{"gene":"SLC38A9","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2015,"finding":"SLC38A9 is a lysosomal transmembrane protein that interacts with the Rag GTPases and Ragulator complex in an amino acid-sensitive fashion, transports arginine with a high Km, and functions upstream of the Rag GTPases to signal arginine sufficiency to mTORC1; overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity.","method":"Co-immunoprecipitation, amino acid transport assays, loss-of-function (siRNA knockdown), gain-of-function (overexpression), lysosomal fractionation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, transport assay, KD/OE with defined phenotype; independently replicated in same year by two other groups","pmids":["25567906"],"is_preprint":false},{"year":2015,"finding":"SLC38A9 is an integral part of the Ragulator-RAG GTPases machinery at the lysosomal membrane; gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 impaired amino-acid-induced mTORC1 activation, establishing it as a physical and functional component of the amino acid sensing machinery.","method":"Functional proteomic analysis (AP-MS), Co-immunoprecipitation, siRNA knockdown, lysosomal localization by immunofluorescence, amino acid transport assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MS interactome, Co-IP, KD with defined phenotype, transport assay); independently replicated","pmids":["25561175"],"is_preprint":false},{"year":2015,"finding":"SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner; SLC38A9 depletion retains mTOR at the lysosome but prevents its activation; SLC38A9 overexpression causes RHEB GTPase-dependent hyperactivation of mTORC1.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence localization, nucleotide state-specific Rag mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, nucleotide-state dependency established; replicated by two concurrent independent groups","pmids":["25963655"],"is_preprint":false},{"year":2017,"finding":"SLC38A9 mediates transport of many essential amino acids (including leucine) out of lysosomes in an arginine-regulated fashion; SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1; pancreatic cancer cells using macropinocytosed protein as nutrient require SLC38A9 for tumor formation, establishing arginine as a lysosomal messenger coupling mTORC1 activation to essential amino acid release.","method":"Isotope tracing (lysosomal amino acid efflux), SLC38A9 knockout cells, in vitro transport reconstitution, tumor xenograft assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — isotope tracing efflux assay, KO cells with multiple phenotypic readouts, in vivo tumor assay; single lab with multiple orthogonal methods","pmids":["29053970"],"is_preprint":false},{"year":2017,"finding":"Lysosomal cholesterol drives mTORC1 activation through SLC38A9 via conserved cholesterol-responsive motifs; SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function; NPC1 binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function, forming an SLC38A9-NPC1 signaling complex.","method":"Co-immunoprecipitation (SLC38A9-NPC1 interaction), cholesterol manipulation (cyclodextrin delivery), SLC38A9 knockout/knockdown, mutagenesis of cholesterol-responsive motifs","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — Co-IP of SLC38A9-NPC1 complex, KO cells, mutagenesis of functional motifs, multiple orthogonal approaches","pmids":["28336668"],"is_preprint":false},{"year":2018,"finding":"SLC38A9 acts as a guanine exchange factor (GEF) for RagA: upon arginine binding, SLC38A9 converts RagA from GDP- to GTP-loaded state, thereby activating the Rag GTPase heterodimer toward the active state; this is mechanistically distinct from Ragulator, which acts as a GEF for RagC.","method":"In vitro GEF assay (nucleotide exchange kinetics), nucleotide state-specific mutants, biochemical reconstitution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro GEF assay with reconstitution and nucleotide exchange kinetics; mechanistically distinct from prior work","pmids":["30181260"],"is_preprint":false},{"year":2018,"finding":"Crystal structure of zebrafish SLC38A9 in complex with arginine in the cytosol-open state reveals that arginine is locked in a transitional state stabilized by TM1 anchored at the groove between TM5 and TM7 via the conserved WNTMM motif; mutations in this motif abolished arginine transport.","method":"X-ray crystallography, site-directed mutagenesis, transport assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis with functional validation in a single study","pmids":["29872228"],"is_preprint":false},{"year":2019,"finding":"Human SLC38A9 reconstituted in liposomes shows cooperative transport of glutamine and arginine; a novel Na+ binding site (T453) was identified; cholesterol stimulates glutamine and arginine transport; SLC38A9 is competent for glutamine efflux but not arginine efflux; arginine acts as a modulator stimulating glutamine efflux and binds at a site distinct from glutamine; the N-terminal tail is not required for intrinsic transport function.","method":"Protein purification from E. coli, reconstitution in liposomes, transport assay, site-directed mutagenesis (T453), deletion mutagenesis of N-terminus, bioinformatics","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in liposomes with mutagenesis and kinetic analysis; multiple orthogonal approaches in single study","pmids":["31295473"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of the lysosomal folliculin complex (LFC) — consisting of inactive Rag dimer, Ragulator, and FLCN:FNIP2 — with the cytoplasmic tail of SLC38A9 reveal that the SLC38A9 cytoplasmic tail destabilizes the LFC, thereby triggering GAP activity of FLCN:FNIP2 toward RagC and promoting Rag dimer activation in pre- and post-GTP hydrolysis states.","method":"Cryo-EM structure determination, in vitro reconstitution of LFC, GAP activity assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with functional reconstitution and GAP activity validation","pmids":["32868926"],"is_preprint":false},{"year":2021,"finding":"SLC38A9 interacts with SLC36A1 at the lysosomal surface; they enhance each other's expression levels and lysosomal localization; interacting proteins of SLC38A9 in C2C12 cells participate in amino acid sensing, mTORC1 signaling, and protein synthesis.","method":"Co-immunoprecipitation, immunofluorescence colocalization, mass spectrometry interactome","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and colocalization without in-depth functional follow-up of the specific interaction","pmids":["34572527"],"is_preprint":false},{"year":2021,"finding":"ATF4 binds to two amino acid response elements (AAREs) in the SLC38A9 promoter region, including one in the first intron within the core promoter, and regulates SLC38A9 mRNA expression in porcine skeletal muscle cells in response to amino acid availability.","method":"Promoter analysis, chromatin immunoprecipitation (ChIP), siRNA knockdown, RT-qPCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP establishes direct ATF4 binding, single lab, single model organism cell type","pmids":["34246831"],"is_preprint":false},{"year":2024,"finding":"The multibasic motif on SARS-CoV-2 S1 protein (exposed after furin cleavage) interacts with SLC38A9 in the endolysosome; SLC38A9 knockdown prevents S1-induced endolysosome de-acidification and blocks S protein-mediated pseudo-SARS-CoV-2 entry in multiple cell lines.","method":"Co-immunoprecipitation (S1-SLC38A9 interaction), siRNA knockdown, pseudovirus entry assay, endolysosomal pH measurement","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus KD with defined viral entry phenotype across multiple cell lines, single lab","pmids":["39071889"],"is_preprint":false},{"year":2025,"finding":"HIV-1 Tat protein interacts with SLC38A9 via its arginine-rich basic domain in endolysosomes; this interaction causes endolysosome dysfunction, enhanced HIV-1 LTR transactivation, and cellular senescence in human astrocytes.","method":"Co-immunoprecipitation (Tat-SLC38A9), domain mapping (arginine-rich domain), endolysosomal pH/function assays, senescence markers, SLC38A9 knockdown","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with domain mapping, KD with multiple cellular phenotype readouts, single lab","pmids":["40324823"],"is_preprint":false},{"year":2025,"finding":"SLC38A9 arginine uptake is pH-dependent; histidine residue His544 serves as the pH sensor — mutating His544 abolishes pH dependence of arginine uptake without impairing overall transport activity; cryo-EM structures at high and low pH reveal a working model for pH-induced conformational activation of SLC38A9.","method":"Transport assay (pH titration), site-directed mutagenesis (His544), cryo-EM structure determination at two pH conditions","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — transport assay with mutagenesis plus structural comparison; preprint, not yet peer-reviewed","pmids":["41279478"],"is_preprint":true},{"year":2024,"finding":"SLC38A9 mediates amino acid-induced lysosome redistribution toward the cell periphery via the SLC38A9-BORC-kinesin 1/3 axis; this peripheral lysosome positioning synergizes with arginine-mediated mTOR activation to enhance mTORC1 activity.","method":"High-content imaging of lysosome positioning, kinesin 1/3 KO cells, siRNA knockdown, mTOR activity assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint with imaging and KO but limited mechanistic depth for SLC38A9-specific role in BORC axis","pmids":["bio_10.1101_2024.10.12.618047"],"is_preprint":true}],"current_model":"SLC38A9 is a lysosomal transmembrane transporter-receptor ('transceptor') that senses intra-lysosomal arginine and cholesterol, acts as a GEF for RagA (converting it to the GTP-bound active state) and destabilizes the lysosomal folliculin complex to trigger FLCN:FNIP2 GAP activity toward RagC, collectively driving Rag GTPase activation and mTORC1 recruitment/activation at the lysosomal surface; it also mediates arginine-regulated efflux of essential amino acids (including leucine) from lysosomes, couples lysosomal proteolysis-derived amino acids to mTORC1 signaling, interacts with NPC1 to transduce cholesterol status, and its cytoplasmic tail and conserved WNTMM transmembrane motif are structurally defined as critical functional elements."},"narrative":{"teleology":[{"year":2015,"claim":"Three independent groups simultaneously established that SLC38A9 is a physical component of the Rag-Ragulator machinery at the lysosomal membrane, resolving the long-sought identity of a lysosomal amino acid sensor upstream of mTORC1.","evidence":"Co-IP, AP-MS proteomics, siRNA knockdown, overexpression, amino acid transport assays, and nucleotide state-dependent interaction studies in mammalian cells","pmids":["25567906","25561175","25963655"],"confidence":"High","gaps":["Mechanism by which SLC38A9 activates Rag GTPases was unknown","Whether SLC38A9 senses nutrients other than arginine was unresolved","Structural basis of arginine recognition not yet determined"]},{"year":2017,"claim":"SLC38A9 was shown to have a dual signaling role—functioning as an arginine-regulated transporter that effluxes essential amino acids (notably leucine) from lysosomes to activate mTORC1 via proteolysis-derived nutrients, and independently sensing lysosomal cholesterol via a complex with NPC1.","evidence":"Isotope tracing of lysosomal amino acid efflux in KO cells, tumor xenograft assays for macropinocytosis-dependent pancreatic cancer; Co-IP of SLC38A9-NPC1, cholesterol manipulation, and mutagenesis of cholesterol-responsive motifs","pmids":["29053970","28336668"],"confidence":"High","gaps":["Whether cholesterol directly binds SLC38A9 or acts allosterically was unclear","Structural basis of cholesterol-responsive motifs not resolved","Relative contribution of arginine sensing versus cholesterol sensing in physiological contexts unknown"]},{"year":2018,"claim":"The enzymatic mechanism of Rag activation by SLC38A9 was defined: SLC38A9 acts as a GEF specifically for RagA, converting it from GDP- to GTP-bound state upon arginine binding, and the crystal structure of SLC38A9 revealed how arginine is trapped in a transitional state stabilized by the conserved WNTMM motif.","evidence":"In vitro GEF reconstitution with nucleotide exchange kinetics; X-ray crystallography of zebrafish SLC38A9 with arginine bound, site-directed mutagenesis of WNTMM motif","pmids":["30181260","29872228"],"confidence":"High","gaps":["How GEF activity toward RagA is coordinated with RagC regulation was unknown","Structure of human SLC38A9 in complex with Rag-Ragulator not yet resolved","Allosteric coupling between arginine binding and GEF activity not structurally defined"]},{"year":2019,"claim":"Reconstitution of human SLC38A9 in liposomes revealed cooperative transport of glutamine and arginine, identified a Na+ binding site at T453, and showed that cholesterol stimulates transport activity while the N-terminal tail is dispensable for intrinsic transport.","evidence":"Purified protein reconstituted in liposomes, transport kinetics, site-directed mutagenesis of T453 and N-terminal deletion","pmids":["31295473"],"confidence":"High","gaps":["Whether glutamine efflux is physiologically relevant to mTORC1 signaling was untested in cells","Mechanism by which cholesterol stimulates transport activity not structurally resolved","Role of Na+ binding in lysosomal context (low luminal Na+) not addressed"]},{"year":2020,"claim":"Cryo-EM structures revealed how the SLC38A9 cytoplasmic tail destabilizes the lysosomal folliculin complex, triggering FLCN:FNIP2 GAP activity toward RagC and completing the picture of how SLC38A9 drives both halves of Rag heterodimer activation.","evidence":"Cryo-EM of LFC with SLC38A9 tail, in vitro reconstitution, GAP activity assays","pmids":["32868926"],"confidence":"High","gaps":["How conformational changes in the transmembrane domain are transmitted to the cytoplasmic tail upon arginine binding is unknown","Whether cholesterol sensing also triggers LFC destabilization was not tested","Full-length SLC38A9 in complex with Rag-Ragulator-LFC not structurally resolved"]},{"year":2021,"claim":"Transcriptional regulation of SLC38A9 was linked to amino acid availability via ATF4 binding to AAREs in the SLC38A9 promoter, and a physical interaction with the lysosomal transporter SLC36A1 was identified.","evidence":"ChIP for ATF4 at SLC38A9 promoter, siRNA knockdown, RT-qPCR in porcine cells; Co-IP and colocalization of SLC38A9-SLC36A1 in C2C12 cells","pmids":["34246831","34572527"],"confidence":"Medium","gaps":["Functional consequence of SLC38A9-SLC36A1 interaction on mTORC1 signaling not established","ATF4 regulation shown only in porcine cells; relevance across species not confirmed","Whether ATF4-driven upregulation constitutes a feedback loop for mTORC1 sensing not tested"]},{"year":2024,"claim":"SLC38A9 was identified as a host factor for SARS-CoV-2 entry, where the furin-exposed multibasic motif on S1 interacts with SLC38A9 in endolysosomes to promote de-acidification and viral entry.","evidence":"Co-IP of S1-SLC38A9, siRNA knockdown blocking pseudovirus entry, endolysosomal pH measurement in multiple cell lines","pmids":["39071889"],"confidence":"Medium","gaps":["Direct binding site on SLC38A9 for S1 multibasic motif not mapped","Whether the arginine-binding pocket mediates S1 recognition is unknown","Not independently replicated by a second group"]},{"year":null,"claim":"Key unresolved questions include the structural basis of pH-dependent activation in human SLC38A9, how cholesterol binding is allosterically coupled to transport and signaling, and whether SLC38A9's role in lysosome positioning via the BORC-kinesin axis represents a physiologically significant signaling output.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full-length human SLC38A9 structure in complex with Rag-Ragulator not available","Cholesterol-binding site not structurally defined","SLC38A9-BORC axis for lysosome redistribution reported only in preprint with limited mechanistic depth"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1,2,3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,5,8]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]}],"complexes":["Rag-Ragulator complex","SLC38A9-NPC1 signaling complex","Lysosomal folliculin complex (LFC)"],"partners":["RRAGA","RRAGC","LAMTOR1","NPC1","FLCN","FNIP2","SLC36A1"],"other_free_text":[]},"mechanistic_narrative":"SLC38A9 is a lysosomal transmembrane transceptor that integrates amino acid and cholesterol sensing with mTORC1 activation at the lysosomal surface. It transports arginine with high Km and mediates arginine-regulated efflux of essential amino acids (including leucine) from lysosomes, coupling lysosomal proteolysis to mTORC1 signaling and supporting macropinocytosis-dependent tumor growth [PMID:25567906, PMID:29053970]. Mechanistically, SLC38A9 functions as a guanine nucleotide exchange factor (GEF) for RagA upon arginine binding and its cytoplasmic tail destabilizes the lysosomal folliculin complex to trigger FLCN:FNIP2 GAP activity toward RagC, collectively driving the Rag GTPase heterodimer into its active configuration [PMID:30181260, PMID:32868926]. SLC38A9 also senses lysosomal cholesterol through conserved cholesterol-responsive motifs and forms a signaling complex with NPC1 that transduces sterol status to mTORC1 independently of arginine [PMID:28336668]."},"prefetch_data":{"uniprot":{"accession":"Q8NBW4","full_name":"Neutral amino acid transporter 9","aliases":["Solute carrier family 38 member 9","Up-regulated in lung cancer 11"],"length_aa":561,"mass_kda":63.8,"function":"Lysosomal amino acid transporter involved in the activation of mTORC1 in response to amino acid levels (PubMed:25561175, PubMed:25567906, PubMed:29053970). Probably acts as an amino acid sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:25567906, PubMed:29053970). Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:25561175, PubMed:25567906). SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids (PubMed:25561175, PubMed:25567906). Acts as an arginine sensor (PubMed:25567906, PubMed:29053970, PubMed:31295473). Following activation by arginine binding, mediates transport of L-glutamine, leucine and tyrosine with high efficiency, and is required for the efficient utilization of these amino acids after lysosomal protein degradation (PubMed:29053970, PubMed:31295473). However, the transport mechanism is not well defined and the role of sodium is not clear (PubMed:25561175, PubMed:31295473). Can disassemble the lysosomal folliculin complex (LFC), and thereby triggers GAP activity of FLCN:FNIP2 toward RRAGC (PubMed:32868926). Acts as an cholesterol sensor that conveys increases in lysosomal cholesterol, leading to lysosomal recruitment and activation of mTORC1 via the Rag GTPases (PubMed:28336668). Guanine exchange factor (GEF) that, upon arginine binding, stimulates GDP release from RRAGA and therefore activates the Rag GTPase heterodimer and the mTORC1 pathway in response to nutrient sufficiency (PubMed:30181260)","subcellular_location":"Lysosome membrane; Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q8NBW4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC38A9","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC38A9","total_profiled":1310},"omim":[{"mim_id":"616203","title":"SOLUTE CARRIER FAMILY 38, MEMBER 9; SLC38A9","url":"https://www.omim.org/entry/616203"},{"mim_id":"613510","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 1; LAMTOR1","url":"https://www.omim.org/entry/613510"},{"mim_id":"607623","title":"NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC1","url":"https://www.omim.org/entry/607623"},{"mim_id":"601231","title":"MECHANISTIC TARGET OF RAPAMYCIN; MTOR","url":"https://www.omim.org/entry/601231"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":54.3}],"url":"https://www.proteinatlas.org/search/SLC38A9"},"hgnc":{"alias_symbol":["FLJ90709","SNAT9"],"prev_symbol":[]},"alphafold":{"accession":"Q8NBW4","domains":[{"cath_id":"-","chopping":"43-105","consensus_level":"high","plddt":59.7457,"start":43,"end":105},{"cath_id":"1.20.1740.10","chopping":"118-249_285-559","consensus_level":"medium","plddt":86.5171,"start":118,"end":559}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBW4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBW4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBW4-F1-predicted_aligned_error_v6.png","plddt_mean":76.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC38A9","jax_strain_url":"https://www.jax.org/strain/search?query=SLC38A9"},"sequence":{"accession":"Q8NBW4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NBW4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NBW4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBW4"}},"corpus_meta":[{"pmid":"25567906","id":"PMC_25567906","title":"Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.","date":"2015","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/25567906","citation_count":674,"is_preprint":false},{"pmid":"25561175","id":"PMC_25561175","title":"SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25561175","citation_count":546,"is_preprint":false},{"pmid":"28336668","id":"PMC_28336668","title":"Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex.","date":"2017","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/28336668","citation_count":438,"is_preprint":false},{"pmid":"29053970","id":"PMC_29053970","title":"mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/29053970","citation_count":361,"is_preprint":false},{"pmid":"25963655","id":"PMC_25963655","title":"Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25963655","citation_count":217,"is_preprint":false},{"pmid":"30181260","id":"PMC_30181260","title":"Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30181260","citation_count":117,"is_preprint":false},{"pmid":"32868926","id":"PMC_32868926","title":"Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9.","date":"2020","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32868926","citation_count":49,"is_preprint":false},{"pmid":"29872228","id":"PMC_29872228","title":"Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state.","date":"2018","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29872228","citation_count":47,"is_preprint":false},{"pmid":"26431368","id":"PMC_26431368","title":"SLC38A9: A lysosomal amino acid transporter at the core of the amino acid-sensing machinery that controls MTORC1.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26431368","citation_count":29,"is_preprint":false},{"pmid":"31295473","id":"PMC_31295473","title":"Insights into the transport side of the human SLC38A9 transceptor.","date":"2019","source":"Biochimica et biophysica acta. 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hannai.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34685533","citation_count":5,"is_preprint":false},{"pmid":"37953772","id":"PMC_37953772","title":"RBM25 binds to and regulates alternative splicing levels of Slc38a9, Csf1, and Coro6 to affect immune and inflammatory processes in H9c2 cells.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/37953772","citation_count":5,"is_preprint":false},{"pmid":"40613244","id":"PMC_40613244","title":"mTORC1 Selective Nano-Inhibitor by Disrupting the Lysosomal Arginine-SLC38A9- mTORC1-CDKs Axis for Precision Bladder Cancer Therapy.","date":"2025","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/40613244","citation_count":4,"is_preprint":false},{"pmid":"39071889","id":"PMC_39071889","title":"SLC38A9 regulates SARS-CoV-2 viral entry.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39071889","citation_count":4,"is_preprint":false},{"pmid":"38142034","id":"PMC_38142034","title":"The SLC38A9-mTOR axis is involved in autophagy in the juvenile yellow catfish (Pelteobagrus fulvidraco) under ammonia stress.","date":"2023","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/38142034","citation_count":3,"is_preprint":false},{"pmid":"34246831","id":"PMC_34246831","title":"Identification of amino acid response element of SLC38A9 as an ATF4-binding site in porcine skeletal muscle cells.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34246831","citation_count":2,"is_preprint":false},{"pmid":"36364703","id":"PMC_36364703","title":"The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36364703","citation_count":2,"is_preprint":false},{"pmid":"40324823","id":"PMC_40324823","title":"SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes.","date":"2025","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/40324823","citation_count":1,"is_preprint":false},{"pmid":"41279478","id":"PMC_41279478","title":"pH-dependent regulation in SLC38A9.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279478","citation_count":0,"is_preprint":false},{"pmid":"41811103","id":"PMC_41811103","title":"SLC38A9 Regulation Affects Hippocampal Neuronal Autophagy: A Potential Alzheimer's Therapeutic Approach by Suppressing Alzheimer's Disease-Related Protein Deposition.","date":"2026","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41811103","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.12.618047","title":"Synergistic Role of Amino Acids in Enhancing mTOR Activation Through Lysosome Positioning","date":"2024-10-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.12.618047","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13211,"output_tokens":3792,"usd":0.048257},"stage2":{"model":"claude-opus-4-6","input_tokens":7202,"output_tokens":2649,"usd":0.153353},"total_usd":0.20161,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC38A9 is a lysosomal transmembrane protein that interacts with the Rag GTPases and Ragulator complex in an amino acid-sensitive fashion, transports arginine with a high Km, and functions upstream of the Rag GTPases to signal arginine sufficiency to mTORC1; overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity.\",\n      \"method\": \"Co-immunoprecipitation, amino acid transport assays, loss-of-function (siRNA knockdown), gain-of-function (overexpression), lysosomal fractionation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, transport assay, KD/OE with defined phenotype; independently replicated in same year by two other groups\",\n      \"pmids\": [\"25567906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC38A9 is an integral part of the Ragulator-RAG GTPases machinery at the lysosomal membrane; gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 impaired amino-acid-induced mTORC1 activation, establishing it as a physical and functional component of the amino acid sensing machinery.\",\n      \"method\": \"Functional proteomic analysis (AP-MS), Co-immunoprecipitation, siRNA knockdown, lysosomal localization by immunofluorescence, amino acid transport assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MS interactome, Co-IP, KD with defined phenotype, transport assay); independently replicated\",\n      \"pmids\": [\"25561175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner; SLC38A9 depletion retains mTOR at the lysosome but prevents its activation; SLC38A9 overexpression causes RHEB GTPase-dependent hyperactivation of mTORC1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence localization, nucleotide state-specific Rag mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, nucleotide-state dependency established; replicated by two concurrent independent groups\",\n      \"pmids\": [\"25963655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLC38A9 mediates transport of many essential amino acids (including leucine) out of lysosomes in an arginine-regulated fashion; SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1; pancreatic cancer cells using macropinocytosed protein as nutrient require SLC38A9 for tumor formation, establishing arginine as a lysosomal messenger coupling mTORC1 activation to essential amino acid release.\",\n      \"method\": \"Isotope tracing (lysosomal amino acid efflux), SLC38A9 knockout cells, in vitro transport reconstitution, tumor xenograft assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — isotope tracing efflux assay, KO cells with multiple phenotypic readouts, in vivo tumor assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29053970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lysosomal cholesterol drives mTORC1 activation through SLC38A9 via conserved cholesterol-responsive motifs; SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function; NPC1 binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function, forming an SLC38A9-NPC1 signaling complex.\",\n      \"method\": \"Co-immunoprecipitation (SLC38A9-NPC1 interaction), cholesterol manipulation (cyclodextrin delivery), SLC38A9 knockout/knockdown, mutagenesis of cholesterol-responsive motifs\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of SLC38A9-NPC1 complex, KO cells, mutagenesis of functional motifs, multiple orthogonal approaches\",\n      \"pmids\": [\"28336668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC38A9 acts as a guanine exchange factor (GEF) for RagA: upon arginine binding, SLC38A9 converts RagA from GDP- to GTP-loaded state, thereby activating the Rag GTPase heterodimer toward the active state; this is mechanistically distinct from Ragulator, which acts as a GEF for RagC.\",\n      \"method\": \"In vitro GEF assay (nucleotide exchange kinetics), nucleotide state-specific mutants, biochemical reconstitution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro GEF assay with reconstitution and nucleotide exchange kinetics; mechanistically distinct from prior work\",\n      \"pmids\": [\"30181260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structure of zebrafish SLC38A9 in complex with arginine in the cytosol-open state reveals that arginine is locked in a transitional state stabilized by TM1 anchored at the groove between TM5 and TM7 via the conserved WNTMM motif; mutations in this motif abolished arginine transport.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, transport assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis with functional validation in a single study\",\n      \"pmids\": [\"29872228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Human SLC38A9 reconstituted in liposomes shows cooperative transport of glutamine and arginine; a novel Na+ binding site (T453) was identified; cholesterol stimulates glutamine and arginine transport; SLC38A9 is competent for glutamine efflux but not arginine efflux; arginine acts as a modulator stimulating glutamine efflux and binds at a site distinct from glutamine; the N-terminal tail is not required for intrinsic transport function.\",\n      \"method\": \"Protein purification from E. coli, reconstitution in liposomes, transport assay, site-directed mutagenesis (T453), deletion mutagenesis of N-terminus, bioinformatics\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in liposomes with mutagenesis and kinetic analysis; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"31295473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of the lysosomal folliculin complex (LFC) — consisting of inactive Rag dimer, Ragulator, and FLCN:FNIP2 — with the cytoplasmic tail of SLC38A9 reveal that the SLC38A9 cytoplasmic tail destabilizes the LFC, thereby triggering GAP activity of FLCN:FNIP2 toward RagC and promoting Rag dimer activation in pre- and post-GTP hydrolysis states.\",\n      \"method\": \"Cryo-EM structure determination, in vitro reconstitution of LFC, GAP activity assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with functional reconstitution and GAP activity validation\",\n      \"pmids\": [\"32868926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLC38A9 interacts with SLC36A1 at the lysosomal surface; they enhance each other's expression levels and lysosomal localization; interacting proteins of SLC38A9 in C2C12 cells participate in amino acid sensing, mTORC1 signaling, and protein synthesis.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, mass spectrometry interactome\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and colocalization without in-depth functional follow-up of the specific interaction\",\n      \"pmids\": [\"34572527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATF4 binds to two amino acid response elements (AAREs) in the SLC38A9 promoter region, including one in the first intron within the core promoter, and regulates SLC38A9 mRNA expression in porcine skeletal muscle cells in response to amino acid availability.\",\n      \"method\": \"Promoter analysis, chromatin immunoprecipitation (ChIP), siRNA knockdown, RT-qPCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP establishes direct ATF4 binding, single lab, single model organism cell type\",\n      \"pmids\": [\"34246831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The multibasic motif on SARS-CoV-2 S1 protein (exposed after furin cleavage) interacts with SLC38A9 in the endolysosome; SLC38A9 knockdown prevents S1-induced endolysosome de-acidification and blocks S protein-mediated pseudo-SARS-CoV-2 entry in multiple cell lines.\",\n      \"method\": \"Co-immunoprecipitation (S1-SLC38A9 interaction), siRNA knockdown, pseudovirus entry assay, endolysosomal pH measurement\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus KD with defined viral entry phenotype across multiple cell lines, single lab\",\n      \"pmids\": [\"39071889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIV-1 Tat protein interacts with SLC38A9 via its arginine-rich basic domain in endolysosomes; this interaction causes endolysosome dysfunction, enhanced HIV-1 LTR transactivation, and cellular senescence in human astrocytes.\",\n      \"method\": \"Co-immunoprecipitation (Tat-SLC38A9), domain mapping (arginine-rich domain), endolysosomal pH/function assays, senescence markers, SLC38A9 knockdown\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with domain mapping, KD with multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"40324823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC38A9 arginine uptake is pH-dependent; histidine residue His544 serves as the pH sensor — mutating His544 abolishes pH dependence of arginine uptake without impairing overall transport activity; cryo-EM structures at high and low pH reveal a working model for pH-induced conformational activation of SLC38A9.\",\n      \"method\": \"Transport assay (pH titration), site-directed mutagenesis (His544), cryo-EM structure determination at two pH conditions\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — transport assay with mutagenesis plus structural comparison; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41279478\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC38A9 mediates amino acid-induced lysosome redistribution toward the cell periphery via the SLC38A9-BORC-kinesin 1/3 axis; this peripheral lysosome positioning synergizes with arginine-mediated mTOR activation to enhance mTORC1 activity.\",\n      \"method\": \"High-content imaging of lysosome positioning, kinesin 1/3 KO cells, siRNA knockdown, mTOR activity assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint with imaging and KO but limited mechanistic depth for SLC38A9-specific role in BORC axis\",\n      \"pmids\": [\"bio_10.1101_2024.10.12.618047\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SLC38A9 is a lysosomal transmembrane transporter-receptor ('transceptor') that senses intra-lysosomal arginine and cholesterol, acts as a GEF for RagA (converting it to the GTP-bound active state) and destabilizes the lysosomal folliculin complex to trigger FLCN:FNIP2 GAP activity toward RagC, collectively driving Rag GTPase activation and mTORC1 recruitment/activation at the lysosomal surface; it also mediates arginine-regulated efflux of essential amino acids (including leucine) from lysosomes, couples lysosomal proteolysis-derived amino acids to mTORC1 signaling, interacts with NPC1 to transduce cholesterol status, and its cytoplasmic tail and conserved WNTMM transmembrane motif are structurally defined as critical functional elements.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC38A9 is a lysosomal transmembrane transceptor that integrates amino acid and cholesterol sensing with mTORC1 activation at the lysosomal surface. It transports arginine with high Km and mediates arginine-regulated efflux of essential amino acids (including leucine) from lysosomes, coupling lysosomal proteolysis to mTORC1 signaling and supporting macropinocytosis-dependent tumor growth [PMID:25567906, PMID:29053970]. Mechanistically, SLC38A9 functions as a guanine nucleotide exchange factor (GEF) for RagA upon arginine binding and its cytoplasmic tail destabilizes the lysosomal folliculin complex to trigger FLCN:FNIP2 GAP activity toward RagC, collectively driving the Rag GTPase heterodimer into its active configuration [PMID:30181260, PMID:32868926]. SLC38A9 also senses lysosomal cholesterol through conserved cholesterol-responsive motifs and forms a signaling complex with NPC1 that transduces sterol status to mTORC1 independently of arginine [PMID:28336668].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Three independent groups simultaneously established that SLC38A9 is a physical component of the Rag-Ragulator machinery at the lysosomal membrane, resolving the long-sought identity of a lysosomal amino acid sensor upstream of mTORC1.\",\n      \"evidence\": \"Co-IP, AP-MS proteomics, siRNA knockdown, overexpression, amino acid transport assays, and nucleotide state-dependent interaction studies in mammalian cells\",\n      \"pmids\": [\"25567906\", \"25561175\", \"25963655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which SLC38A9 activates Rag GTPases was unknown\",\n        \"Whether SLC38A9 senses nutrients other than arginine was unresolved\",\n        \"Structural basis of arginine recognition not yet determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SLC38A9 was shown to have a dual signaling role—functioning as an arginine-regulated transporter that effluxes essential amino acids (notably leucine) from lysosomes to activate mTORC1 via proteolysis-derived nutrients, and independently sensing lysosomal cholesterol via a complex with NPC1.\",\n      \"evidence\": \"Isotope tracing of lysosomal amino acid efflux in KO cells, tumor xenograft assays for macropinocytosis-dependent pancreatic cancer; Co-IP of SLC38A9-NPC1, cholesterol manipulation, and mutagenesis of cholesterol-responsive motifs\",\n      \"pmids\": [\"29053970\", \"28336668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether cholesterol directly binds SLC38A9 or acts allosterically was unclear\",\n        \"Structural basis of cholesterol-responsive motifs not resolved\",\n        \"Relative contribution of arginine sensing versus cholesterol sensing in physiological contexts unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The enzymatic mechanism of Rag activation by SLC38A9 was defined: SLC38A9 acts as a GEF specifically for RagA, converting it from GDP- to GTP-bound state upon arginine binding, and the crystal structure of SLC38A9 revealed how arginine is trapped in a transitional state stabilized by the conserved WNTMM motif.\",\n      \"evidence\": \"In vitro GEF reconstitution with nucleotide exchange kinetics; X-ray crystallography of zebrafish SLC38A9 with arginine bound, site-directed mutagenesis of WNTMM motif\",\n      \"pmids\": [\"30181260\", \"29872228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How GEF activity toward RagA is coordinated with RagC regulation was unknown\",\n        \"Structure of human SLC38A9 in complex with Rag-Ragulator not yet resolved\",\n        \"Allosteric coupling between arginine binding and GEF activity not structurally defined\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution of human SLC38A9 in liposomes revealed cooperative transport of glutamine and arginine, identified a Na+ binding site at T453, and showed that cholesterol stimulates transport activity while the N-terminal tail is dispensable for intrinsic transport.\",\n      \"evidence\": \"Purified protein reconstituted in liposomes, transport kinetics, site-directed mutagenesis of T453 and N-terminal deletion\",\n      \"pmids\": [\"31295473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether glutamine efflux is physiologically relevant to mTORC1 signaling was untested in cells\",\n        \"Mechanism by which cholesterol stimulates transport activity not structurally resolved\",\n        \"Role of Na+ binding in lysosomal context (low luminal Na+) not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cryo-EM structures revealed how the SLC38A9 cytoplasmic tail destabilizes the lysosomal folliculin complex, triggering FLCN:FNIP2 GAP activity toward RagC and completing the picture of how SLC38A9 drives both halves of Rag heterodimer activation.\",\n      \"evidence\": \"Cryo-EM of LFC with SLC38A9 tail, in vitro reconstitution, GAP activity assays\",\n      \"pmids\": [\"32868926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How conformational changes in the transmembrane domain are transmitted to the cytoplasmic tail upon arginine binding is unknown\",\n        \"Whether cholesterol sensing also triggers LFC destabilization was not tested\",\n        \"Full-length SLC38A9 in complex with Rag-Ragulator-LFC not structurally resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Transcriptional regulation of SLC38A9 was linked to amino acid availability via ATF4 binding to AAREs in the SLC38A9 promoter, and a physical interaction with the lysosomal transporter SLC36A1 was identified.\",\n      \"evidence\": \"ChIP for ATF4 at SLC38A9 promoter, siRNA knockdown, RT-qPCR in porcine cells; Co-IP and colocalization of SLC38A9-SLC36A1 in C2C12 cells\",\n      \"pmids\": [\"34246831\", \"34572527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of SLC38A9-SLC36A1 interaction on mTORC1 signaling not established\",\n        \"ATF4 regulation shown only in porcine cells; relevance across species not confirmed\",\n        \"Whether ATF4-driven upregulation constitutes a feedback loop for mTORC1 sensing not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SLC38A9 was identified as a host factor for SARS-CoV-2 entry, where the furin-exposed multibasic motif on S1 interacts with SLC38A9 in endolysosomes to promote de-acidification and viral entry.\",\n      \"evidence\": \"Co-IP of S1-SLC38A9, siRNA knockdown blocking pseudovirus entry, endolysosomal pH measurement in multiple cell lines\",\n      \"pmids\": [\"39071889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding site on SLC38A9 for S1 multibasic motif not mapped\",\n        \"Whether the arginine-binding pocket mediates S1 recognition is unknown\",\n        \"Not independently replicated by a second group\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of pH-dependent activation in human SLC38A9, how cholesterol binding is allosterically coupled to transport and signaling, and whether SLC38A9's role in lysosome positioning via the BORC-kinesin axis represents a physiologically significant signaling output.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Full-length human SLC38A9 structure in complex with Rag-Ragulator not available\",\n        \"Cholesterol-binding site not structurally defined\",\n        \"SLC38A9-BORC axis for lysosome redistribution reported only in preprint with limited mechanistic depth\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 8]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"Rag-Ragulator complex\",\n      \"SLC38A9-NPC1 signaling complex\",\n      \"Lysosomal folliculin complex (LFC)\"\n    ],\n    \"partners\": [\n      \"RRAGA\",\n      \"RRAGC\",\n      \"LAMTOR1\",\n      \"NPC1\",\n      \"FLCN\",\n      \"FNIP2\",\n      \"SLC36A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}