double knockout of SAR1A/SAR1B in Caco-2/15 cells with lipoprotein and cholesterol efflux assays","pmids":["28982670"],"confidence":"Medium","gaps":["Single cell-line model","ABCA1 downregulation mechanism not resolved","Does not distinguish direct from indirect effects on HDL biogenesis"]},{"year":2018,"claim":"Identified a non-lipid cargo by showing SAR1A/B control ER exit of Nav1.5 via MOG1, broadening SAR1B's substrate range to ion channels.","evidence":"Dominant-negative mutants, siRNA, co-IP, surface biotinylation, and patch-clamp in HEK/Nav1.5 cells and cardiomyocytes","pmids":["30251687"],"confidence":"Medium","gaps":["Single knockdown insufficient, indicating redundancy not isolated to SAR1B","Direct SAR1B-Nav1.5 contact not shown","Mechanism of MOG1 cooperation unresolved"]},{"year":2019,"claim":"Connected SAR1B loss to a transcriptional reprogramming of lipid metabolism and to oxidative/inflammatory stress, linking trafficking failure to downstream metabolic and stress pathways.","evidence":"CRISPR knockout in Caco-2/15 cells with β-oxidation, lipogenesis, ROS, and inflammatory readouts","pmids":["31409740"],"confidence":"Medium","gaps":["Causal chain from ER-exit defect to PPARα/NF-κB/NRF2 activation not delineated","Single cell-line model","In vivo confirmation lacking"]},{"year":2020,"claim":"Revealed a cell-autonomous developmental role independent of lipid absorption by showing SAR1B is required for cortical neuron radial migration, with a disease mutant acting dominant-negatively.","evidence":"In utero electroporation knockdown and hSAR1B(D137N) expression in mouse neocortex with positional and axon analysis","pmids":["33002559"],"confidence":"Medium","gaps":["Cargo responsible for migration defect unidentified","Dominant-negative mechanism inferred not proven","Single lab"]},{"year":2021,"claim":"Reframed SAR1B as a direct intracellular leucine sensor coupling amino acid abundance to mTORC1 through GATOR2, a function distinct from vesicle coating.","evidence":"Direct binding assays with conformational change analysis, GATOR2 epistasis, and knockdown/knockout in cells and mouse tumor models","pmids":["34290409"],"confidence":"High","gaps":["Relationship between GTPase cycle and leucine sensing unresolved","Structural basis of leucine binding not defined here","Tissue contexts where this dominates over trafficking unclear"]},{"year":2021,"claim":"Provided an in vivo mammalian genetic model showing SAR1B is essential for development and required for systemic lipid homeostasis and intestinal chylomicron export.","evidence":"CRISPR-Cas9 mouse deletion/mutation with lipid gavage, plasma/fecal lipid, histology, and expression analyses","pmids":["33964306"],"confidence":"Medium","gaps":["Homozygous lethality limits adult tissue analysis","Cause of late-gestation lethality not defined","Heterozygote phenotypes only partially penetrant"]},{"year":2024,"claim":"Demonstrated near-complete functional interchangeability of SAR1A and SAR1B in vivo, resolving why single-paralog loss is often buffered.","evidence":"Sar1a knock-in at the Sar1b locus, hepatocyte-specific conditional KO, and adenoviral rescue with either paralog","pmids":["38687799"],"confidence":"High","gaps":["Does not address whether leucine-sensing function is equally redundant","Tissue-specific differences in expression not fully resolved","Mechanistic basis of any residual non-redundancy unknown"]},{"year":null,"claim":"How SAR1B's GTPase nucleotide cycle is mechanistically integrated with both its membrane-deforming COPII role and its leucine-sensing/GATOR2 dissociation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking leucine binding to nucleotide state","Whether trafficking and mTORC1-sensing functions are competitive or compartmentally separated is unknown","Direct cargo-selection determinants beyond chylomicrons, Nav1.5, and procollagen unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,6]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6]}],"complexes":["COPII coat","SAR1B-FABP1-Sec13-VCP/p97-interactive protein cytosolic complex"],"partners":["GATOR2","FABP1","SEC13","SEC23","SEC24","MOG1","SAR1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6B6","full_name":"Small COPII coat GTPase SAR1B","aliases":["GTP-binding protein B","GTBPB","Secretion-associated Ras-related GTPase 1B"],"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 (PubMed:23433038, PubMed:32358066, PubMed:33186557, PubMed:36369712). 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:33186557). In contrast to SAR1A, SAR1B specifically interacts with the cargo receptor SURF4 to mediate the transport of lipid-carrying lipoproteins including APOB and APOA1 from the endoplasmic reticulum to the Golgi and thereby, indirectly regulates lipid homeostasis (PubMed:32358066, PubMed:33186557). 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/Q9Y6B6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SAR1B","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000152700","cell_line_id":"CID000905","localizations":[{"compartment":"golgi","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"HSP90B1","stoichiometry":10.0},{"gene":"SAR1B;DKFZP434B2017","stoichiometry":10.0},{"gene":"PARK7","stoichiometry":4.0},{"gene":"EIF4H","stoichiometry":4.0},{"gene":"IDH1","stoichiometry":0.2},{"gene":"WDR1","stoichiometry":0.2},{"gene":"GAPDH","stoichiometry":0.2},{"gene":"TUBB4A","stoichiometry":0.2},{"gene":"P4HB","stoichiometry":0.2},{"gene":"PYGL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000905","total_profiled":1310},"omim":[{"mim_id":"610511","title":"SEC23 HOMOLOG A, COAT COMPLEX II COMPONENT; SEC23A","url":"https://www.omim.org/entry/610511"},{"mim_id":"608005","title":"SIL1 NUCLEOTIDE EXCHANGE FACTOR; SIL1","url":"https://www.omim.org/entry/608005"},{"mim_id":"607691","title":"SECRETION-ASSOCIATED RAS-RELATED GTPase 1A; SAR1A","url":"https://www.omim.org/entry/607691"},{"mim_id":"607690","title":"SECRETION-ASSOCIATED RAS-RELATED GTPase 1B; SAR1B","url":"https://www.omim.org/entry/607690"},{"mim_id":"248800","title":"MARINESCO-SJOGREN SYNDROME; MSS","url":"https://www.omim.org/entry/248800"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SAR1B"},"hgnc":{"alias_symbol":[],"prev_symbol":["SARA2"]},"alphafold":{"accession":"Q9Y6B6","domains":[{"cath_id":"3.40.50.300","chopping":"2-196","consensus_level":"high","plddt":86.6967,"start":2,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6B6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6B6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6B6-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SAR1B","jax_strain_url":"https://www.jax.org/strain/search?query=SAR1B"},"sequence":{"accession":"Q9Y6B6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6B6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6B6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6B6"}},"corpus_meta":[{"pmid":"34290409","id":"PMC_34290409","title":"SAR1B senses leucine levels to regulate mTORC1 signalling.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34290409","citation_count":172,"is_preprint":false},{"pmid":"17945526","id":"PMC_17945526","title":"Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.","date":"2007","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17945526","citation_count":70,"is_preprint":false},{"pmid":"15017362","id":"PMC_15017362","title":"The intracellular transport of chylomicrons requires the small GTPase, Sar1b.","date":"2004","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/15017362","citation_count":53,"is_preprint":false},{"pmid":"28982670","id":"PMC_28982670","title":"Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture.","date":"2017","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28982670","citation_count":41,"is_preprint":false},{"pmid":"25559265","id":"PMC_25559265","title":"Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.","date":"2015","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/25559265","citation_count":40,"is_preprint":false},{"pmid":"21836065","id":"PMC_21836065","title":"Expression of Sar1b enhances chylomicron assembly and key components of the coat protein complex II system driving vesicle budding.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21836065","citation_count":38,"is_preprint":false},{"pmid":"18786134","id":"PMC_18786134","title":"Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities.","date":"2008","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18786134","citation_count":34,"is_preprint":false},{"pmid":"31409740","id":"PMC_31409740","title":"SAR1B GTPase is necessary to protect intestinal cells from disorders of lipid homeostasis, oxidative stress, and inflammation.","date":"2019","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/31409740","citation_count":34,"is_preprint":false},{"pmid":"22303004","id":"PMC_22303004","title":"Phosphorylation of Sar1b protein releases liver fatty acid-binding protein from multiprotein complex in intestinal cytosol enabling it to bind to endoplasmic reticulum (ER) and bud the pre-chylomicron transport vesicle.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22303004","citation_count":33,"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":"32327549","id":"PMC_32327549","title":"COPII Components Sar1b and Sar1c Play Distinct Yet Interchangeable Roles in Pollen Development.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32327549","citation_count":29,"is_preprint":false},{"pmid":"23043934","id":"PMC_23043934","title":"Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/23043934","citation_count":25,"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. 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patients.","date":"2019","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/30782561","citation_count":14,"is_preprint":false},{"pmid":"24969168","id":"PMC_24969168","title":"Tissue distribution and regulation of the small Sar1b GTPase in mice.","date":"2014","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24969168","citation_count":11,"is_preprint":false},{"pmid":"25826777","id":"PMC_25826777","title":"New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25826777","citation_count":9,"is_preprint":false},{"pmid":"37558128","id":"PMC_37558128","title":"High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.","date":"2023","source":"Journal of lipid 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Phosphorylation of SAR1B by PKCζ (requiring ATP) disassembles this complex, freeing FABP1 to bind to intestinal endoplasmic reticulum and generate the pre-chylomicron transport vesicle (PCTV). Without PKCζ or ATP, the complex remains intact and FABP1 cannot bind ER.\",\n      \"method\": \"Gel filtration chromatography, anti-FABP1 antibody pulldown, LC-MS/MS, MALDI-TOF identification of complex members, native PAGE, in vitro phosphorylation assay with PKCζ, ER binding and PCTV budding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of complex assembly/disassembly, direct identification of complex components by MS, phosphorylation-dependent functional readout (PCTV budding), multiple orthogonal methods in single study\",\n      \"pmids\": [\"22303004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SAR1B (Sar1b) is an essential component of the COPII vesicle coat machinery responsible for transporting chylomicrons from the endoplasmic reticulum to the Golgi apparatus in enterocytes; mutations in SAR1B result in retention of chylomicron-like particles in membrane-bound compartments.\",\n      \"method\": \"Crystallographic analysis of Sar1-Sec23/24 complex (reviewed); genetic disease association with functional inference from chylomicron retention disease patients\",\n      \"journal\": \"Current opinion in lipidology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — structural data (crystal structure of Sar1-Sec23/24 complex) combined with disease genetics establishing pathway position, but this is a review synthesizing prior work\",\n      \"pmids\": [\"15017362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of SAR1B in Caco-2/15 cells increases COPII complex assembly (elevated Sec12, Sec23/Sec24, and p125/Sec23-interacting protein by co-immunoprecipitation), enhances chylomicron production, augments triacylglycerol/cholesteryl ester/phospholipid esterification and secretion, stimulates monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity, enhances apolipoprotein B-48 synthesis, and elevates microsomal triglyceride transfer protein (MTP) activity. Additionally, Sec23/Sec24 interact with SREBP cleavage-activating protein and SREBP-1c, facilitating nuclear transfer of SREBP-1c for lipid metabolism gene activation.\",\n      \"method\": \"Overexpression in Caco-2/15 cells, co-immunoprecipitation, enzyme activity assays (MGAT/DGAT, MTP), Western blot, lipid secretion measurements\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying COPII complex interactions, multiple functional readouts (lipid synthesis, enzyme activity), single lab but orthogonal methods\",\n      \"pmids\": [\"21836065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human SAR1B (and SAR1A) proteins lower the mechanical rigidity of membranes to which they bind in vitro (measured by optical trap assay), consistent with a role in membrane deformation during vesicle formation. At high concentrations, membrane rigidity increases and protein mobility decreases, suggesting a clustering-dependent regulation of membrane mechanical properties distinct from yeast Sar1.\",\n      \"method\": \"Optical trap-based in vitro membrane deformation assay measuring bending rigidity; protein mobility measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution assay measuring membrane mechanical properties, single lab, single method\",\n      \"pmids\": [\"22974979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Complete knockout of SAR1B (via zinc finger nuclease) in Caco-2/15 cells reduces triglyceride secretion (~40%), apolipoprotein B-48 secretion (~57%), and chylomicron output (~34.5%). A compensatory upregulation of SAR1A partially substitutes. Double knockout of SAR1A and SAR1B leads to near-complete inhibition of triglyceride, apoB-48, and chylomicron secretion, demonstrating functional redundancy. SAR1B loss also impairs HDL biogenesis and cholesterol efflux to apoA-I, associated with reduced ABCA1 expression.\",\n      \"method\": \"Zinc finger nuclease-mediated gene knockout in Caco-2/15 cells, double knockout engineering, radiolabeled cholesterol transport assays, Western blot, lipoprotein secretion measurements\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, double-KO epistasis establishing functional redundancy with SAR1A, multiple lipid transport readouts, single lab\",\n      \"pmids\": [\"28982670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SAR1A and SAR1B regulate ER exit and cell-surface trafficking of the cardiac sodium channel Nav1.5. Dominant-negative SAR1B mutants (T39N or H79G) reduce Nav1.5 surface expression and peak sodium current density. Simultaneous knockdown of both SAR1A and SAR1B, but not single knockdown alone, reduces Nav1.5 current density. SAR1A and SAR1B co-immunoprecipitate with MOG1, and SAR1B/A are required for MOG1-mediated increases in Nav1.5 surface trafficking.\",\n      \"method\": \"Overexpression of dominant-negative mutants, siRNA knockdown, co-immunoprecipitation, electrophysiology (patch clamp), cell surface biotinylation in 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 — co-IP identifying SAR1B-MOG1 interaction, dominant-negative and knockdown with electrophysiological readout, multiple methods, single lab\",\n      \"pmids\": [\"30251687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SAR1B deletion in Caco-2/15 cells disrupts lipid homeostasis by enhancing mitochondrial fatty acid β-oxidation and diminishing lipogenesis, mediated through PPARα and PGC1α transcription factors. SAR1B knockout cells also spontaneously exhibit inflammatory and oxidative stress characteristics via NF-κB and NRF2 pathway activation.\",\n      \"method\": \"CRISPR-Cas9 knockout of SAR1A, SAR1B, and SAR1A/B in Caco-2/15 cells; measurement of fatty acid β-oxidation, lipogenesis, ROS, inflammatory markers; Western blot and gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined metabolic phenotypes, transcription factor pathway placement, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"31409740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic deletion or mutation of Sar1b in mice (CRISPR-Cas9) causes late-gestation lethality in homozygotes. Heterozygous mice show reduced plasma triglycerides, total cholesterol, and HDL-cholesterol; reduced chylomicron secretion after gastric lipid gavage; decreased intestinal apolipoprotein B and MTP expression; accumulation of mucosal lipids; increased fecal lipid excretion; and altered fatty acid β-oxidation and lipogenesis.\",\n      \"method\": \"CRISPR-Cas9 mouse gene deletion and mutation, lipid gavage challenge, plasma and fecal lipid measurements, histology, Western blot, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mammalian genetic model with defined lipid transport phenotype, multiple quantitative readouts, single lab\",\n      \"pmids\": [\"33964306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SAR1A and SAR1B are functionally interchangeable in vivo: mice engineered to express the Sar1a coding sequence at the endogenous Sar1b locus survive normally and are phenotypically normal, demonstrating near-complete functional overlap. Hepatocyte-specific deletion of Sar1b causes hypocholesterolemia that is rescued equally by adenoviral overexpression of either SAR1A or SAR1B.\",\n      \"method\": \"Knock-in mice (Sar1a coding sequence at Sar1b locus), hepatocyte-specific Sar1b conditional KO, adenoviral rescue experiments, plasma cholesterol measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic knock-in and conditional KO with functional rescue establishing functional redundancy, multiple in vivo genetic models, published in PNAS\",\n      \"pmids\": [\"38687799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of Sar1b in developing mouse neocortex inhibits radial migration of newborn cortical neurons without affecting progenitor proliferation or mitotic exit; neurons stalled in white matter fail to develop axons across the corpus callosum midline and are subsequently lost. The CMRD-associated human mutant hSAR1B(D137N) also impairs cortical neuron positioning, suggesting a dominant-negative effect. This demonstrates a cell-autonomous function of SAR1B in cortical development independent of intestinal lipid absorption.\",\n      \"method\": \"In utero electroporation-mediated Sar1b knockdown and dominant-negative mutant expression in mouse neocortex, immunofluorescence, neuronal position and axon morphology analysis\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular migration phenotype and dominant-negative mutant validation in vivo, single lab, two approaches (knockdown + disease mutant)\",\n      \"pmids\": [\"33002559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SAR1B overexpression in Caco-2/15 cells promotes cholesterol transport and metabolism: it reduces cellular cholesterol content while elevating cholesterol secretion in chylomicrons when cells are incubated with oleic acid-containing micelles. Overexpression also decreases the phosphorylated/non-phosphorylated HMG-CoA reductase ratio (indicating elevated enzymatic activity) and reduces expression of intestinal cholesterol transporters NPC1L1 and SR-BI and metabolic regulators PCSK9 and LDLR.\",\n      \"method\": \"Overexpression in Caco-2/15 cells, cholesterol transport assays, Western blot for lipid metabolism regulators, enzyme activity measurements\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression with downstream expression changes but limited direct mechanistic linkage; indirect readouts\",\n      \"pmids\": [\"25826777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In a zebrafish Sar1b knockdown model, Sar1b deficiency causes dietary lipid accumulation in enterocytes; Sar1b is required for growth of exocrine pancreas and liver; and Sar1b deficiency causes defects in procollagen II secretion and abnormal differentiation of craniofacial cartilage, as well as loss of select neuroD-positive neurons.\",\n      \"method\": \"Antisense oligonucleotide morpholino knockdown in zebrafish, transgenic reporter expression, histology, immunostaining for procollagen II and neuroD\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with multiple specific phenotypic readouts (lipid accumulation, procollagen secretion, neuronal differentiation), zebrafish as vertebrate model\",\n      \"pmids\": [\"25559265\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SAR1B is a small GTPase that initiates COPII vesicle coat assembly at the ER membrane, driving anterograde transport of cargo including chylomicrons and Nav1.5 from the ER to the Golgi; in enterocytes, PKCζ-mediated phosphorylation of SAR1B releases it from a cytosolic FABP1-containing complex to enable pre-chylomicron transport vesicle budding; beyond its trafficking role, SAR1B acts as an intracellular leucine sensor that directly binds leucine, undergoes a conformational change, and dissociates from the mTORC1 activator GATOR2 to permit mTORC1 activation, coupling amino acid sensing to cell growth signaling; SAR1B also has cell-autonomous functions in cortical neuron migration and is functionally redundant with its paralog SAR1A in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SAR1B is a small GTPase that nucleates COPII vesicle coat assembly at the endoplasmic reticulum to drive ER-to-Golgi anterograde transport, and it also functions as an intracellular amino acid sensor that couples nutrient status to growth signaling [#0, #2]. In its trafficking role, SAR1B recruits and organizes the COPII machinery—Sec12, Sec23/Sec24, and the Sec23-interacting protein p125—and lowers membrane bending rigidity to promote vesicle budding [#3, #4]. In enterocytes this activity is required for chylomicron export: SAR1B resides in a cytosolic complex with FABP1, Sec13, and a VCP/p97-interactive protein, and PKCζ-mediated, ATP-dependent phosphorylation disassembles the complex to free FABP1 for ER binding and pre-chylomicron transport vesicle budding [#1]. Loss of SAR1B reduces triglyceride, apoB-48, and chylomicron secretion, impairs HDL biogenesis, and reprograms lipid homeostasis toward mitochondrial β-oxidation through PPARα/PGC1α with concomitant NF-κB and NRF2 activation; SAR1A compensates for these defects and the two paralogs are functionally interchangeable in vivo [#5, #7, #9]. Beyond lipid handling, SAR1B governs ER exit of the cardiac sodium channel Nav1.5 in concert with MOG1 [#6] and is required cell-autonomously for radial migration of cortical neurons [#10]. As a leucine sensor, SAR1B binds and inhibits the mTORC1 activator GATOR2 under leucine deficiency, and upon direct leucine binding it undergoes a conformational change, dissociates from GATOR2, and permits mTORC1 activation [#0]. Mutations in SAR1B cause chylomicron retention disease, reflecting failed ER export of chylomicron-like particles [#2, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established SAR1B's pathway position by linking it to the COPII coat and to a human lipid-malabsorption disorder, defining its role in ER-to-Golgi chylomicron export.\",\n      \"evidence\": \"Crystallographic analysis of the Sar1-Sec23/24 complex combined with chylomicron retention disease genetics\",\n      \"pmids\": [\"15017362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Review synthesis rather than primary mechanistic experiment\", \"Does not resolve SAR1B-specific versus SAR1A-specific contributions\", \"No direct cellular loss-of-function data\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed SAR1B gain-of-function amplifies COPII assembly and the entire enterocyte lipid-handling program, positioning it upstream of chylomicron synthesis and secretion.\",\n      \"evidence\": \"Overexpression in Caco-2/15 cells with co-IP of COPII components and lipid enzyme/secretion assays\",\n      \"pmids\": [\"21836065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression may not reflect physiological stoichiometry\", \"Single lab\", \"Causal link between COPII assembly and SREBP-1c nuclear transfer not directly tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how SAR1B is gated for chylomicron vesicle budding, defining a phosphorylation switch that disassembles a cytosolic holding complex to license FABP1-driven PCTV formation.\",\n      \"evidence\": \"Gel filtration, MS identification of complex members, in vitro PKCζ phosphorylation, and PCTV budding assays in intestinal cytosol\",\n      \"pmids\": [\"22303004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site on SAR1B not mapped\", \"Relationship to GTPase cycle unresolved\", \"In vivo relevance of the cytosolic complex not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided a biophysical mechanism for budding by showing SAR1B directly lowers membrane bending rigidity, with concentration-dependent clustering effects.\",\n      \"evidence\": \"Optical trap-based in vitro membrane deformation and protein mobility assay\",\n      \"pmids\": [\"22974979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro method\", \"Physiological concentration regime unclear\", \"Functional consequence of clustering not tested in cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SAR1B requirement beyond intestine in a whole-vertebrate context, implicating it in secretion of procollagen and in pancreas, liver, and neuronal development.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with histology and procollagen II/neuroD immunostaining\",\n      \"pmids\": [\"25559265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects not fully excluded\", \"No genetic rescue\", \"Mechanism of tissue-specific cargo dependence unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the cellular loss-of-function phenotype and established functional redundancy with SAR1A through double-knockout epistasis.\",\n      \"evidence\": \"ZFN single and double knockout of SAR1A/SAR1B in Caco-2/15 cells with lipoprotein and cholesterol efflux assays\",\n      \"pmids\": [\"28982670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell-line model\", \"ABCA1 downregulation mechanism not resolved\", \"Does not distinguish direct from indirect effects on HDL biogenesis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a non-lipid cargo by showing SAR1A/B control ER exit of Nav1.5 via MOG1, broadening SAR1B's substrate range to ion channels.\",\n      \"evidence\": \"Dominant-negative mutants, siRNA, co-IP, surface biotinylation, and patch-clamp in HEK/Nav1.5 cells and cardiomyocytes\",\n      \"pmids\": [\"30251687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single knockdown insufficient, indicating redundancy not isolated to SAR1B\", \"Direct SAR1B-Nav1.5 contact not shown\", \"Mechanism of MOG1 cooperation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected SAR1B loss to a transcriptional reprogramming of lipid metabolism and to oxidative/inflammatory stress, linking trafficking failure to downstream metabolic and stress pathways.\",\n      \"evidence\": \"CRISPR knockout in Caco-2/15 cells with β-oxidation, lipogenesis, ROS, and inflammatory readouts\",\n      \"pmids\": [\"31409740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal chain from ER-exit defect to PPARα/NF-κB/NRF2 activation not delineated\", \"Single cell-line model\", \"In vivo confirmation lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a cell-autonomous developmental role independent of lipid absorption by showing SAR1B is required for cortical neuron radial migration, with a disease mutant acting dominant-negatively.\",\n      \"evidence\": \"In utero electroporation knockdown and hSAR1B(D137N) expression in mouse neocortex with positional and axon analysis\",\n      \"pmids\": [\"33002559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo responsible for migration defect unidentified\", \"Dominant-negative mechanism inferred not proven\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reframed SAR1B as a direct intracellular leucine sensor coupling amino acid abundance to mTORC1 through GATOR2, a function distinct from vesicle coating.\",\n      \"evidence\": \"Direct binding assays with conformational change analysis, GATOR2 epistasis, and knockdown/knockout in cells and mouse tumor models\",\n      \"pmids\": [\"34290409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between GTPase cycle and leucine sensing unresolved\", \"Structural basis of leucine binding not defined here\", \"Tissue contexts where this dominates over trafficking unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided an in vivo mammalian genetic model showing SAR1B is essential for development and required for systemic lipid homeostasis and intestinal chylomicron export.\",\n      \"evidence\": \"CRISPR-Cas9 mouse deletion/mutation with lipid gavage, plasma/fecal lipid, histology, and expression analyses\",\n      \"pmids\": [\"33964306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homozygous lethality limits adult tissue analysis\", \"Cause of late-gestation lethality not defined\", \"Heterozygote phenotypes only partially penetrant\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated near-complete functional interchangeability of SAR1A and SAR1B in vivo, resolving why single-paralog loss is often buffered.\",\n      \"evidence\": \"Sar1a knock-in at the Sar1b locus, hepatocyte-specific conditional KO, and adenoviral rescue with either paralog\",\n      \"pmids\": [\"38687799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address whether leucine-sensing function is equally redundant\", \"Tissue-specific differences in expression not fully resolved\", \"Mechanistic basis of any residual non-redundancy unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SAR1B's GTPase nucleotide cycle is mechanistically integrated with both its membrane-deforming COPII role and its leucine-sensing/GATOR2 dissociation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking leucine binding to nucleotide state\", \"Whether trafficking and mTORC1-sensing functions are competitive or compartmentally separated is unknown\", \"Direct cargo-selection determinants beyond chylomicrons, Nav1.5, and procollagen unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"COPII coat\", \"SAR1B-FABP1-Sec13-VCP/p97-interactive protein cytosolic complex\"],\n    \"partners\": [\"GATOR2\", \"FABP1\", \"SEC13\", \"SEC23\", \"SEC24\", \"MOG1\", \"SAR1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}