Affinage

SLC38A9

Neutral amino acid transporter 9 · UniProt Q8NBW4

Length
561 aa
Mass
63.8 kDa
Annotated
2026-04-28
25 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2015 High

    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

    PMID:25561175 PMID:25567906 PMID:25963655

    Open questions at the time
    • 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
  2. 2017 High

    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

    PMID:28336668 PMID:29053970

    Open questions at the time
    • 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
  3. 2018 High

    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

    PMID:29872228 PMID:30181260

    Open questions at the time
    • 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
  4. 2019 High

    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

    PMID:31295473

    Open questions at the time
    • 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
  5. 2020 High

    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

    PMID:32868926

    Open questions at the time
    • 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
  6. 2021 Medium

    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

    PMID:34246831 PMID:34572527

    Open questions at the time
    • 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
  7. 2024 Medium

    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

    PMID:39071889

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005764 lysosome 5
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-382551 Transport of small molecules 2 R-HSA-9612973 Autophagy 1
Partners
FLCNFNIP2LAMTOR1NPC1RRAGARRAGCSLC36A1
Complex memberships
Lysosomal folliculin complex (LFC)Rag-Ragulator complexSLC38A9-NPC1 signaling complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. Co-immunoprecipitation, amino acid transport assays, loss-of-function (siRNA knockdown), gain-of-function (overexpression), lysosomal fractionation Science High 25567906
2015 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. Functional proteomic analysis (AP-MS), Co-immunoprecipitation, siRNA knockdown, lysosomal localization by immunofluorescence, amino acid transport assay Nature High 25561175
2015 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. Co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence localization, nucleotide state-specific Rag mutants Molecular and cellular biology High 25963655
2017 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. Isotope tracing (lysosomal amino acid efflux), SLC38A9 knockout cells, in vitro transport reconstitution, tumor xenograft assay Cell High 29053970
2017 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. Co-immunoprecipitation (SLC38A9-NPC1 interaction), cholesterol manipulation (cyclodextrin delivery), SLC38A9 knockout/knockdown, mutagenesis of cholesterol-responsive motifs Science High 28336668
2018 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. In vitro GEF assay (nucleotide exchange kinetics), nucleotide state-specific mutants, biochemical reconstitution Proceedings of the National Academy of Sciences of the United States of America High 30181260
2018 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. X-ray crystallography, site-directed mutagenesis, transport assay Nature structural & molecular biology High 29872228
2019 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. Protein purification from E. coli, reconstitution in liposomes, transport assay, site-directed mutagenesis (T453), deletion mutagenesis of N-terminus, bioinformatics Biochimica et biophysica acta. Biomembranes High 31295473
2020 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. Cryo-EM structure determination, in vitro reconstitution of LFC, GAP activity assay Nature structural & molecular biology High 32868926
2021 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. Co-immunoprecipitation, immunofluorescence colocalization, mass spectrometry interactome Biomolecules Medium 34572527
2021 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. Promoter analysis, chromatin immunoprecipitation (ChIP), siRNA knockdown, RT-qPCR Biochemical and biophysical research communications Medium 34246831
2024 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. Co-immunoprecipitation (S1-SLC38A9 interaction), siRNA knockdown, pseudovirus entry assay, endolysosomal pH measurement iScience Medium 39071889
2025 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. Co-immunoprecipitation (Tat-SLC38A9), domain mapping (arginine-rich domain), endolysosomal pH/function assays, senescence markers, SLC38A9 knockdown Life science alliance Medium 40324823
2025 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. Transport assay (pH titration), site-directed mutagenesis (His544), cryo-EM structure determination at two pH conditions bioRxivpreprint Medium 41279478
2024 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. High-content imaging of lysosome positioning, kinesin 1/3 KO cells, siRNA knockdown, mTOR activity assay bioRxivpreprint Low bio_10.1101_2024.10.12.618047

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science (New York, N.Y.) 674 25567906
2015 SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature 546 25561175
2017 Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science (New York, N.Y.) 438 28336668
2017 mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient. Cell 361 29053970
2015 Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9. Molecular and cellular biology 217 25963655
2018 Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proceedings of the National Academy of Sciences of the United States of America 117 30181260
2020 Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. Nature structural & molecular biology 49 32868926
2018 Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state. Nature structural & molecular biology 47 29872228
2015 SLC38A9: A lysosomal amino acid transporter at the core of the amino acid-sensing machinery that controls MTORC1. Autophagy 29 26431368
2019 Insights into the transport side of the human SLC38A9 transceptor. Biochimica et biophysica acta. Biomembranes 24 31295473
2015 The amino acid transporter SLC38A9 regulates MTORC1 and autophagy. Autophagy 11 26506891
2024 Arginine alleviates Clostridium perfringens α toxin-induced intestinal injury in vivo and in vitro via the SLC38A9/mTORC1 pathway. Frontiers in immunology 9 38638435
2021 Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells. Biomolecules 9 34572527
2022 Slc38a9 Deficiency Induces Apoptosis and Metabolic Dysregulation and Leads to Premature Death in Zebrafish. International journal of molecular sciences 6 35457018
2021 D-Tryptophan enhances the reproductive organ-specific expression of the amino acid transporter homolog Dr-SLC38A9 involved in the sexual induction of planarian Dugesia ryukyuensis. Zoological letters 6 33743841
2023 RBM25 binds to and regulates alternative splicing levels of Slc38a9, Csf1, and Coro6 to affect immune and inflammatory processes in H9c2 cells. PeerJ 5 37953772
2021 Arginine Regulates TOR Signaling Pathway through SLC38A9 in Abalone Haliotis discus hannai. Cells 5 34685533
2025 mTORC1 Selective Nano-Inhibitor by Disrupting the Lysosomal Arginine-SLC38A9- mTORC1-CDKs Axis for Precision Bladder Cancer Therapy. Advanced materials (Deerfield Beach, Fla.) 4 40613244
2024 SLC38A9 regulates SARS-CoV-2 viral entry. iScience 4 39071889
2023 The SLC38A9-mTOR axis is involved in autophagy in the juvenile yellow catfish (Pelteobagrus fulvidraco) under ammonia stress. Environmental pollution (Barking, Essex : 1987) 3 38142034
2022 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. Nutrients 2 36364703
2021 Identification of amino acid response element of SLC38A9 as an ATF4-binding site in porcine skeletal muscle cells. Biochemical and biophysical research communications 2 34246831
2025 SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes. Life science alliance 1 40324823
2026 SLC38A9 Regulation Affects Hippocampal Neuronal Autophagy: A Potential Alzheimer's Therapeutic Approach by Suppressing Alzheimer's Disease-Related Protein Deposition. CNS neuroscience & therapeutics 0 41811103
2025 pH-dependent regulation in SLC38A9. bioRxiv : the preprint server for biology 0 41279478