Affinage

SAR1B

Small COPII coat GTPase SAR1B · UniProt Q9Y6B6

Length
198 aa
Mass
22.4 kDa
Annotated
2026-06-10
34 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Medium

    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

    PMID:15017362

    Open questions at the time
    • Review synthesis rather than primary mechanistic experiment
    • Does not resolve SAR1B-specific versus SAR1A-specific contributions
    • No direct cellular loss-of-function data
  2. 2011 Medium

    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

    PMID:21836065

    Open questions at the time
    • Overexpression may not reflect physiological stoichiometry
    • Single lab
    • Causal link between COPII assembly and SREBP-1c nuclear transfer not directly tested
  3. 2012 High

    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

    PMID:22303004

    Open questions at the time
    • Phosphorylation site on SAR1B not mapped
    • Relationship to GTPase cycle unresolved
    • In vivo relevance of the cytosolic complex not tested
  4. 2012 Medium

    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

    PMID:22974979

    Open questions at the time
    • Single in vitro method
    • Physiological concentration regime unclear
    • Functional consequence of clustering not tested in cells
  5. 2015 Medium

    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

    PMID:25559265

    Open questions at the time
    • Morpholino off-target effects not fully excluded
    • No genetic rescue
    • Mechanism of tissue-specific cargo dependence unknown
  6. 2017 Medium

    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

    PMID:28982670

    Open questions at the time
    • Single cell-line model
    • ABCA1 downregulation mechanism not resolved
    • Does not distinguish direct from indirect effects on HDL biogenesis
  7. 2018 Medium

    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

    PMID:30251687

    Open questions at the time
    • Single knockdown insufficient, indicating redundancy not isolated to SAR1B
    • Direct SAR1B-Nav1.5 contact not shown
    • Mechanism of MOG1 cooperation unresolved
  8. 2019 Medium

    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

    PMID:31409740

    Open questions at the time
    • Causal chain from ER-exit defect to PPARα/NF-κB/NRF2 activation not delineated
    • Single cell-line model
    • In vivo confirmation lacking
  9. 2020 Medium

    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

    PMID:33002559

    Open questions at the time
    • Cargo responsible for migration defect unidentified
    • Dominant-negative mechanism inferred not proven
    • Single lab
  10. 2021 High

    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

    PMID:34290409

    Open questions at the time
    • Relationship between GTPase cycle and leucine sensing unresolved
    • Structural basis of leucine binding not defined here
    • Tissue contexts where this dominates over trafficking unclear
  11. 2021 Medium

    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

    PMID:33964306

    Open questions at the time
    • Homozygous lethality limits adult tissue analysis
    • Cause of late-gestation lethality not defined
    • Heterozygote phenotypes only partially penetrant
  12. 2024 High

    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

    PMID:38687799

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SAR1B's GTPase nucleotide cycle is mechanistically integrated with both its membrane-deforming COPII role and its leucine-sensing/GATOR2 dissociation remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 2 GO:0008289 lipid binding 1 GO:0098772 molecular function regulator activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 1 R-HSA-9609507 Protein localization 1
Partners
FABP1GATOR2MOG1SAR1ASEC13SEC23SEC24
Complex memberships
COPII coatSAR1B-FABP1-Sec13-VCP/p97-interactive protein cytosolic complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 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. Biochemical binding assays, co-immunoprecipitation, conformational change analysis, and genetic knockdown/knockout experiments in cells and mouse tumor models Nature High 34290409
2012 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. 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 The Journal of biological chemistry High 22303004
2004 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. Crystallographic analysis of Sar1-Sec23/24 complex (reviewed); genetic disease association with functional inference from chylomicron retention disease patients Current opinion in lipidology Medium 15017362
2011 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. Overexpression in Caco-2/15 cells, co-immunoprecipitation, enzyme activity assays (MGAT/DGAT, MTP), Western blot, lipid secretion measurements Arteriosclerosis, thrombosis, and vascular biology Medium 21836065
2012 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. Optical trap-based in vitro membrane deformation assay measuring bending rigidity; protein mobility measurements Biochemical and biophysical research communications Medium 22974979
2017 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. Zinc finger nuclease-mediated gene knockout in Caco-2/15 cells, double knockout engineering, radiolabeled cholesterol transport assays, Western blot, lipoprotein secretion measurements Arteriosclerosis, thrombosis, and vascular biology Medium 28982670
2018 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. Overexpression of dominant-negative mutants, siRNA knockdown, co-immunoprecipitation, electrophysiology (patch clamp), cell surface biotinylation in HEK/Nav1.5 cells and neonatal rat cardiomyocytes Biochimica et biophysica acta. Molecular basis of disease Medium 30251687
2019 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. 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 of lipid research Medium 31409740
2021 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. CRISPR-Cas9 mouse gene deletion and mutation, lipid gavage challenge, plasma and fecal lipid measurements, histology, Western blot, gene expression analysis Journal of lipid research Medium 33964306
2024 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. Knock-in mice (Sar1a coding sequence at Sar1b locus), hepatocyte-specific Sar1b conditional KO, adenoviral rescue experiments, plasma cholesterol measurements Proceedings of the National Academy of Sciences of the United States of America High 38687799
2020 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. In utero electroporation-mediated Sar1b knockdown and dominant-negative mutant expression in mouse neocortex, immunofluorescence, neuronal position and axon morphology analysis Neuroscience Medium 33002559
2015 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. Overexpression in Caco-2/15 cells, cholesterol transport assays, Western blot for lipid metabolism regulators, enzyme activity measurements Journal of cellular biochemistry Low 25826777
2015 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. Antisense oligonucleotide morpholino knockdown in zebrafish, transgenic reporter expression, histology, immunostaining for procollagen II and neuroD Journal of molecular medicine (Berlin, Germany) Medium 25559265

Source papers

Stage 0 corpus · 34 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 SAR1B senses leucine levels to regulate mTORC1 signalling. Nature 172 34290409
2007 Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. Molecular genetics and metabolism 70 17945526
2004 The intracellular transport of chylomicrons requires the small GTPase, Sar1b. Current opinion in lipidology 53 15017362
2017 Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture. Arteriosclerosis, thrombosis, and vascular biology 41 28982670
2015 Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease. Journal of molecular medicine (Berlin, Germany) 40 25559265
2011 Expression of Sar1b enhances chylomicron assembly and key components of the coat protein complex II system driving vesicle budding. Arteriosclerosis, thrombosis, and vascular biology 38 21836065
2019 SAR1B GTPase is necessary to protect intestinal cells from disorders of lipid homeostasis, oxidative stress, and inflammation. Journal of lipid research 34 31409740
2008 Anderson's disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities. Clinical genetics 34 18786134
2012 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. The Journal of biological chemistry 33 22303004
2012 Modulation of membrane rigidity by the human vesicle trafficking proteins Sar1A and Sar1B. Biochemical and biophysical research communications 30 22974979
2020 COPII Components Sar1b and Sar1c Play Distinct Yet Interchangeable Roles in Pollen Development. Plant physiology 29 32327549
2012 Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia. Gene 25 23043934
2021 Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease. Journal of lipid research 22 33964306
2018 Small GTPases SAR1A and SAR1B regulate the trafficking of the cardiac sodium channel Nav1.5. Biochimica et biophysica acta. Molecular basis of disease 22 30251687
2014 Sar1b transgenic male mice are more susceptible to high-fat diet-induced obesity, insulin insensitivity and intestinal chylomicron overproduction. The Journal of nutritional biochemistry 20 24657056
2011 Anderson's disease/chylomicron retention disease in a Japanese patient with uniparental disomy 7 and a normal SAR1B gene protein coding sequence. Orphanet journal of rare diseases 20 22104167
2009 Variable phenotypic expression of chylomicron retention disease in a kindred carrying a mutation of the Sara2 gene. Metabolism: clinical and experimental 18 19846172
2024 Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo. Proceedings of the National Academy of Sciences of the United States of America 14 38687799
2019 Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: Evidence supporting polygenicity in mutation-negative patients. Atherosclerosis 14 30782561
2014 Tissue distribution and regulation of the small Sar1b GTPase in mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 11 24969168
2015 New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis. Journal of cellular biochemistry 9 25826777
2023 High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism. Journal of lipid research 7 37558128
2020 Knockdown of SAR1B suppresses proliferation and induces apoptosis of RKO colorectal cancer cells. Oncology letters 7 32952655
2020 Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons. Neuroscience 6 33002559
2019 Novel mutations of SAR1B gene in four children with chylomicron retention disease. Journal of clinical lipidology 6 31253576
2005 Expression of Sara2 human gene in erythroid progenitors. Journal of biochemistry and molecular biology 6 15943909
2021 Chylomicron retention disease caused by a new pathogenic variant in sar1b protein: a rare case report from Syria. BMC pediatrics 4 34629076
2024 [Chylomicron retention disease caused by SAR1B gene variations in 2 cases and literatures review]. Zhonghua er ke za zhi = Chinese journal of pediatrics 2 38763880
2006 Sequence identification, tissue distribution, mapping and polymorphism of the porcine sar1b gene. Animal biotechnology 2 16621763
2026 Dietary phospholipids alleviate high fat diet-induced intestinal lipid deposition through ATF4-PPARα-MTTP/SAR1B pathway in yellow catfish. The Journal of nutritional biochemistry 1 41506489
2025 Advances in the basic function of the small GTPase SAR1B and its regulatory role in the biological behavior of tumor cells (Review). Molecular and clinical oncology 0 41220399
2024 Functional overlap between the mammalian Sar1a and Sar1b paralogs in vivo. bioRxiv : the preprint server for biology 0 38463989
2024 Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking. Biomedicines 0 39062121
2024 Study on the mechanism of SAR1B in sodium acetate promoting milk fat synthesis. In vitro cellular & developmental biology. Animal 0 39316237

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