{"gene":"SLC38A1","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2000,"finding":"Human ATA1/SLC38A1 encodes a 487-amino acid protein with 11 putative transmembrane domains that mediates Na+-coupled transport of neutral amino acids (system A-specific substrate α-methylaminoisobutyric acid) with 1:1 Na+:amino acid stoichiometry and Km of ~0.89 mM; the gene maps to human chromosome 12.","method":"Heterologous expression in mammalian cells, radiotracer uptake assays, Na+-activation kinetics","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional reconstitution with kinetic characterization in heterologous expression system, single lab but multiple quantitative assays","pmids":["10891391"],"is_preprint":false},{"year":2003,"finding":"SNAT1 mediates electrogenic, Na+-driven transport of glutamine (K0.5 ~0.3 mM), alanine, and MeAIB with 1:1 Na+:amino acid stoichiometry; Na+ binding precedes amino acid in a simultaneous mechanism; Li+ substitutes for Na+ but reduces Vmax; the transporter generates Na+-dependent presteady-state currents and a nonsaturable cation leak. SNAT1 protein localizes to somata and proximal dendrites of glutamatergic and GABAergic neurons throughout adult CNS but is absent from nerve terminals and astrocytes; luminal ependymal expression also detected.","method":"Radiotracer uptake and electrophysiology (current/flux) in Xenopus oocytes; confocal laser-scanning immunofluorescence; mutagenesis/kinetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Xenopus oocytes with simultaneous flux and current measurements, stoichiometry determination, and detailed subcellular localization with multiple neuronal markers","pmids":["12684517"],"is_preprint":false},{"year":2001,"finding":"cAMP elevation (forskolin, cholera toxin, dibutyryl-cAMP) increases steady-state ATA1 (SLC38A1) mRNA levels and system A transport activity (increased Vmax, unchanged Km) in HepG2 cells; effect is blocked by protein kinase inhibitor H7, cycloheximide, and actinomycin D, indicating transcription- and translation-dependent upregulation.","method":"Northern blot/RT-PCR for mRNA levels; radiotracer MeAIB uptake assay; pharmacological inhibitors","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological probes with functional transport readout in cell culture, single lab","pmids":["11566196"],"is_preprint":false},{"year":2010,"finding":"SNAT1 contributes the majority (~75%) of system A amino acid transport activity in term human placental cytotrophoblast cells, as demonstrated by siRNA knockdown of SNAT1 significantly reducing MeAIB uptake; kinetic analysis resolved two transport systems consistent with SNAT1/SNAT2 (Km ~0.38 mM) and SNAT4 (Km ~45 mM).","method":"siRNA knockdown, 14C-MeAIB radiotracer uptake, kinetic (Michaelis-Menten) analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with quantitative transport readout and kinetic analysis, single lab","pmids":["20599747"],"is_preprint":false},{"year":2010,"finding":"Oxidative stress (H2O2) selectively upregulates SNAT1 protein expression in rat cardiomyocytes and enhances system A-mediated (αMeAIB-inhibitable) cysteine uptake; cysteine supplied via SNAT1 contributes to glutathione synthesis under oxidative conditions.","method":"qRT-PCR, Western blot, 35S-cysteine radiotracer uptake with oil filtration, glutathione enzymatic assay","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary methods (expression + functional uptake + metabolic readout) in primary cardiomyocytes, single lab","pmids":["20602128"],"is_preprint":false},{"year":2011,"finding":"SNAT1 (Snat1) localizes to luminal membranes of larger cortical microvessels in mouse brain but is absent from BBB capillaries (where Snat3 is expressed), as shown by in vivo biotinylation and immunofluorescence colocalization, indicating distinct vascular roles for system A vs. system N transporters.","method":"In vivo luminal membrane biotinylation, immunofluorescence colocalization with cellular markers","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular/vascular localization by two complementary methods (biotinylation + immunofluorescence) in vivo, single lab","pmids":["21364602"],"is_preprint":false},{"year":2015,"finding":"MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1/SLC38A1. In MeCP2-deficient microglia, SNAT1 overexpression causes glutamine-dependent mitochondrial dysfunction (proliferating mitochondria, increased ROS, increased O2 consumption but decreased ATP), and overproduction of glutamate leading to NMDA receptor-dependent neurotoxicity. These defects are rescued by mitochondria-targeted catalase or SS-31 antioxidant peptide.","method":"MeCP2 knockdown/KO mouse model, SNAT1 overexpression in microglia, mitochondrial functional assays (OCR, ATP), ROS measurement, neurotoxicity assay, mitochondria-targeted antioxidant rescue","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model combined with overexpression, multiple orthogonal functional readouts, and mechanistic rescue experiments","pmids":["25673846"],"is_preprint":false},{"year":2016,"finding":"Net glutamine uptake in HeLa and 143B cancer cells does not depend on ASCT2 (SLC1A5) but requires SNAT1 (SLC38A1) and SNAT2 (SLC38A2). ASCT2 deletion does not reduce cell growth but triggers an amino acid starvation response (GCN2 activation) and upregulates SNAT1 to replace ASCT2 functionally; combined GCN2 silencing in ASCT2−/− background reduces cancer cell growth.","method":"CRISPR/Cas9 knockout of ASCT2, siRNA knockdown of SNAT1/SNAT2, amino acid uptake assays, GCN2 silencing, cell growth assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic knockouts with functional uptake and growth assays; epistasis established by double-KO approach; two cell lines","pmids":["27129276"],"is_preprint":false},{"year":2016,"finding":"SNAT1 is an N-glycoprotein with three glycosylation sites at asparagine residues 251, 257, and 310 (N251 and N257 are primary sites). N-glycosylation-impaired mutants traffic normally to the cell surface but show significantly reduced glutamine (L-Gln) and MeAIB transport, indicating N-glycosylation is required for transport activity but not plasma membrane localization.","method":"N-glycosylation site mutagenesis, cell surface biotinylation, confocal immunofluorescence, 3H-MeAIB transport assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis combined with surface biotinylation and functional transport assay, single lab with multiple orthogonal methods","pmids":["27655909"],"is_preprint":false},{"year":2019,"finding":"Genetic disruption of Slc38a1 in mice impairs GABA synthesis, alters synaptic vesicle morphology in GABAergic presynapses, reduces vesicular GABA content, impairs critical period cortical plasticity, and affects high-frequency membrane oscillations and cortical processing.","method":"Slc38a1 knockout mice, GABA synthesis/content assays, electron microscopy of synaptic vesicles, electrophysiology, cortical plasticity assays","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple cellular and functional phenotypic readouts (biochemistry, ultrastructure, electrophysiology, plasticity)","pmids":["31050701"],"is_preprint":false},{"year":2019,"finding":"Neuron-specific deletion of Slc38a1 (using Synapsin I-Cre) reduces infarct size in mouse MCAO stroke model. SNAT1 promotes ischemic neuronal death via mTORC1 (p70S6K1 phosphorylation) activation; autophagy inhibitors abolish the neuroprotective effect of SNAT1 deficiency in vitro, placing SNAT1 upstream of mTORC1-autophagy-dependent neuronal death.","method":"Conditional Slc38a1 KO mice, MCAO model (TTC staining, MAP2-negative area), mTORC1 phosphorylation assays, rapamycin treatment, autophagy inhibitors, in vitro stroke culture","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO with in vivo stroke model plus in vitro mechanistic dissection using epistatic pharmacological rescue experiments","pmids":["31552299"],"is_preprint":false},{"year":2013,"finding":"Suppression of SNAT1 in breast cancer cells lowers phospho-Akt levels and inhibits cell growth, cell cycle progression, and induces apoptosis, linking SNAT1 activity to Akt signaling in cancer cells.","method":"shRNA knockdown of SNAT1, Western blot for p-Akt, cell viability, cell cycle, apoptosis assays","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with phenotypic and signaling readouts in cancer cells, single lab, no direct mechanistic linkage established","pmids":["23848995"],"is_preprint":false},{"year":2017,"finding":"Silencing SNAT1 in osteosarcoma cells reduces proliferation, colony formation, and migration in vitro and tumor growth in xenograft models, and decreases expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF, suggesting SNAT1 acts upstream of Akt/mTOR signaling in osteosarcoma.","method":"shRNA knockdown, xenograft mouse model, Western blot for signaling proteins, proliferation and migration assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft plus in vitro signaling assays, single lab","pmids":["29108276"],"is_preprint":false},{"year":2023,"finding":"SLC38A1 modulates hepatocellular carcinoma cell growth and migration via PI3K/AKT/mTOR signaling through glutamine-mediated energy metabolism; SLC38A1 knockdown suppresses this pathway.","method":"siRNA knockdown, Western blot for PI3K/AKT/mTOR pathway components, cell proliferation and migration assays","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with pathway readout, no direct biochemical linkage established","pmids":["37673823"],"is_preprint":false},{"year":2024,"finding":"OTUD5 deubiquitinase directly binds SLC38A1 (confirmed by Co-IP and mass spectrometry) and prevents its ubiquitin-mediated proteasomal degradation, thereby stabilizing SLC38A1 protein levels. OTUD5 knockdown reduces SLC38A1 protein but not mRNA; SLC38A1 silencing attenuates OTUD5-driven HCC cell proliferation.","method":"Mass spectrometry, co-immunoprecipitation, OTUD5 overexpression/knockdown, proteasome inhibitor treatment, Western blot, xenograft mouse model","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and mass spectrometry to identify interaction, functional epistasis with proteasomal degradation assay, single lab","pmids":["38658981"],"is_preprint":false},{"year":2024,"finding":"CENPA directly regulates transcriptional activity of SLC38A1, increasing glutamine uptake and metabolism to promote endometrial cancer progression; CENPA overexpression/silencing reciprocally modulates SLC38A1 expression and glutamine metabolism.","method":"ChIP or luciferase transcriptional reporter assay (CENPA binding to SLC38A1 promoter), CENPA overexpression/knockdown, glutamine uptake measurement, tumor xenograft assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional regulation by CENPA shown with promoter assay and reciprocal genetic manipulation, single lab","pmids":["38382691"],"is_preprint":false},{"year":2024,"finding":"METTL3-mediated m6A methylation of the SLC38A1 3'UTR enhances SLC38A1 mRNA stability through IGF2BP3 recruitment; METTL3 silencing reduces intracellular glutamine content and inhibits cervical cancer cell viability, which is reversed by SLC38A1 overexpression.","method":"RNA immunoprecipitation (RIP) for METTL3/IGF2BP3 on SLC38A1 3'UTR, mRNA stability assay, METTL3/SLC38A1 overexpression/knockdown, glutamine content assay, tumor xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay identifies writer and reader of m6A modification on SLC38A1, with functional epistasis, single lab","pmids":["38701556"],"is_preprint":false},{"year":2022,"finding":"DSCR3 directly binds internalized SLC38A1 and mediates its sorting into a recycling pathway back to the plasma membrane, maintaining surface SLC38A1 abundance and enhancing glutamine uptake in MGMT-deficient glioblastoma cells; DSCR3 or SLC38A1 silencing increases temozolomide sensitivity.","method":"Label-free quantitative proteomics (plasma membrane fraction), co-immunoprecipitation, immunofluorescence of recycling, siRNA knockdown, in vitro and orthotopic brain tumor model","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified interaction confirmed by Co-IP, immunofluorescence of trafficking, and functional consequence in vivo, single lab","pmids":["35187626"],"is_preprint":false},{"year":2014,"finding":"SNAT1 mediates L-citrulline transport into pulmonary arterial endothelial cells; SNAT1 siRNA knockdown reduces basal NO production and prevents L-citrulline-induced increases in NO production and eNOS dimer-to-monomer ratios in both normoxic and hypoxic conditions, establishing that SNAT1-mediated citrulline transport regulates eNOS coupling and NO signaling.","method":"siRNA knockdown of SNAT1, NO production assay, eNOS dimer-to-monomer ratio (Western blot under non-reducing conditions), normoxia/hypoxia culture","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal functional readouts (NO, eNOS coupling) in primary cells under two conditions, single lab","pmids":["24454923"],"is_preprint":false},{"year":2017,"finding":"Slc38a1 expression in brown adipose tissue is upregulated in obese mice in vivo and is induced in brown adipocytes by hypoxic stress through hypoxia-inducible factor-1α (HIF-1α), identifying HIF-1α as a transcriptional regulator of Slc38a1.","method":"In vivo obesity models (genetic and diet-induced), hypoxia treatment in brown adipocytes, HIF-1α manipulation, qRT-PCR and Western blot","journal":"Pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative in vivo plus in vitro HIF-1α manipulation without direct promoter mechanistic proof","pmids":["29065407"],"is_preprint":false},{"year":2023,"finding":"HPV16 E6 and E7 oncoproteins increase SNAT1 protein levels and stimulate glutaminolysis; cell proliferation in the presence of glutamine is partially dependent on SNAT1, as SNAT1 knockdown reduces proliferation and E6/E7-driven glutamine-dependent growth.","method":"HPV E6/E7 expression, E6/E7 siRNA knockdown, SNAT1 siRNA knockdown, glutamine dependence assay, cell proliferation assay","journal":"Viruses","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with proliferation readout, no direct mechanistic link between E6/E7 and SNAT1 transcription established","pmids":["36851539"],"is_preprint":false},{"year":2023,"finding":"SLC38A1 deficiency in Th1 cells (via CRISPR) reduces mTORC1 signaling and glycolytic activity, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation; SLC38A1 is required for Th1- but not Th17-driven autoimmune neuroinflammation (EAE) in a tissue-specific manner, while dispensable for lung inflammation.","method":"In vivo CRISPR screen, conditional genetic deletion, mTORC1 phosphorylation assay, metabolomics (glutamine, hexosamine pathway), glycolysis assay, EAE model, IBD model","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo CRISPR screen with conditional KO, mechanistic metabolic readouts (mTORC1, hexosamine pathway, redox), multiple disease models, and pharmacological validation","pmids":["41875885"],"is_preprint":false},{"year":2026,"finding":"In melanoma cells, SNAT1 does not primarily mediate glutamine influx but instead signals in response to extracellular glutamine levels. SNAT1 interacts with P62 (SQSTM1) (confirmed by Co-IP and AlphaFold3 in silico modeling) and activates P62/cMYC signaling axis to regulate melanoma cell metabolism depending on glutamine availability, suggesting SNAT1 acts as a glutamine 'transceptor' rather than solely a transporter.","method":"siPool-mediated SNAT1 knockdown, intracellular/extracellular glutamine measurement, Co-IP, AlphaFold3 in silico protein interaction modeling, qRT-PCR and Western blot, Seahorse flux analysis, flow cytometry for mitochondria","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms P62 interaction, Seahorse metabolic assay, glutamine transport measurement, multiple orthogonal methods; single lab and novel unexpected claim","pmids":["41976291"],"is_preprint":false},{"year":2026,"finding":"SLC38A1 overexpression in alveolar type II epithelial cells promotes chaperone-mediated autophagy (CMA) degradation of divalent metal transporter 1 (DMT1) by facilitating interactions among DMT1, HSP90, HSC70, and Lamp-2a, enhancing lysosomal translocation of DMT1. This reduces intracellular iron and inhibits ferroptosis in acute lung injury.","method":"AAV6-mediated SLC38A1 overexpression in vivo (mouse LPS-ALI model), lentiviral overexpression in primary ATII cells, co-immunoprecipitation for DMT1/HSP90/HSC70/Lamp-2a complex, Western blot, TUNEL staining, shRNA knockdowns (SLC38A1, ULK1, HSP90)","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies multi-protein complex, in vivo and in vitro rescue experiments, single lab, novel mechanism","pmids":["41483240"],"is_preprint":false},{"year":2016,"finding":"miR-593-3p targets Slc38a1 (and CLIP3) to negatively regulate insulin-promoted glucose consumption in HepG2 cells; insulin downregulates miR-593-3p, leading to increased Slc38a1 expression and enhanced glucose metabolism.","method":"miR-593-3p overexpression/inhibition, 3'UTR luciferase reporter assay for Slc38a1, glucose consumption assay, insulin treatment, Western blot and qRT-PCR","journal":"Journal of molecular endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter validates miRNA targeting, functional readout is glucose consumption (indirect for SLC38A1 mechanism), single lab","pmids":["27613819"],"is_preprint":false}],"current_model":"SLC38A1/SNAT1 is a Na+-coupled neutral amino acid transporter (1:1 stoichiometry) with 11 transmembrane domains that primarily transports glutamine, alanine, and MeAIB; N-glycosylation at N251/N257/N310 is required for transport activity but not surface trafficking; in neurons it localizes to somata/proximal dendrites to supply glutamine for GABA/glutamate neurotransmitter synthesis and regulate synaptic vesicle GABA content and cortical plasticity; in microglia its transcription is repressed by MeCP2 and its overexpression causes mitochondrial dysfunction and neurotoxic glutamate overproduction; in cancer cells it promotes mTORC1/Akt signaling and glutaminolysis, is stabilized by OTUD5-mediated deubiquitination, and is transcriptionally regulated by CENPA and epigenetically by METTL3/IGF2BP3 m6A modification; in Th1 cells it is required for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific inflammatory responses; in glioblastoma its plasma membrane abundance is maintained by DSCR3-mediated recycling; and in melanoma cells it may function as a glutamine 'transceptor' activating a P62/cMYC signaling axis independent of bulk glutamine transport."},"narrative":{"mechanistic_narrative":"SLC38A1 (SNAT1/ATA1) is a Na+-coupled system A neutral amino acid transporter that supplies glutamine, alanine, and the system A-specific analog MeAIB with 1:1 Na+:amino acid stoichiometry and submillimolar affinity for glutamine, operating via an electrogenic, simultaneous transport mechanism in which Na+ binding precedes substrate [PMID:10891391, PMID:12684517]. Transport activity requires N-glycosylation at N251/N257/N310, which is dispensable for plasma membrane trafficking [PMID:27655909]. In the CNS, SNAT1 localizes to neuronal somata and proximal dendrites rather than nerve terminals or astrocytes [PMID:12684517], where it provides glutamine for GABA neurotransmitter synthesis: genetic disruption reduces vesicular GABA content, alters GABAergic synaptic vesicle morphology, and impairs critical-period cortical plasticity [PMID:31050701]. The transporter is a hub for cellular amino acid economy beyond neurotransmission, mediating cysteine uptake to support glutathione synthesis under oxidative stress [PMID:20602128] and citrulline transport that sustains eNOS coupling and NO production [PMID:24454923]. In cancer cells SLC38A1 drives glutaminolysis and growth through Akt/mTOR signaling [PMID:27129276, PMID:23848995, PMID:29108276], and its expression is controlled at multiple regulatory layers — by MeCP2-mediated transcriptional repression in microglia, where its derepression causes glutamine-dependent mitochondrial dysfunction and NMDA-receptor-dependent neurotoxicity [PMID:25673846], by CENPA-driven transcription [PMID:38382691], by METTL3/IGF2BP3 m6A-dependent mRNA stabilization [PMID:38701556], by OTUD5-mediated deubiquitination that protects it from proteasomal degradation [PMID:38658981], and by DSCR3-mediated endosomal recycling that maintains its surface abundance [PMID:35187626]. In Th1 cells SLC38A1 is required for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific autoimmune inflammation [PMID:41875885]. In ischemic neurons it acts upstream of mTORC1-autophagy-dependent cell death [PMID:31552299].","teleology":[{"year":2000,"claim":"Establishing the molecular identity of system A activity: the cloned human ATA1/SLC38A1 was shown to be a Na+-coupled neutral amino acid transporter, defining the gene's core biochemical function.","evidence":"Heterologous expression with radiotracer uptake and Na+-activation kinetics","pmids":["10891391"],"confidence":"High","gaps":["Stoichiometry mechanism and full substrate range not yet resolved","No structural model of the transporter"]},{"year":2003,"claim":"Defining substrate selectivity, transport mechanism, and where in the CNS the transporter acts: SNAT1 was shown to be an electrogenic glutamine/alanine/MeAIB transporter in neuronal somata and dendrites, framing it as a supplier of glutamine to neurons.","evidence":"Radiotracer flux and electrophysiology in Xenopus oocytes plus confocal immunofluorescence","pmids":["12684517"],"confidence":"High","gaps":["Functional consequence of neuronal localization for neurotransmission not yet tested","Mechanism linking transport to downstream metabolism unaddressed"]},{"year":2001,"claim":"Showing the transporter is dynamically regulated: cAMP signaling upregulates SLC38A1 transcription and transport, establishing inducible control of system A capacity.","evidence":"cAMP agonists with mRNA and MeAIB uptake assays plus transcription/translation inhibitors in HepG2","pmids":["11566196"],"confidence":"Medium","gaps":["Transcription factor mediating the cAMP response not identified","Promoter elements undefined"]},{"year":2010,"claim":"Quantifying the physiological transport contribution and broadening substrate scope: SNAT1 accounts for most placental system A activity and can mediate cysteine uptake supporting glutathione synthesis under oxidative stress.","evidence":"siRNA knockdown with MeAIB kinetics in cytotrophoblasts; H2O2 stress with cysteine uptake and glutathione assays in cardiomyocytes","pmids":["20599747","20602128"],"confidence":"Medium","gaps":["Stress-induced upregulation mechanism not defined","Tissue-specific regulation of substrate preference unclear"]},{"year":2011,"claim":"Resolving vascular localization: SNAT1 was found on larger cortical microvessels but excluded from BBB capillaries, distinguishing system A from system N transport at the brain vasculature.","evidence":"In vivo luminal biotinylation and immunofluorescence in mouse brain","pmids":["21364602"],"confidence":"Medium","gaps":["Functional role at cortical microvessels not tested","Directionality of transport in vivo unknown"]},{"year":2014,"claim":"Linking transport to signaling output: SNAT1-mediated citrulline uptake was shown to sustain eNOS coupling and NO production, extending its role beyond glutamine supply.","evidence":"siRNA knockdown with NO and eNOS dimer/monomer assays in pulmonary endothelial cells under normoxia/hypoxia","pmids":["24454923"],"confidence":"Medium","gaps":["Kinetics of citrulline transport not characterized","In vivo relevance to vascular NO signaling untested"]},{"year":2016,"claim":"Establishing SLC38A1 as a redundant but inducible glutamine route in cancer and identifying neurotoxic consequences of dysregulation: SNAT1 substitutes for ASCT2 to sustain glutamine uptake, while in microglia MeCP2 represses it to prevent glutamine-driven mitochondrial dysfunction and neurotoxicity.","evidence":"ASCT2 CRISPR knockout with SNAT1 siRNA, GCN2 silencing and growth assays; MeCP2 KO with SNAT1 overexpression, mitochondrial/ROS assays and antioxidant rescue","pmids":["27129276","25673846"],"confidence":"High","gaps":["How MeCP2 represses the SLC38A1 promoter mechanistically not detailed","Whether transport per se or signaling drives microglial mitochondrial defects unresolved"]},{"year":2019,"claim":"Defining the in vivo neuronal function: genetic deletion of Slc38a1 impairs GABA synthesis, vesicular GABA loading, and cortical plasticity, and promotes mTORC1-autophagy-dependent neuronal death in ischemia.","evidence":"Slc38a1 KO and conditional (Synapsin-Cre) mice with GABA biochemistry, EM, electrophysiology, MCAO model and mTORC1/autophagy pharmacology","pmids":["31050701","31552299"],"confidence":"High","gaps":["Direct biochemical link between SNAT1 and mTORC1 activation not established","Whether glutamine flux alone explains both GABA synthesis and ischemic death effects unclear"]},{"year":2017,"claim":"Building the cancer signaling picture: SLC38A1 knockdown reduces Akt/mTOR signaling, proliferation, migration, and tumor growth across breast and osteosarcoma models, placing it upstream of growth signaling.","evidence":"shRNA knockdown with signaling Westerns, proliferation/apoptosis assays and xenografts","pmids":["23848995","29108276"],"confidence":"Medium","gaps":["No direct biochemical mechanism connecting transport to Akt/mTOR","Correlative signaling readouts without epistasis"]},{"year":2024,"claim":"Uncovering multilayered post-transcriptional and post-translational control: SLC38A1 is stabilized by OTUD5 deubiquitination, transcriptionally activated by CENPA, mRNA-stabilized by METTL3/IGF2BP3 m6A, and surface-maintained by DSCR3 recycling, each enhancing glutamine-fueled tumor growth.","evidence":"Co-IP/MS (OTUD5, DSCR3), promoter/reporter (CENPA), RIP and mRNA stability (METTL3/IGF2BP3) with glutamine uptake, proteasome assays and xenograft/orthotopic models","pmids":["38658981","38382691","38701556","35187626"],"confidence":"Medium","gaps":["Whether these regulators act in the same tumors or distinct contexts unknown","Reciprocal validation of physical interactions limited to single labs"]},{"year":2023,"claim":"Defining a context-specific immunometabolic requirement: SLC38A1 is required in Th1 cells for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific autoimmune inflammation, linking the transporter to adaptive immunity.","evidence":"In vivo CRISPR screen, conditional deletion, metabolomics, glycolysis assays and EAE/IBD/lung models","pmids":["41875885"],"confidence":"High","gaps":["Basis of tissue-specific dependence (CNS vs lung) not mechanistically resolved","Whether glutamine supply alone accounts for the hexosamine and redox effects unclear"]},{"year":2026,"claim":"Proposing a non-canonical transceptor mode: in melanoma SNAT1 senses extracellular glutamine and signals via a P62/cMYC axis rather than mediating bulk influx, and in lung epithelium it scaffolds CMA-mediated DMT1 degradation to suppress ferroptosis.","evidence":"siPool knockdown with glutamine measurement, Co-IP and AlphaFold3 modeling (P62), Seahorse flux; AAV/lentiviral overexpression with Co-IP of DMT1/HSP90/HSC70/Lamp-2a complex in ALI models","pmids":["41976291","41483240"],"confidence":"Medium","gaps":["Transceptor signaling mechanism distinct from transport not biochemically defined","Structural basis of the proposed P62 and chaperone complex interactions unconfirmed"]},{"year":null,"claim":"How SLC38A1 transport activity is mechanistically coupled to mTORC1/Akt signaling, and whether its transceptor signaling role is general or melanoma-specific, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the human transporter","No direct biochemical link between substrate flux and downstream kinase activation","Transporter vs transceptor contributions not separated genetically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,8]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,4,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,8,17]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,15,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,12,21,22]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["OTUD5","DSCR3","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2H9","full_name":"Sodium-coupled neutral amino acid symporter 1","aliases":["Amino acid transporter A1","N-system amino acid transporter 2","Solute carrier family 38 member 1","System A amino acid transporter 1","System N amino acid transporter 1"],"length_aa":487,"mass_kda":54.0,"function":"Symporter that cotransports short-chain neutral amino acids and sodium ions from the extracellular to the intracellular side of the cell membrane (PubMed:10891391, PubMed:20599747). The transport is elctrogenic, pH dependent and driven by the Na(+) electrochemical gradient (PubMed:10891391). Participates in the astroglia-derived glutamine transport into GABAergic interneurons for neurotransmitter GABA de novo synthesis (By similarity). May also contributes to amino acid transport in placental trophoblasts (PubMed:20599747). Also regulates synaptic plasticity (PubMed:12388062)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9H2H9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC38A1","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SLC38A1","total_profiled":1310},"omim":[{"mim_id":"616526","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 11; SLC38A11","url":"https://www.omim.org/entry/616526"},{"mim_id":"608490","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 1; SLC38A1","url":"https://www.omim.org/entry/608490"},{"mim_id":"608065","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 4; SLC38A4","url":"https://www.omim.org/entry/608065"},{"mim_id":"605180","title":"SOLUTE CARRIER FAMILY 38 (AMINO ACID TRANSPORTER), MEMBER 2; SLC38A2","url":"https://www.omim.org/entry/605180"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLC38A1"},"hgnc":{"alias_symbol":["ATA1","NAT2","SAT1","SNAT1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H2H9","domains":[{"cath_id":"1.20.1740.10","chopping":"74-244_264-480","consensus_level":"high","plddt":89.498,"start":74,"end":480}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2H9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2H9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2H9-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC38A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC38A1"},"sequence":{"accession":"Q9H2H9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2H9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2H9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2H9"}},"corpus_meta":[{"pmid":"27129276","id":"PMC_27129276","title":"Deletion of Amino Acid Transporter ASCT2 (SLC1A5) Reveals an Essential Role for Transporters SNAT1 (SLC38A1) and SNAT2 (SLC38A2) to Sustain Glutaminolysis in Cancer Cells.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27129276","citation_count":211,"is_preprint":false},{"pmid":"32453709","id":"PMC_32453709","title":"lncRNA ZFAS1 promotes lung fibroblast-to-myofibroblast transition and ferroptosis via functioning as a ceRNA through miR-150-5p/SLC38A1 axis.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32453709","citation_count":152,"is_preprint":false},{"pmid":"12684517","id":"PMC_12684517","title":"Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12684517","citation_count":126,"is_preprint":false},{"pmid":"10891391","id":"PMC_10891391","title":"Cloning and functional expression of ATA1, a subtype of amino acid transporter A, from human placenta.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10891391","citation_count":93,"is_preprint":false},{"pmid":"25673846","id":"PMC_25673846","title":"Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25673846","citation_count":77,"is_preprint":false},{"pmid":"23848995","id":"PMC_23848995","title":"Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt overexpression.","date":"2013","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23848995","citation_count":58,"is_preprint":false},{"pmid":"17549407","id":"PMC_17549407","title":"Activation of a system A amino acid transporter, ATA1/SLC38A1, in human hepatocellular carcinoma and preneoplastic liver tissues.","date":"2007","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17549407","citation_count":54,"is_preprint":false},{"pmid":"20599747","id":"PMC_20599747","title":"The contribution of SNAT1 to system A amino acid transporter activity in human placental trophoblast.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20599747","citation_count":45,"is_preprint":false},{"pmid":"31050701","id":"PMC_31050701","title":"The Glutamine Transporter Slc38a1 Regulates GABAergic Neurotransmission and Synaptic Plasticity.","date":"2019","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/31050701","citation_count":38,"is_preprint":false},{"pmid":"31552299","id":"PMC_31552299","title":"Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system.","date":"2019","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/31552299","citation_count":36,"is_preprint":false},{"pmid":"28224429","id":"PMC_28224429","title":"SLC38A1 promotes proliferation and migration of human colorectal cancer cells.","date":"2017","source":"Journal of Huazhong University of Science and Technology. 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SNAT1 protein localizes to somata and proximal dendrites of glutamatergic and GABAergic neurons throughout adult CNS but is absent from nerve terminals and astrocytes; luminal ependymal expression also detected.\",\n      \"method\": \"Radiotracer uptake and electrophysiology (current/flux) in Xenopus oocytes; confocal laser-scanning immunofluorescence; mutagenesis/kinetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Xenopus oocytes with simultaneous flux and current measurements, stoichiometry determination, and detailed subcellular localization with multiple neuronal markers\",\n      \"pmids\": [\"12684517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"cAMP elevation (forskolin, cholera toxin, dibutyryl-cAMP) increases steady-state ATA1 (SLC38A1) mRNA levels and system A transport activity (increased Vmax, unchanged Km) in HepG2 cells; effect is blocked by protein kinase inhibitor H7, cycloheximide, and actinomycin D, indicating transcription- and translation-dependent upregulation.\",\n      \"method\": \"Northern blot/RT-PCR for mRNA levels; radiotracer MeAIB uptake assay; pharmacological inhibitors\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological probes with functional transport readout in cell culture, single lab\",\n      \"pmids\": [\"11566196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SNAT1 contributes the majority (~75%) of system A amino acid transport activity in term human placental cytotrophoblast cells, as demonstrated by siRNA knockdown of SNAT1 significantly reducing MeAIB uptake; kinetic analysis resolved two transport systems consistent with SNAT1/SNAT2 (Km ~0.38 mM) and SNAT4 (Km ~45 mM).\",\n      \"method\": \"siRNA knockdown, 14C-MeAIB radiotracer uptake, kinetic (Michaelis-Menten) analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with quantitative transport readout and kinetic analysis, single lab\",\n      \"pmids\": [\"20599747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Oxidative stress (H2O2) selectively upregulates SNAT1 protein expression in rat cardiomyocytes and enhances system A-mediated (αMeAIB-inhibitable) cysteine uptake; cysteine supplied via SNAT1 contributes to glutathione synthesis under oxidative conditions.\",\n      \"method\": \"qRT-PCR, Western blot, 35S-cysteine radiotracer uptake with oil filtration, glutathione enzymatic assay\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary methods (expression + functional uptake + metabolic readout) in primary cardiomyocytes, single lab\",\n      \"pmids\": [\"20602128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SNAT1 (Snat1) localizes to luminal membranes of larger cortical microvessels in mouse brain but is absent from BBB capillaries (where Snat3 is expressed), as shown by in vivo biotinylation and immunofluorescence colocalization, indicating distinct vascular roles for system A vs. system N transporters.\",\n      \"method\": \"In vivo luminal membrane biotinylation, immunofluorescence colocalization with cellular markers\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular/vascular localization by two complementary methods (biotinylation + immunofluorescence) in vivo, single lab\",\n      \"pmids\": [\"21364602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1/SLC38A1. In MeCP2-deficient microglia, SNAT1 overexpression causes glutamine-dependent mitochondrial dysfunction (proliferating mitochondria, increased ROS, increased O2 consumption but decreased ATP), and overproduction of glutamate leading to NMDA receptor-dependent neurotoxicity. These defects are rescued by mitochondria-targeted catalase or SS-31 antioxidant peptide.\",\n      \"method\": \"MeCP2 knockdown/KO mouse model, SNAT1 overexpression in microglia, mitochondrial functional assays (OCR, ATP), ROS measurement, neurotoxicity assay, mitochondria-targeted antioxidant rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model combined with overexpression, multiple orthogonal functional readouts, and mechanistic rescue experiments\",\n      \"pmids\": [\"25673846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Net glutamine uptake in HeLa and 143B cancer cells does not depend on ASCT2 (SLC1A5) but requires SNAT1 (SLC38A1) and SNAT2 (SLC38A2). ASCT2 deletion does not reduce cell growth but triggers an amino acid starvation response (GCN2 activation) and upregulates SNAT1 to replace ASCT2 functionally; combined GCN2 silencing in ASCT2−/− background reduces cancer cell growth.\",\n      \"method\": \"CRISPR/Cas9 knockout of ASCT2, siRNA knockdown of SNAT1/SNAT2, amino acid uptake assays, GCN2 silencing, cell growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic knockouts with functional uptake and growth assays; epistasis established by double-KO approach; two cell lines\",\n      \"pmids\": [\"27129276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SNAT1 is an N-glycoprotein with three glycosylation sites at asparagine residues 251, 257, and 310 (N251 and N257 are primary sites). N-glycosylation-impaired mutants traffic normally to the cell surface but show significantly reduced glutamine (L-Gln) and MeAIB transport, indicating N-glycosylation is required for transport activity but not plasma membrane localization.\",\n      \"method\": \"N-glycosylation site mutagenesis, cell surface biotinylation, confocal immunofluorescence, 3H-MeAIB transport assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis combined with surface biotinylation and functional transport assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27655909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic disruption of Slc38a1 in mice impairs GABA synthesis, alters synaptic vesicle morphology in GABAergic presynapses, reduces vesicular GABA content, impairs critical period cortical plasticity, and affects high-frequency membrane oscillations and cortical processing.\",\n      \"method\": \"Slc38a1 knockout mice, GABA synthesis/content assays, electron microscopy of synaptic vesicles, electrophysiology, cortical plasticity assays\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple cellular and functional phenotypic readouts (biochemistry, ultrastructure, electrophysiology, plasticity)\",\n      \"pmids\": [\"31050701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Neuron-specific deletion of Slc38a1 (using Synapsin I-Cre) reduces infarct size in mouse MCAO stroke model. SNAT1 promotes ischemic neuronal death via mTORC1 (p70S6K1 phosphorylation) activation; autophagy inhibitors abolish the neuroprotective effect of SNAT1 deficiency in vitro, placing SNAT1 upstream of mTORC1-autophagy-dependent neuronal death.\",\n      \"method\": \"Conditional Slc38a1 KO mice, MCAO model (TTC staining, MAP2-negative area), mTORC1 phosphorylation assays, rapamycin treatment, autophagy inhibitors, in vitro stroke culture\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO with in vivo stroke model plus in vitro mechanistic dissection using epistatic pharmacological rescue experiments\",\n      \"pmids\": [\"31552299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Suppression of SNAT1 in breast cancer cells lowers phospho-Akt levels and inhibits cell growth, cell cycle progression, and induces apoptosis, linking SNAT1 activity to Akt signaling in cancer cells.\",\n      \"method\": \"shRNA knockdown of SNAT1, Western blot for p-Akt, cell viability, cell cycle, apoptosis assays\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with phenotypic and signaling readouts in cancer cells, single lab, no direct mechanistic linkage established\",\n      \"pmids\": [\"23848995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Silencing SNAT1 in osteosarcoma cells reduces proliferation, colony formation, and migration in vitro and tumor growth in xenograft models, and decreases expression of MMP9, vimentin, fibronectin, p-Akt, p-mTOR, and VEGF, suggesting SNAT1 acts upstream of Akt/mTOR signaling in osteosarcoma.\",\n      \"method\": \"shRNA knockdown, xenograft mouse model, Western blot for signaling proteins, proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft plus in vitro signaling assays, single lab\",\n      \"pmids\": [\"29108276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC38A1 modulates hepatocellular carcinoma cell growth and migration via PI3K/AKT/mTOR signaling through glutamine-mediated energy metabolism; SLC38A1 knockdown suppresses this pathway.\",\n      \"method\": \"siRNA knockdown, Western blot for PI3K/AKT/mTOR pathway components, cell proliferation and migration assays\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with pathway readout, no direct biochemical linkage established\",\n      \"pmids\": [\"37673823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTUD5 deubiquitinase directly binds SLC38A1 (confirmed by Co-IP and mass spectrometry) and prevents its ubiquitin-mediated proteasomal degradation, thereby stabilizing SLC38A1 protein levels. OTUD5 knockdown reduces SLC38A1 protein but not mRNA; SLC38A1 silencing attenuates OTUD5-driven HCC cell proliferation.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, OTUD5 overexpression/knockdown, proteasome inhibitor treatment, Western blot, xenograft mouse model\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and mass spectrometry to identify interaction, functional epistasis with proteasomal degradation assay, single lab\",\n      \"pmids\": [\"38658981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CENPA directly regulates transcriptional activity of SLC38A1, increasing glutamine uptake and metabolism to promote endometrial cancer progression; CENPA overexpression/silencing reciprocally modulates SLC38A1 expression and glutamine metabolism.\",\n      \"method\": \"ChIP or luciferase transcriptional reporter assay (CENPA binding to SLC38A1 promoter), CENPA overexpression/knockdown, glutamine uptake measurement, tumor xenograft assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional regulation by CENPA shown with promoter assay and reciprocal genetic manipulation, single lab\",\n      \"pmids\": [\"38382691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3-mediated m6A methylation of the SLC38A1 3'UTR enhances SLC38A1 mRNA stability through IGF2BP3 recruitment; METTL3 silencing reduces intracellular glutamine content and inhibits cervical cancer cell viability, which is reversed by SLC38A1 overexpression.\",\n      \"method\": \"RNA immunoprecipitation (RIP) for METTL3/IGF2BP3 on SLC38A1 3'UTR, mRNA stability assay, METTL3/SLC38A1 overexpression/knockdown, glutamine content assay, tumor xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay identifies writer and reader of m6A modification on SLC38A1, with functional epistasis, single lab\",\n      \"pmids\": [\"38701556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DSCR3 directly binds internalized SLC38A1 and mediates its sorting into a recycling pathway back to the plasma membrane, maintaining surface SLC38A1 abundance and enhancing glutamine uptake in MGMT-deficient glioblastoma cells; DSCR3 or SLC38A1 silencing increases temozolomide sensitivity.\",\n      \"method\": \"Label-free quantitative proteomics (plasma membrane fraction), co-immunoprecipitation, immunofluorescence of recycling, siRNA knockdown, in vitro and orthotopic brain tumor model\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified interaction confirmed by Co-IP, immunofluorescence of trafficking, and functional consequence in vivo, single lab\",\n      \"pmids\": [\"35187626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNAT1 mediates L-citrulline transport into pulmonary arterial endothelial cells; SNAT1 siRNA knockdown reduces basal NO production and prevents L-citrulline-induced increases in NO production and eNOS dimer-to-monomer ratios in both normoxic and hypoxic conditions, establishing that SNAT1-mediated citrulline transport regulates eNOS coupling and NO signaling.\",\n      \"method\": \"siRNA knockdown of SNAT1, NO production assay, eNOS dimer-to-monomer ratio (Western blot under non-reducing conditions), normoxia/hypoxia culture\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal functional readouts (NO, eNOS coupling) in primary cells under two conditions, single lab\",\n      \"pmids\": [\"24454923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Slc38a1 expression in brown adipose tissue is upregulated in obese mice in vivo and is induced in brown adipocytes by hypoxic stress through hypoxia-inducible factor-1α (HIF-1α), identifying HIF-1α as a transcriptional regulator of Slc38a1.\",\n      \"method\": \"In vivo obesity models (genetic and diet-induced), hypoxia treatment in brown adipocytes, HIF-1α manipulation, qRT-PCR and Western blot\",\n      \"journal\": \"Pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative in vivo plus in vitro HIF-1α manipulation without direct promoter mechanistic proof\",\n      \"pmids\": [\"29065407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HPV16 E6 and E7 oncoproteins increase SNAT1 protein levels and stimulate glutaminolysis; cell proliferation in the presence of glutamine is partially dependent on SNAT1, as SNAT1 knockdown reduces proliferation and E6/E7-driven glutamine-dependent growth.\",\n      \"method\": \"HPV E6/E7 expression, E6/E7 siRNA knockdown, SNAT1 siRNA knockdown, glutamine dependence assay, cell proliferation assay\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with proliferation readout, no direct mechanistic link between E6/E7 and SNAT1 transcription established\",\n      \"pmids\": [\"36851539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC38A1 deficiency in Th1 cells (via CRISPR) reduces mTORC1 signaling and glycolytic activity, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation; SLC38A1 is required for Th1- but not Th17-driven autoimmune neuroinflammation (EAE) in a tissue-specific manner, while dispensable for lung inflammation.\",\n      \"method\": \"In vivo CRISPR screen, conditional genetic deletion, mTORC1 phosphorylation assay, metabolomics (glutamine, hexosamine pathway), glycolysis assay, EAE model, IBD model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo CRISPR screen with conditional KO, mechanistic metabolic readouts (mTORC1, hexosamine pathway, redox), multiple disease models, and pharmacological validation\",\n      \"pmids\": [\"41875885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In melanoma cells, SNAT1 does not primarily mediate glutamine influx but instead signals in response to extracellular glutamine levels. SNAT1 interacts with P62 (SQSTM1) (confirmed by Co-IP and AlphaFold3 in silico modeling) and activates P62/cMYC signaling axis to regulate melanoma cell metabolism depending on glutamine availability, suggesting SNAT1 acts as a glutamine 'transceptor' rather than solely a transporter.\",\n      \"method\": \"siPool-mediated SNAT1 knockdown, intracellular/extracellular glutamine measurement, Co-IP, AlphaFold3 in silico protein interaction modeling, qRT-PCR and Western blot, Seahorse flux analysis, flow cytometry for mitochondria\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms P62 interaction, Seahorse metabolic assay, glutamine transport measurement, multiple orthogonal methods; single lab and novel unexpected claim\",\n      \"pmids\": [\"41976291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SLC38A1 overexpression in alveolar type II epithelial cells promotes chaperone-mediated autophagy (CMA) degradation of divalent metal transporter 1 (DMT1) by facilitating interactions among DMT1, HSP90, HSC70, and Lamp-2a, enhancing lysosomal translocation of DMT1. This reduces intracellular iron and inhibits ferroptosis in acute lung injury.\",\n      \"method\": \"AAV6-mediated SLC38A1 overexpression in vivo (mouse LPS-ALI model), lentiviral overexpression in primary ATII cells, co-immunoprecipitation for DMT1/HSP90/HSC70/Lamp-2a complex, Western blot, TUNEL staining, shRNA knockdowns (SLC38A1, ULK1, HSP90)\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies multi-protein complex, in vivo and in vitro rescue experiments, single lab, novel mechanism\",\n      \"pmids\": [\"41483240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-593-3p targets Slc38a1 (and CLIP3) to negatively regulate insulin-promoted glucose consumption in HepG2 cells; insulin downregulates miR-593-3p, leading to increased Slc38a1 expression and enhanced glucose metabolism.\",\n      \"method\": \"miR-593-3p overexpression/inhibition, 3'UTR luciferase reporter assay for Slc38a1, glucose consumption assay, insulin treatment, Western blot and qRT-PCR\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter validates miRNA targeting, functional readout is glucose consumption (indirect for SLC38A1 mechanism), single lab\",\n      \"pmids\": [\"27613819\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC38A1/SNAT1 is a Na+-coupled neutral amino acid transporter (1:1 stoichiometry) with 11 transmembrane domains that primarily transports glutamine, alanine, and MeAIB; N-glycosylation at N251/N257/N310 is required for transport activity but not surface trafficking; in neurons it localizes to somata/proximal dendrites to supply glutamine for GABA/glutamate neurotransmitter synthesis and regulate synaptic vesicle GABA content and cortical plasticity; in microglia its transcription is repressed by MeCP2 and its overexpression causes mitochondrial dysfunction and neurotoxic glutamate overproduction; in cancer cells it promotes mTORC1/Akt signaling and glutaminolysis, is stabilized by OTUD5-mediated deubiquitination, and is transcriptionally regulated by CENPA and epigenetically by METTL3/IGF2BP3 m6A modification; in Th1 cells it is required for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific inflammatory responses; in glioblastoma its plasma membrane abundance is maintained by DSCR3-mediated recycling; and in melanoma cells it may function as a glutamine 'transceptor' activating a P62/cMYC signaling axis independent of bulk glutamine transport.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC38A1 (SNAT1/ATA1) is a Na+-coupled system A neutral amino acid transporter that supplies glutamine, alanine, and the system A-specific analog MeAIB with 1:1 Na+:amino acid stoichiometry and submillimolar affinity for glutamine, operating via an electrogenic, simultaneous transport mechanism in which Na+ binding precedes substrate [#0, #1]. Transport activity requires N-glycosylation at N251/N257/N310, which is dispensable for plasma membrane trafficking [#8]. In the CNS, SNAT1 localizes to neuronal somata and proximal dendrites rather than nerve terminals or astrocytes [#1], where it provides glutamine for GABA neurotransmitter synthesis: genetic disruption reduces vesicular GABA content, alters GABAergic synaptic vesicle morphology, and impairs critical-period cortical plasticity [#9]. The transporter is a hub for cellular amino acid economy beyond neurotransmission, mediating cysteine uptake to support glutathione synthesis under oxidative stress [#4] and citrulline transport that sustains eNOS coupling and NO production [#18]. In cancer cells SLC38A1 drives glutaminolysis and growth through Akt/mTOR signaling [#7, #11, #12], and its expression is controlled at multiple regulatory layers — by MeCP2-mediated transcriptional repression in microglia, where its derepression causes glutamine-dependent mitochondrial dysfunction and NMDA-receptor-dependent neurotoxicity [#6], by CENPA-driven transcription [#15], by METTL3/IGF2BP3 m6A-dependent mRNA stabilization [#16], by OTUD5-mediated deubiquitination that protects it from proteasomal degradation [#14], and by DSCR3-mediated endosomal recycling that maintains its surface abundance [#17]. In Th1 cells SLC38A1 is required for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific autoimmune inflammation [#21]. In ischemic neurons it acts upstream of mTORC1-autophagy-dependent cell death [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the molecular identity of system A activity: the cloned human ATA1/SLC38A1 was shown to be a Na+-coupled neutral amino acid transporter, defining the gene's core biochemical function.\",\n      \"evidence\": \"Heterologous expression with radiotracer uptake and Na+-activation kinetics\",\n      \"pmids\": [\"10891391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry mechanism and full substrate range not yet resolved\", \"No structural model of the transporter\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining substrate selectivity, transport mechanism, and where in the CNS the transporter acts: SNAT1 was shown to be an electrogenic glutamine/alanine/MeAIB transporter in neuronal somata and dendrites, framing it as a supplier of glutamine to neurons.\",\n      \"evidence\": \"Radiotracer flux and electrophysiology in Xenopus oocytes plus confocal immunofluorescence\",\n      \"pmids\": [\"12684517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of neuronal localization for neurotransmission not yet tested\", \"Mechanism linking transport to downstream metabolism unaddressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing the transporter is dynamically regulated: cAMP signaling upregulates SLC38A1 transcription and transport, establishing inducible control of system A capacity.\",\n      \"evidence\": \"cAMP agonists with mRNA and MeAIB uptake assays plus transcription/translation inhibitors in HepG2\",\n      \"pmids\": [\"11566196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating the cAMP response not identified\", \"Promoter elements undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Quantifying the physiological transport contribution and broadening substrate scope: SNAT1 accounts for most placental system A activity and can mediate cysteine uptake supporting glutathione synthesis under oxidative stress.\",\n      \"evidence\": \"siRNA knockdown with MeAIB kinetics in cytotrophoblasts; H2O2 stress with cysteine uptake and glutathione assays in cardiomyocytes\",\n      \"pmids\": [\"20599747\", \"20602128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stress-induced upregulation mechanism not defined\", \"Tissue-specific regulation of substrate preference unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolving vascular localization: SNAT1 was found on larger cortical microvessels but excluded from BBB capillaries, distinguishing system A from system N transport at the brain vasculature.\",\n      \"evidence\": \"In vivo luminal biotinylation and immunofluorescence in mouse brain\",\n      \"pmids\": [\"21364602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role at cortical microvessels not tested\", \"Directionality of transport in vivo unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking transport to signaling output: SNAT1-mediated citrulline uptake was shown to sustain eNOS coupling and NO production, extending its role beyond glutamine supply.\",\n      \"evidence\": \"siRNA knockdown with NO and eNOS dimer/monomer assays in pulmonary endothelial cells under normoxia/hypoxia\",\n      \"pmids\": [\"24454923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinetics of citrulline transport not characterized\", \"In vivo relevance to vascular NO signaling untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing SLC38A1 as a redundant but inducible glutamine route in cancer and identifying neurotoxic consequences of dysregulation: SNAT1 substitutes for ASCT2 to sustain glutamine uptake, while in microglia MeCP2 represses it to prevent glutamine-driven mitochondrial dysfunction and neurotoxicity.\",\n      \"evidence\": \"ASCT2 CRISPR knockout with SNAT1 siRNA, GCN2 silencing and growth assays; MeCP2 KO with SNAT1 overexpression, mitochondrial/ROS assays and antioxidant rescue\",\n      \"pmids\": [\"27129276\", \"25673846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MeCP2 represses the SLC38A1 promoter mechanistically not detailed\", \"Whether transport per se or signaling drives microglial mitochondrial defects unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining the in vivo neuronal function: genetic deletion of Slc38a1 impairs GABA synthesis, vesicular GABA loading, and cortical plasticity, and promotes mTORC1-autophagy-dependent neuronal death in ischemia.\",\n      \"evidence\": \"Slc38a1 KO and conditional (Synapsin-Cre) mice with GABA biochemistry, EM, electrophysiology, MCAO model and mTORC1/autophagy pharmacology\",\n      \"pmids\": [\"31050701\", \"31552299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between SNAT1 and mTORC1 activation not established\", \"Whether glutamine flux alone explains both GABA synthesis and ischemic death effects unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Building the cancer signaling picture: SLC38A1 knockdown reduces Akt/mTOR signaling, proliferation, migration, and tumor growth across breast and osteosarcoma models, placing it upstream of growth signaling.\",\n      \"evidence\": \"shRNA knockdown with signaling Westerns, proliferation/apoptosis assays and xenografts\",\n      \"pmids\": [\"23848995\", \"29108276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical mechanism connecting transport to Akt/mTOR\", \"Correlative signaling readouts without epistasis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovering multilayered post-transcriptional and post-translational control: SLC38A1 is stabilized by OTUD5 deubiquitination, transcriptionally activated by CENPA, mRNA-stabilized by METTL3/IGF2BP3 m6A, and surface-maintained by DSCR3 recycling, each enhancing glutamine-fueled tumor growth.\",\n      \"evidence\": \"Co-IP/MS (OTUD5, DSCR3), promoter/reporter (CENPA), RIP and mRNA stability (METTL3/IGF2BP3) with glutamine uptake, proteasome assays and xenograft/orthotopic models\",\n      \"pmids\": [\"38658981\", \"38382691\", \"38701556\", \"35187626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these regulators act in the same tumors or distinct contexts unknown\", \"Reciprocal validation of physical interactions limited to single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining a context-specific immunometabolic requirement: SLC38A1 is required in Th1 cells for mTORC1 signaling, hexosamine biosynthesis, and tissue-specific autoimmune inflammation, linking the transporter to adaptive immunity.\",\n      \"evidence\": \"In vivo CRISPR screen, conditional deletion, metabolomics, glycolysis assays and EAE/IBD/lung models\",\n      \"pmids\": [\"41875885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of tissue-specific dependence (CNS vs lung) not mechanistically resolved\", \"Whether glutamine supply alone accounts for the hexosamine and redox effects unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Proposing a non-canonical transceptor mode: in melanoma SNAT1 senses extracellular glutamine and signals via a P62/cMYC axis rather than mediating bulk influx, and in lung epithelium it scaffolds CMA-mediated DMT1 degradation to suppress ferroptosis.\",\n      \"evidence\": \"siPool knockdown with glutamine measurement, Co-IP and AlphaFold3 modeling (P62), Seahorse flux; AAV/lentiviral overexpression with Co-IP of DMT1/HSP90/HSC70/Lamp-2a complex in ALI models\",\n      \"pmids\": [\"41976291\", \"41483240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transceptor signaling mechanism distinct from transport not biochemically defined\", \"Structural basis of the proposed P62 and chaperone complex interactions unconfirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC38A1 transport activity is mechanistically coupled to mTORC1/Akt signaling, and whether its transceptor signaling role is general or melanoma-specific, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the human transporter\", \"No direct biochemical link between substrate flux and downstream kinase activation\", \"Transporter vs transceptor contributions not separated genetically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 8]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 4, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 8, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 15, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 12, 21, 22]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"OTUD5\", \"DSCR3\", \"SQSTM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}