{"gene":"SLC15A4","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2020,"finding":"SLC15A4 physically interacts with TASL (encoded by CXorf21) on the lysosomal membrane; TASL localization and function depend on this interaction. TASL contains a conserved pLxIS motif that recruits and activates IRF5, linking endolysosomal TLR7/8/9 sensing specifically to the IRF pathway without affecting NF-κB or MAPK signaling.","method":"Co-immunoprecipitation, extensive mutagenesis of TASL, deletion of SLC15A4 or TASL with pathway-specific readouts (IRF vs NF-κB/MAPK), primary and transformed human immune cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, mutagenesis, genetic KO, pathway dissection) in one study, replicated concept across multiple subsequent papers","pmids":["32433612"],"is_preprint":false},{"year":2010,"finding":"Slc15a4 (PHT1) is required for TLR7- and TLR9-mediated type I IFN and proinflammatory cytokine production specifically in plasmacytoid dendritic cells (pDCs), but not in conventional DCs; AP-3, BLOC-1, and BLOC-2 Hermansky-Pudlak syndrome proteins form a membrane trafficking pathway also uniquely required for endosomal TLR signaling in pDCs.","method":"Forward genetic screen (feeble ENU mutant), positional cloning, cell-type-specific cytokine assays, genetic epistasis with AP-3/BLOC complex mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean genetic model with defined cellular phenotype, epistasis with trafficking pathway, replicated by multiple subsequent labs","pmids":["21045126"],"is_preprint":false},{"year":2014,"finding":"SLC15A4 is a lysosome-resident proton-coupled amino-acid transporter that moves histidine and oligopeptides from the lysosomal lumen to the cytosol; its transporter activity (not merely its structural presence) is necessary for TLR7/9-triggered cytokine production. SLC15A4 loss disrupts endolysosomal pH regulation and v-ATPase integrity, leading to impaired mTOR pathway activation and failure of the IRF7-IFN-I regulatory circuit.","method":"Transporter activity assays, pH measurement, mTOR pathway analysis, transporter-dead mutant rescue experiments in B cells and pDCs, mouse lupus model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 — transporter activity requirement shown with activity-dead mutant, mechanistic dissection of mTOR/IRF7 axis, multiple orthogonal readouts","pmids":["25238095"],"is_preprint":false},{"year":2022,"finding":"SLC15A4 is required for trafficking and colocalization of nucleic acid-sensing TLRs and their ligands to endolysosomes, and for formation of the LAMP2+VAMP3+ hybrid compartment in which IFN-I production is initiated. SLC15A4 trafficking to endolysosomes depends on the AP-3 complex. A function-impairing mutation in SLC15A3 does not impair type I IFN production by pDCs, indicating functional divergence within the SLC15 family.","method":"Live-cell fluorescence imaging/colocalization, genetic comparison of SLC15A4 vs SLC15A3 mutant mice, AP-3 complex genetic epistasis, feeble mutant and genomic deletion models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with functional consequence, genetic epistasis, functional distinction from paralog","pmids":["35349343"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human SLC15A4 reveal apo monomeric and dimeric outward-facing conformations (dimeric form stabilized by four cholesterol molecules at the interface), and a TASL-bound complex in which SLC15A4 adopts an inward-facing conformation that forms a binding pocket into which the N-terminal helix of TASL inserts — a previously undescribed interaction mode for solute carriers.","method":"Cryo-EM structure determination at high resolution, structural comparison of apo vs TASL-bound states","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures of multiple conformational states with functional interpretation, independently resolved in same year by a second group","pmids":["37863913"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of SLC15A4 (PHT1) in the outward-open conformation combined with biochemical and structural modeling defines the inward-open cavity as the TASL-binding site; the first 16 N-terminal residues of TASL fold into a helix that inserts into this cavity.","method":"Cryo-EM, biochemical binding assays, structural modeling of PHT1-TASL complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — independent cryo-EM structure corroborating Chen et al. 2023, with biochemical validation","pmids":["37709742"],"is_preprint":false},{"year":2023,"finding":"Feeblin, a small-molecule inhibitor, binds SLC15A4 in a lysosomal outward-open conformation that is incompatible with TASL binding on the cytoplasmic side; this conformation-locking mechanism prevents TASL recruitment and leads to TASL proteostatic degradation, thereby blocking TLR7/8-IRF5 signaling.","method":"Cryo-EM structure of feeblin-SLC15A4 complex, phenotypic assay for TASL degradation, TLR pathway activity assays in human immune cells including SLE patient cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with mechanistic pharmacological validation and functional readouts","pmids":["37863876"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of SLC15A3 (apo) and SLC15A4 (apo and dipeptide-bound) define the specific dipeptide recognition mechanism; each protomer adopts an outward-facing conformation, and the N-terminal helix of TASL inserts deeply into the inward-facing cavity of SLC15A4 in the complex structure.","method":"Cryo-EM structure determination of SLC15A3 apo, SLC15A4 apo, SLC15A4+substrate, and SLC15A4-TASL complex","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — multiple cryo-EM structures revealing substrate recognition and TASL recruitment mechanism","pmids":["39719710"],"is_preprint":false},{"year":2021,"finding":"SLC15A4 loss in macrophages causes insufficient pyruvate biotransformation to the TCA cycle while increasing glutaminolysis; SLC15A4 is required for M1-prone metabolic shift and inflammatory IL-12 production after TLR9 stimulation. SLC15A4 was found in close proximity to AMPK and mTOR, and its deficiency impaired TLR-mediated AMPK activation. SLC15A4-intact macrophages resist nutrient fluctuations by limiting glutamine use, protecting respiratory homeostasis.","method":"Proximity-dependent biotin identification (BioID), fluxome analysis (metabolic flux), macrophage KO, AMPK/mTOR activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — BioID proximity proteomics plus quantitative fluxome analysis with multiple orthogonal mechanistic readouts","pmids":["34385317"],"is_preprint":false},{"year":2021,"finding":"Human SLC15A4 exhibits pH- and temperature-dependent transport activity for dipeptides and tripeptides; it localizes to LAMP1+ compartments and constitutively associates with Raptor and LAMTORs (mTORC1 regulatory complex components). Knockdown in human pDC line CAL-1 impairs TLR7/8/9-triggered IFN-I production and mTORC1 activity, and impairs autophagy sustainability and mitochondrial membrane potential under starvation.","method":"Transport activity assays in human cells, LAMP1 co-localization, co-immunoprecipitation with Raptor/LAMTORs, SLC15A4 KD in CAL-1 cells with IFN-I/mTORC1/autophagy/mitochondrial readouts","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — direct transport assay, reciprocal co-IP, clean KD with multiple defined cellular phenotypes","pmids":["33560415"],"is_preprint":false},{"year":2017,"finding":"SLC15A4 is required for mast cell secretory-granule (lysosome-derived) homeostasis; its loss diminishes mTORC1 activity, increasing nuclear translocation of TFEB, which causes hyperdegranulation. SLC15A4 controls the mTORC1-TFEB signaling axis to limit FcεRI-mediated and IL-33-triggered inflammatory responses both in vitro and in vivo.","method":"Slc15a4 KO mast cells, mTORC1 activity assays, TFEB localization imaging, degranulation assays, FcεRI and IL-33 stimulation in vitro and in vivo","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined molecular pathway (mTORC1-TFEB) and multiple functional readouts in vitro and in vivo","pmids":["29155995"],"is_preprint":false},{"year":2018,"finding":"SLC15A4 (PHT1) is expressed on endosomal membranes of macrophages (whereas PEPT2 is on the plasma membrane); both transporters transport bacterially derived di/tripeptides (including muramyl dipeptide) to facilitate NOD-dependent cytokine production. Pht1 KO mice show reduced proinflammatory cytokine responses to bacterial peptide ligands.","method":"Fluorescent MDP-rhodamine imaging, Pht1 KO mice cytokine assays, subcellular fractionation/localization","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct localization by live imaging, KO animal model with defined cytokine phenotype","pmids":["29784761"],"is_preprint":false},{"year":2024,"finding":"Chemoproteomic (activity-based protein profiling) approach identified first-in-class covalent inhibitors of SLC15A4 that suppress SLC15A4-mediated endolysosomal TLR and NOD signaling in human and mouse immune cells and suppress inflammation in vivo; mechanistically the inhibitors target SLC15A4 transporter function to block downstream immune signaling.","method":"Chemical proteomics/ABPP, functional inhibitor characterization in multiple human/mouse immune cell types, in vivo inflammation models, clinical ex vivo validation","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1-2 — chemoproteomic target engagement combined with functional pathway assays in vivo and ex vivo","pmids":["38191941"],"is_preprint":false},{"year":2016,"finding":"PHT1 (SLC15A4) plays an important role in histidine transport in brain parenchyma; ablation of Pht1 reduces L-histidine uptake in brain slices by ~50% and reduces brain parenchyma L-histidine levels in vivo, with compensatory upregulation of PEPT2 (~2-fold) in Pht1 null mice.","method":"In vitro brain slice uptake assays, in vivo pharmacokinetics, biodistribution studies, PCR and immunoblot in Pht1 null vs wildtype mice","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KO model with direct transport functional readout, but single lab and no reconstitution","pmids":["27845049"],"is_preprint":false},{"year":2019,"finding":"PHT1 (SLC15A4) mediates carnosine uptake in glioblastoma cells; siRNA-mediated knockdown of PHT1 significantly reduces carnosine uptake, and competitive inhibition with L-histidine (PHT1/2 inhibitor) blocks carnosine entry.","method":"siRNA knockdown, HPLC-MS carnosine uptake assay, competitive inhibition with substrate analogs","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with specific transport substrate readout, but single lab","pmids":["31073693"],"is_preprint":false},{"year":2022,"finding":"miR-31-5p directly targets the 3'UTR of SLC15A4 and negatively regulates SLC15A4 expression; inhibition of miR-31-5p in pDC-like cells increases IRF5 phosphorylation and IFN-stimulated gene induction upon TLR stimulation, while overexpression of miR-31-5p reverses this effect.","method":"Luciferase reporter assay (miRNA-target validation), miR-31-5p mimic/inhibitor transfection, IRF5 phosphorylation immunofluorescence, ISG expression by RT-qPCR","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct luciferase validation of miRNA targeting, functional rescue experiments, but single lab","pmids":["36510495"],"is_preprint":false},{"year":2025,"finding":"Conformation-selective antibodies against SLC15A4 reveal two functional states: clone 107 binds the TASL-binding-incompetent luminal-open (outward-facing) state, while clone 235 stabilizes the TASL-binding-competent cytoplasmic-open (inward-facing) state, demonstrating that TASL recruitment depends on a conformational switch in SLC15A4.","method":"Antibody screening, cryo-EM validation of conformational states, functional assays for TASL binding competence, TLR pathway activity readouts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — structural and antibody-based conformational trapping with functional validation of TASL recruitment mechanism","pmids":["40781080"],"is_preprint":false}],"current_model":"SLC15A4 (PHT1) is an endolysosomal proton-coupled transporter of histidine and di/tripeptides that localizes to LAMP1+ lysosomes via an AP-3-dependent trafficking pathway; upon inward-facing conformational change it recruits the adaptor TASL (via TASL's N-terminal helix inserting into its central cavity), which then activates IRF5 to drive type I interferon production downstream of endolysosomal TLR7/8/9 — while its transporter activity additionally optimizes lysosomal pH, mTORC1/AMPK signaling, and macrophage metabolic reprogramming required for full innate immune responses."},"narrative":{"teleology":[{"year":2010,"claim":"A forward genetic screen established that SLC15A4 is selectively required for TLR7/9-mediated IFN-I production in pDCs but not conventional DCs, and linked it genetically to the AP-3/BLOC trafficking pathway — resolving whether this transporter has a non-redundant immune function.","evidence":"ENU mutagenesis (feeble mutant), positional cloning, cell-type-specific cytokine assays, epistasis with AP-3/BLOC mutants in mouse","pmids":["21045126"],"confidence":"High","gaps":["Mechanism by which SLC15A4 supports IFN-I was unknown","Whether transporter activity per se is required was untested","Downstream signaling pathway not delineated"]},{"year":2014,"claim":"Demonstrating that SLC15A4's transport activity — not merely its physical presence — is required for TLR-triggered cytokine production resolved a key mechanistic question: transporter-dead mutants failed to restore pH regulation, v-ATPase integrity, and mTOR/IRF7 signaling.","evidence":"Transporter activity assays, endolysosomal pH measurements, transporter-dead mutant rescue experiments in B cells and pDCs, mouse lupus model","pmids":["25238095"],"confidence":"High","gaps":["How transport activity couples to mTOR activation was unclear","Identity of direct signaling interactors remained unknown","Role in non-pDC immune cells unexplored"]},{"year":2017,"claim":"Extension of SLC15A4 function beyond pDCs revealed that it governs the mTORC1-TFEB axis in mast cells, controlling secretory granule homeostasis and limiting FcεRI/IL-33-driven inflammatory responses.","evidence":"Slc15a4 KO mast cells, mTORC1 activity assays, TFEB nuclear translocation imaging, degranulation assays in vitro and in vivo","pmids":["29155995"],"confidence":"High","gaps":["How SLC15A4 transporter activity feeds into mTORC1 regulation mechanistically","Whether SLC15A4 physically associates with mTORC1 machinery"]},{"year":2018,"claim":"Localization of SLC15A4 to endosomal membranes of macrophages and demonstration that it transports bacterially derived muramyl dipeptide established a role in NOD-dependent innate sensing beyond TLR pathways.","evidence":"Fluorescent MDP-rhodamine imaging, Pht1 KO mice cytokine assays, subcellular fractionation","pmids":["29784761"],"confidence":"High","gaps":["Whether NOD and TLR functions of SLC15A4 are mechanistically separable","Structural basis of peptide recognition unknown"]},{"year":2020,"claim":"Identification of TASL as a direct lysosomal binding partner of SLC15A4 answered the long-standing question of how SLC15A4 specifically activates the IRF pathway: TASL's pLxIS motif recruits and activates IRF5, decoupling IFN-I signaling from NF-κB/MAPK.","evidence":"Co-immunoprecipitation, extensive TASL mutagenesis, SLC15A4/TASL deletion with pathway-specific readouts, primary and transformed human immune cells","pmids":["32433612"],"confidence":"High","gaps":["Structural basis of SLC15A4-TASL interaction unknown","Whether SLC15A4 conformational state governs TASL recruitment","How transporter function relates to adaptor recruitment"]},{"year":2021,"claim":"BioID and fluxome analyses revealed that SLC15A4 constitutively associates with Raptor and LAMTOR components, and that its loss rewires macrophage metabolism (reduced pyruvate-to-TCA flux, increased glutaminolysis), establishing SLC15A4 as a metabolic sensor coupling lysosomal transport to mTORC1/AMPK signaling.","evidence":"Proximity-dependent biotin identification (BioID), metabolic flux analysis, macrophage KO, AMPK/mTOR activity assays; co-IP with Raptor/LAMTORs in CAL-1 human pDC line","pmids":["34385317","33560415"],"confidence":"High","gaps":["Direct versus indirect nature of SLC15A4-mTORC1 association not resolved","Whether metabolic reprogramming and TASL/IRF5 signaling are independent outputs"]},{"year":2022,"claim":"Live-cell imaging established that SLC15A4 is required for formation of the LAMP2+VAMP3+ hybrid compartment where IFN-I production initiates, and confirmed AP-3-dependent trafficking; functional divergence from paralog SLC15A3 was demonstrated genetically.","evidence":"Live-cell fluorescence imaging/colocalization, SLC15A3 vs SLC15A4 mutant comparison, AP-3 genetic epistasis in mouse models","pmids":["35349343"],"confidence":"High","gaps":["Molecular determinants of AP-3 recognition on SLC15A4 not identified","Whether SLC15A3 and SLC15A4 have overlapping substrates in immune contexts"]},{"year":2023,"claim":"Cryo-EM structures resolved the conformational cycle of SLC15A4 and the unprecedented mechanism of TASL recruitment: TASL's N-terminal helix inserts into the inward-facing cavity, while a cholesterol-stabilized dimer represents the outward-facing apo state. The inhibitor feeblin locks SLC15A4 in the outward-open conformation incompatible with TASL binding, causing TASL degradation and blocking TLR-IRF5 signaling.","evidence":"Multiple independent cryo-EM structures (apo monomeric/dimeric, TASL-bound, feeblin-bound), biochemical binding assays, TLR pathway assays including SLE patient cells","pmids":["37863913","37709742","37863876"],"confidence":"High","gaps":["How lysosomal luminal conditions trigger the outward-to-inward conformational switch in vivo","Whether transport and TASL recruitment are simultaneous or sequential","Substrate-bound inward-facing structure not yet captured"]},{"year":2024,"claim":"Substrate-bound cryo-EM structures defined the dipeptide recognition mechanism in the outward-facing state, and covalent inhibitors identified by chemoproteomics validated SLC15A4 as a druggable target suppressing both TLR and NOD signaling in vivo.","evidence":"Cryo-EM of SLC15A4+dipeptide and SLC15A4-TASL complex; activity-based protein profiling with functional inhibitor validation in human/mouse immune cells and in vivo models","pmids":["39719710","38191941"],"confidence":"High","gaps":["Full transport cycle structures (inward-open with substrate) not available","In vivo pharmacokinetics and selectivity of covalent inhibitors in disease models"]},{"year":2025,"claim":"Conformation-selective antibodies that distinguish the luminal-open (TASL-incompetent) from cytoplasmic-open (TASL-competent) states provided direct evidence that TASL recruitment is gated by a conformational switch, validating the structural model.","evidence":"Antibody screening, cryo-EM conformational trapping, functional TASL binding and TLR pathway readouts","pmids":["40781080"],"confidence":"High","gaps":["Physiological signals that bias SLC15A4 toward the inward-facing, TASL-competent conformation remain unidentified","Whether conformational equilibrium differs across immune cell types"]},{"year":null,"claim":"Key unresolved questions include how luminal substrate sensing triggers the conformational switch that enables TASL recruitment, whether transport and TASL-mediated signaling are temporally coupled or independent outputs, and how SLC15A4's metabolic (mTORC1/AMPK) and signaling (IRF5) functions are coordinated in different immune cell types.","evidence":"","pmids":[],"confidence":"High","gaps":["Conformational trigger mechanism in vivo unknown","Temporal relationship between transport and signaling unresolved","Cell-type-specific regulation of dual functions not systematically addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,9,11,13,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,3,9,10,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,3,11]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3,8,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8,9,10]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,9,13,14]}],"complexes":["SLC15A4-TASL signaling complex"],"partners":["TASL","RPTOR","LAMTOR1","LAMTOR2","PRKAA1","IRF5"],"other_free_text":[]},"mechanistic_narrative":"SLC15A4 (PHT1) is an endolysosomal proton-coupled transporter of histidine, di/tripeptides, and bacterially derived peptides that functions as a central signaling hub coupling endosomal innate immune sensing to type I interferon production and metabolic reprogramming in immune cells. Its transporter activity maintains endolysosomal pH and supports mTORC1 activation, AMPK signaling, and the mTORC1-TFEB axis that controls secretory granule homeostasis and metabolic fitness in macrophages, mast cells, and plasmacytoid dendritic cells [PMID:25238095, PMID:29155995, PMID:34385317]. A conformational switch from outward-facing to inward-facing state creates a cytoplasmic cavity into which the N-terminal helix of the adaptor TASL inserts, enabling TASL-mediated IRF5 activation downstream of TLR7/8/9 without affecting NF-κB or MAPK branches [PMID:32433612, PMID:37863913, PMID:40781080]. SLC15A4 traffics to LAMP1+/LAMP2+ endolysosomes via an AP-3-dependent pathway and is required for proper colocalization of nucleic acid-sensing TLRs with their ligands, and also transports muramyl dipeptide to facilitate NOD-dependent innate responses [PMID:35349343, PMID:29784761]."},"prefetch_data":{"uniprot":{"accession":"Q8N697","full_name":"Solute carrier family 15 member 4","aliases":["Peptide transporter 4","Peptide/histidine transporter 1","hPHT1"],"length_aa":577,"mass_kda":62.0,"function":"Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response (PubMed:16289537, PubMed:25238095, PubMed:29224352, PubMed:39719710). Preferably binds to short peptides with a basic residue at the first position and a hydrophobic residue at the second position (PubMed:39719710). Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans (PubMed:29224352, PubMed:31073693). Transporter activity is pH-dependent and maximized in the acidic lysosomal environment (By similarity). Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand (PubMed:25238095, PubMed:29224352). Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) (PubMed:25238095). Independently of its transporter activity, also promotes the recruitment of innate immune adapter TASL to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment leads to the specific recruitment and activation of IRF5 (PubMed:32433612, PubMed:39719710). Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation (By similarity). Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses (By similarity)","subcellular_location":"Lysosome membrane; Endosome membrane; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q8N697/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC15A4","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000139370","cell_line_id":"CID001382","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CLCN7","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001382","total_profiled":1310},"omim":[{"mim_id":"615806","title":"SOLUTE CARRIER FAMILY 15 (OLIGOPEPTIDE TRANSPORTER), MEMBER 4; SLC15A4","url":"https://www.omim.org/entry/615806"},{"mim_id":"610408","title":"SOLUTE CARRIER FAMILY 15 (OLIGOPEPTIDE TRANSPORTER), MEMBER 3; SLC15A3","url":"https://www.omim.org/entry/610408"},{"mim_id":"605956","title":"NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2","url":"https://www.omim.org/entry/605956"},{"mim_id":"603455","title":"RECEPTOR-INTERACTING SERINE/THREONINE KINASE 2; RIPK2","url":"https://www.omim.org/entry/603455"},{"mim_id":"301049","title":"TLR ADAPTOR INTERACTING WITH ENDOLYSOSOMAL SLC15A4; TASL","url":"https://www.omim.org/entry/301049"}],"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/SLC15A4"},"hgnc":{"alias_symbol":["PHT1","PTR4"],"prev_symbol":[]},"alphafold":{"accession":"Q8N697","domains":[{"cath_id":"1.20.1250.20","chopping":"30-247","consensus_level":"medium","plddt":89.1127,"start":30,"end":247},{"cath_id":"1.20.1250.20","chopping":"332-354_361-539","consensus_level":"medium","plddt":89.9475,"start":332,"end":539}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N697","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N697-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N697-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC15A4","jax_strain_url":"https://www.jax.org/strain/search?query=SLC15A4"},"sequence":{"accession":"Q8N697","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N697.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N697/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N697"}},"corpus_meta":[{"pmid":"15272879","id":"PMC_15272879","title":"Phosphate transport in Arabidopsis: Pht1;1 and Pht1;4 play a major role in phosphate acquisition from both low- and high-phosphate environments.","date":"2004","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15272879","citation_count":509,"is_preprint":false},{"pmid":"12164813","id":"PMC_12164813","title":"Expression analysis suggests novel roles for members of the Pht1 family of phosphate transporters in Arabidopsis.","date":"2002","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12164813","citation_count":330,"is_preprint":false},{"pmid":"32433612","id":"PMC_32433612","title":"TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32433612","citation_count":173,"is_preprint":false},{"pmid":"17400898","id":"PMC_17400898","title":"A mutant of the Arabidopsis phosphate transporter PHT1;1 displays enhanced arsenic accumulation.","date":"2007","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/17400898","citation_count":169,"is_preprint":false},{"pmid":"15604713","id":"PMC_15604713","title":"Transcriptional regulation and functional properties of Arabidopsis Pht1;4, a high affinity transporter contributing greatly to phosphate uptake in phosphate deprived plants.","date":"2004","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15604713","citation_count":168,"is_preprint":false},{"pmid":"21045126","id":"PMC_21045126","title":"Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21045126","citation_count":166,"is_preprint":false},{"pmid":"22578268","id":"PMC_22578268","title":"The Pht1;9 and Pht1;8 transporters mediate inorganic phosphate acquisition by the Arabidopsis thaliana root during phosphorus starvation.","date":"2012","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/22578268","citation_count":164,"is_preprint":false},{"pmid":"25238095","id":"PMC_25238095","title":"The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production.","date":"2014","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25238095","citation_count":133,"is_preprint":false},{"pmid":"16547863","id":"PMC_16547863","title":"Differential regulation of five Pht1 phosphate transporters from maize (Zea mays L.).","date":"2006","source":"Plant biology (Stuttgart, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16547863","citation_count":117,"is_preprint":false},{"pmid":"14756304","id":"PMC_14756304","title":"Characterization of two phosphate transporters from barley; evidence for diverse function and kinetic properties among members of the Pht1 family.","date":"2003","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14756304","citation_count":111,"is_preprint":false},{"pmid":"23382217","id":"PMC_23382217","title":"Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23382217","citation_count":110,"is_preprint":false},{"pmid":"26010225","id":"PMC_26010225","title":"A member of the Phosphate transporter 1 (Pht1) family from the arsenic-hyperaccumulating fern Pteris vittata is a high-affinity arsenate transporter.","date":"2015","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/26010225","citation_count":101,"is_preprint":false},{"pmid":"27304955","id":"PMC_27304955","title":"Systematic Identification, Evolution and Expression Analysis of the Zea mays PHT1 Gene Family Reveals Several New Members Involved in Root Colonization by Arbuscular Mycorrhizal Fungi.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27304955","citation_count":98,"is_preprint":false},{"pmid":"15542491","id":"PMC_15542491","title":"Promoter analysis of the barley Pht1;1 phosphate transporter gene identifies regions controlling root expression and responsiveness to phosphate deprivation.","date":"2004","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15542491","citation_count":90,"is_preprint":false},{"pmid":"15020637","id":"PMC_15020637","title":"Characterization of promoter expression patterns derived from the Pht1 phosphate transporter genes of barley (Hordeum vulgare L.).","date":"2004","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/15020637","citation_count":84,"is_preprint":false},{"pmid":"25615409","id":"PMC_25615409","title":"Plant phosphorus acquisition in a common mycorrhizal network: regulation of phosphate transporter genes of the Pht1 family in sorghum and flax.","date":"2015","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/25615409","citation_count":83,"is_preprint":false},{"pmid":"24618087","id":"PMC_24618087","title":"Genome-wide investigation and expression analysis suggest diverse roles and genetic redundancy of Pht1 family genes in response to Pi deficiency in tomato.","date":"2014","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/24618087","citation_count":81,"is_preprint":false},{"pmid":"23442117","id":"PMC_23442117","title":"Functional analysis of the novel mycorrhiza-specific phosphate transporter AsPT1 and PHT1 family from Astragalus sinicus during the arbuscular mycorrhizal symbiosis.","date":"2013","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/23442117","citation_count":80,"is_preprint":false},{"pmid":"25428623","id":"PMC_25428623","title":"Arabidopsis PHOSPHATE TRANSPORTER1 genes PHT1;8 and PHT1;9 are involved in root-to-shoot translocation of orthophosphate.","date":"2014","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/25428623","citation_count":78,"is_preprint":false},{"pmid":"3406741","id":"PMC_3406741","title":"Legless, a novel mutation found in PHT1-1 transgenic mice.","date":"1988","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/3406741","citation_count":73,"is_preprint":false},{"pmid":"18596039","id":"PMC_18596039","title":"Closely related members of the Medicago truncatula PHT1 phosphate transporter gene family encode phosphate transporters with distinct biochemical activities.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18596039","citation_count":67,"is_preprint":false},{"pmid":"23133521","id":"PMC_23133521","title":"Functional characterization of 14 Pht1 family genes in yeast and their expressions in response to nutrient starvation in soybean.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23133521","citation_count":63,"is_preprint":false},{"pmid":"25251671","id":"PMC_25251671","title":"Phosphate concentration and arbuscular mycorrhizal colonisation influence the growth, yield and expression of twelve PHT1 family phosphate transporters in foxtail millet (Setaria italica).","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25251671","citation_count":57,"is_preprint":false},{"pmid":"28443126","id":"PMC_28443126","title":"Genome-wide Identification, Characterization, and Expression Analysis of PHT1 Phosphate Transporters in Wheat.","date":"2017","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/28443126","citation_count":49,"is_preprint":false},{"pmid":"29784761","id":"PMC_29784761","title":"SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29784761","citation_count":47,"is_preprint":false},{"pmid":"32680974","id":"PMC_32680974","title":"Spatial Divergence of PHR-PHT1 Modules Maintains Phosphorus Homeostasis in Soybean Nodules.","date":"2020","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32680974","citation_count":44,"is_preprint":false},{"pmid":"23571341","id":"PMC_23571341","title":"Expression of the peptide transporters PepT1, PepT2, and PHT1 in the embryonic and posthatch chick.","date":"2013","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/23571341","citation_count":44,"is_preprint":false},{"pmid":"34385317","id":"PMC_34385317","title":"SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34385317","citation_count":37,"is_preprint":false},{"pmid":"25754174","id":"PMC_25754174","title":"Increased phosphate transport of Arabidopsis thaliana Pht1;1 by site-directed mutagenesis of tyrosine 312 may be attributed to the disruption of homomeric interactions.","date":"2015","source":"Plant, cell & environment","url":"https://pubmed.ncbi.nlm.nih.gov/25754174","citation_count":37,"is_preprint":false},{"pmid":"23028315","id":"PMC_23028315","title":"Slc15a4, a gene required for pDC sensing of TLR ligands, is required to control persistent viral infection.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/23028315","citation_count":37,"is_preprint":false},{"pmid":"33560415","id":"PMC_33560415","title":"Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity.","date":"2021","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33560415","citation_count":35,"is_preprint":false},{"pmid":"29070807","id":"PMC_29070807","title":"Functional characterization of the PHT1 family transporters of foxtail millet with development of a novel Agrobacterium-mediated transformation procedure.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29070807","citation_count":33,"is_preprint":false},{"pmid":"25194430","id":"PMC_25194430","title":"A Brassica napus PHT1 phosphate transporter, BnPht1;4, promotes phosphate uptake and affects roots architecture of transgenic Arabidopsis.","date":"2014","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25194430","citation_count":33,"is_preprint":false},{"pmid":"24091983","id":"PMC_24091983","title":"Variants in TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3 interact to confer risk of systemic lupus erythematosus in Chinese population.","date":"2013","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/24091983","citation_count":32,"is_preprint":false},{"pmid":"35349343","id":"PMC_35349343","title":"The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35349343","citation_count":30,"is_preprint":false},{"pmid":"29155995","id":"PMC_29155995","title":"Lysosome biogenesis regulated by the amino-acid transporter SLC15A4 is critical for functional integrity of mast cells.","date":"2017","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29155995","citation_count":30,"is_preprint":false},{"pmid":"37863876","id":"PMC_37863876","title":"A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37863876","citation_count":28,"is_preprint":false},{"pmid":"31073693","id":"PMC_31073693","title":"The proton-coupled oligopeptide transporters PEPT2, PHT1 and PHT2 mediate the uptake of carnosine in glioblastoma cells.","date":"2019","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/31073693","citation_count":28,"is_preprint":false},{"pmid":"21698287","id":"PMC_21698287","title":"Molecular cloning, characterization and expression analysis of two members of the Pht1 family of phosphate transporters in Glycine max.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21698287","citation_count":27,"is_preprint":false},{"pmid":"35639954","id":"PMC_35639954","title":"Phosphate transporter PHT1;1 is a key determinant of phosphorus acquisition in Arabidopsis natural accessions.","date":"2022","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35639954","citation_count":26,"is_preprint":false},{"pmid":"37863913","id":"PMC_37863913","title":"Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37863913","citation_count":25,"is_preprint":false},{"pmid":"38191941","id":"PMC_38191941","title":"Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity.","date":"2024","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/38191941","citation_count":25,"is_preprint":false},{"pmid":"33444326","id":"PMC_33444326","title":"The peptide symporter SLC15a4 is essential for the development of systemic lupus erythematosus in murine models.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33444326","citation_count":24,"is_preprint":false},{"pmid":"31121904","id":"PMC_31121904","title":"Integrative Analysis of the Wheat PHT1 Gene Family Reveals A Novel Member Involved in Arbuscular Mycorrhizal Phosphate Transport and Immunity.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31121904","citation_count":24,"is_preprint":false},{"pmid":"24548120","id":"PMC_24548120","title":"Divergent developmental expression and function of the proton-coupled oligopeptide transporters PepT2 and PhT1 in regional brain slices of mouse and rat.","date":"2014","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24548120","citation_count":24,"is_preprint":false},{"pmid":"36940527","id":"PMC_36940527","title":"Wheat PHT1;9 acts as one candidate arsenate absorption transporter for phytoremediation.","date":"2023","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/36940527","citation_count":23,"is_preprint":false},{"pmid":"29148171","id":"PMC_29148171","title":"Identification and expression profiling of Pht1 phosphate transporters in wheat in controlled environments and in the field.","date":"2017","source":"Plant biology (Stuttgart, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/29148171","citation_count":22,"is_preprint":false},{"pmid":"29261175","id":"PMC_29261175","title":"Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency.","date":"2017","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29261175","citation_count":20,"is_preprint":false},{"pmid":"36510495","id":"PMC_36510495","title":"miR-31-5p Regulates Type I Interferon by Targeting SLC15A4 in Plasmacytoid Dendritic Cells of Systemic Lupus Erythematosus.","date":"2022","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/36510495","citation_count":18,"is_preprint":false},{"pmid":"31300887","id":"PMC_31300887","title":"Phosphate supply influenced the growth, yield and expression of PHT1 family phosphate transporters in seven millets.","date":"2019","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/31300887","citation_count":17,"is_preprint":false},{"pmid":"33159589","id":"PMC_33159589","title":"Expression of PHT1 family transporter genes contributes for low phosphate stress tolerance in foxtail millet (Setaria italica) genotypes.","date":"2020","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/33159589","citation_count":17,"is_preprint":false},{"pmid":"25310967","id":"PMC_25310967","title":"Slc15a4 function is required for intact class switch recombination to IgG2c in response to TLR9 stimulation.","date":"2014","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25310967","citation_count":17,"is_preprint":false},{"pmid":"27911737","id":"PMC_27911737","title":"The conservation of phosphate-binding residues among PHT1 transporters suggests that distinct transport affinities are unlikely to result from differences in the phosphate-binding site.","date":"2016","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/27911737","citation_count":14,"is_preprint":false},{"pmid":"27362648","id":"PMC_27362648","title":"Association Study Between SLC15A4 Polymorphisms and Haplotypes and Systemic Lupus Erythematosus in a Han Chinese Population.","date":"2016","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/27362648","citation_count":13,"is_preprint":false},{"pmid":"37709742","id":"PMC_37709742","title":"Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37709742","citation_count":13,"is_preprint":false},{"pmid":"34740248","id":"PMC_34740248","title":"The Caenorhabditis elegans Patched domain protein PTR-4 is required for proper organization of the precuticular apical extracellular matrix.","date":"2021","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34740248","citation_count":13,"is_preprint":false},{"pmid":"27845049","id":"PMC_27845049","title":"A novel role for PHT1 in the disposition of l-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice.","date":"2016","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27845049","citation_count":12,"is_preprint":false},{"pmid":"34288396","id":"PMC_34288396","title":"GTPase ROP6 negatively modulates phosphate deficiency through inhibition of PHT1;1 and PHT1;4 in Arabidopsis thaliana.","date":"2021","source":"Journal of integrative plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/34288396","citation_count":11,"is_preprint":false},{"pmid":"30262916","id":"PMC_30262916","title":"A requirement for slc15a4 in imiquimod-induced systemic inflammation and psoriasiform inflammation in mice.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30262916","citation_count":11,"is_preprint":false},{"pmid":"34312721","id":"PMC_34312721","title":"The enhanced phosphorus use efficiency in phosphate-deficient and mycorrhiza-inoculated barley seedlings involves activation of different sets of PHT1 transporters in roots.","date":"2021","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/34312721","citation_count":10,"is_preprint":false},{"pmid":"22057342","id":"PMC_22057342","title":"Arabidopsis Pht1;5 plays an integral role in phosphate homeostasis.","date":"2011","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/22057342","citation_count":9,"is_preprint":false},{"pmid":"31776735","id":"PMC_31776735","title":"Expression analysis and functional characterization of two PHT1 family phosphate transporters in ryegrass.","date":"2019","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/31776735","citation_count":8,"is_preprint":false},{"pmid":"36361959","id":"PMC_36361959","title":"Identification of SLC15A4/PHT1 Gene Products Upregulation Marking the Intestinal Epithelial Monolayer of Ulcerative Colitis Patients.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36361959","citation_count":7,"is_preprint":false},{"pmid":"37758243","id":"PMC_37758243","title":"PHT1;5 Repressed by ANT Mediates Pi Acquisition and Distribution under Low Pi and Salinity in Salt Cress.","date":"2024","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37758243","citation_count":6,"is_preprint":false},{"pmid":"23888104","id":"PMC_23888104","title":"THE EVALUATION OF PEPTIDE/HISTIDINE TRANSPORTER 1 (PHT1) FUNCTION: UPTAKE KINETICS UTILIZING A COS-7 STABLY TRANSFECTED CELL LINE.","date":"2011","source":"Revista mexicana de ciencias farmaceutica","url":"https://pubmed.ncbi.nlm.nih.gov/23888104","citation_count":6,"is_preprint":false},{"pmid":"37960116","id":"PMC_37960116","title":"Isolation and Characterization of Erianthus arundinaceus Phosphate Transporter 1 (PHT1) Gene Promoter and 5' Deletion Analysis of Transcriptional Regulation Regions under Phosphate Stress in Transgenic Tobacco.","date":"2023","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/37960116","citation_count":6,"is_preprint":false},{"pmid":"36227088","id":"PMC_36227088","title":"A Eucalyptus Pht1 Family Gene EgPT8 Is Essential for Arbuscule Elongation of Rhizophagus irregularis.","date":"2022","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/36227088","citation_count":5,"is_preprint":false},{"pmid":"32363413","id":"PMC_32363413","title":"Expression dynamics of solute carrier family 15 member 4 (SLC15A4) and its potential regulatory role in ovarian development of the Indian white shrimp, Penaeus indicus.","date":"2020","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32363413","citation_count":5,"is_preprint":false},{"pmid":"38317862","id":"PMC_38317862","title":"A Non-Coding Variant in SLC15A4 Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.","date":"2023","source":"Frontiers in lupus","url":"https://pubmed.ncbi.nlm.nih.gov/38317862","citation_count":4,"is_preprint":false},{"pmid":"35562597","id":"PMC_35562597","title":"Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer.","date":"2022","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/35562597","citation_count":4,"is_preprint":false},{"pmid":"38790218","id":"PMC_38790218","title":"Genome-Wide Identification and Characterization of the PHT1 Gene Family and Its Response to Mycorrhizal Symbiosis in Salvia miltiorrhiza under Phosphate Stress.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/38790218","citation_count":3,"is_preprint":false},{"pmid":"39136390","id":"PMC_39136390","title":"Identification and expression analysis of Phosphate Transporter 1 (PHT1) genes in the highly phosphorus-use-efficient Hakea prostrata (Proteaceae).","date":"2024","source":"Plant, cell & environment","url":"https://pubmed.ncbi.nlm.nih.gov/39136390","citation_count":2,"is_preprint":false},{"pmid":"32779343","id":"PMC_32779343","title":"Function and application of the Eutrema salsugineum PHT1;1 gene in phosphate deficiency stress.","date":"2020","source":"Plant biology (Stuttgart, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/32779343","citation_count":2,"is_preprint":false},{"pmid":"36430345","id":"PMC_36430345","title":"Systematic Identification and Expression Analysis of the Sorghum Pht1 Gene Family Reveals Several New Members Encoding High-Affinity Phosphate Transporters.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36430345","citation_count":2,"is_preprint":false},{"pmid":"37546883","id":"PMC_37546883","title":"A Non-Coding Variant in SLC15A4 Modulates Enhancer Activity and Lysosomal Deacidification Linked to Lupus Susceptibility.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37546883","citation_count":1,"is_preprint":false},{"pmid":"40367618","id":"PMC_40367618","title":"Crucial role of the Pht1;4 Gene in Sb(V) tolerance and uptake in Arabidopsis thaliana.","date":"2025","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/40367618","citation_count":1,"is_preprint":false},{"pmid":"40781080","id":"PMC_40781080","title":"Development of conformation-selective antibodies targeting human SLC15A4.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40781080","citation_count":0,"is_preprint":false},{"pmid":"39719710","id":"PMC_39719710","title":"The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL.","date":"2024","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/39719710","citation_count":0,"is_preprint":false},{"pmid":"40556045","id":"PMC_40556045","title":"Functional Characterization of Acer Truncatum PHT1 Family Phosphate Transporter Genes and Their Involvement in Arbuscular Mycorrhizal Symbiosis.","date":"2025","source":"Physiologia plantarum","url":"https://pubmed.ncbi.nlm.nih.gov/40556045","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.25.25340948","title":"Genome-wide analysis of tandem repeat variation identifies  <i>SLC15A4</i>  as a susceptibility gene for idiopathic pulmonary fibrosis","date":"2025-11-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.25.25340948","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.03.673468","title":"PHOSPHATE OVERACCUMULATOR 2 (PHO2) is a negative regulator of arbuscular mycorrhizal symbiosis","date":"2025-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.03.673468","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.04.668567","title":"Structural and dynamic insights into phosphate uptake by PHT1 transporter in rice","date":"2025-08-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.04.668567","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.09.632146","title":"Involvement of PHOSPHATE TRANSPORTER TRAFFIC FACILITATOR1 in COPII assembly by interacting with SAR1 GTPase","date":"2025-01-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632146","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.20.599911","title":"Phosphate starvation-induced CORNICHON HOMOLOG 5 as endoplasmic reticulum cargo receptor for PHT1 transporters in <i>Arabidopsis</i>","date":"2024-06-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.20.599911","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.09.607312","title":"<i>Phosphate transporter</i>(<i>Pht</i>) gene families in rye (<i>Secale cereale</i>L.) – genome-wide identification and sequence diversity assessment","date":"2024-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.09.607312","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.30.630708","title":"CORNICHON HOMOLOG 5-dependent ER export of membrane cargoes in phosphate-starved <i>Arabidopsis</i> root as revealed by membrane proteomic analysis","date":"2024-12-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.30.630708","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44807,"output_tokens":4422,"usd":0.100376},"stage2":{"model":"claude-opus-4-6","input_tokens":7880,"output_tokens":3054,"usd":0.173625},"total_usd":0.274001,"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\": 2020,\n      \"finding\": \"SLC15A4 physically interacts with TASL (encoded by CXorf21) on the lysosomal membrane; TASL localization and function depend on this interaction. TASL contains a conserved pLxIS motif that recruits and activates IRF5, linking endolysosomal TLR7/8/9 sensing specifically to the IRF pathway without affecting NF-κB or MAPK signaling.\",\n      \"method\": \"Co-immunoprecipitation, extensive mutagenesis of TASL, deletion of SLC15A4 or TASL with pathway-specific readouts (IRF vs NF-κB/MAPK), primary and transformed human immune cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, mutagenesis, genetic KO, pathway dissection) in one study, replicated concept across multiple subsequent papers\",\n      \"pmids\": [\"32433612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Slc15a4 (PHT1) is required for TLR7- and TLR9-mediated type I IFN and proinflammatory cytokine production specifically in plasmacytoid dendritic cells (pDCs), but not in conventional DCs; AP-3, BLOC-1, and BLOC-2 Hermansky-Pudlak syndrome proteins form a membrane trafficking pathway also uniquely required for endosomal TLR signaling in pDCs.\",\n      \"method\": \"Forward genetic screen (feeble ENU mutant), positional cloning, cell-type-specific cytokine assays, genetic epistasis with AP-3/BLOC complex mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic model with defined cellular phenotype, epistasis with trafficking pathway, replicated by multiple subsequent labs\",\n      \"pmids\": [\"21045126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC15A4 is a lysosome-resident proton-coupled amino-acid transporter that moves histidine and oligopeptides from the lysosomal lumen to the cytosol; its transporter activity (not merely its structural presence) is necessary for TLR7/9-triggered cytokine production. SLC15A4 loss disrupts endolysosomal pH regulation and v-ATPase integrity, leading to impaired mTOR pathway activation and failure of the IRF7-IFN-I regulatory circuit.\",\n      \"method\": \"Transporter activity assays, pH measurement, mTOR pathway analysis, transporter-dead mutant rescue experiments in B cells and pDCs, mouse lupus model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — transporter activity requirement shown with activity-dead mutant, mechanistic dissection of mTOR/IRF7 axis, multiple orthogonal readouts\",\n      \"pmids\": [\"25238095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SLC15A4 is required for trafficking and colocalization of nucleic acid-sensing TLRs and their ligands to endolysosomes, and for formation of the LAMP2+VAMP3+ hybrid compartment in which IFN-I production is initiated. SLC15A4 trafficking to endolysosomes depends on the AP-3 complex. A function-impairing mutation in SLC15A3 does not impair type I IFN production by pDCs, indicating functional divergence within the SLC15 family.\",\n      \"method\": \"Live-cell fluorescence imaging/colocalization, genetic comparison of SLC15A4 vs SLC15A3 mutant mice, AP-3 complex genetic epistasis, feeble mutant and genomic deletion models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequence, genetic epistasis, functional distinction from paralog\",\n      \"pmids\": [\"35349343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human SLC15A4 reveal apo monomeric and dimeric outward-facing conformations (dimeric form stabilized by four cholesterol molecules at the interface), and a TASL-bound complex in which SLC15A4 adopts an inward-facing conformation that forms a binding pocket into which the N-terminal helix of TASL inserts — a previously undescribed interaction mode for solute carriers.\",\n      \"method\": \"Cryo-EM structure determination at high resolution, structural comparison of apo vs TASL-bound states\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures of multiple conformational states with functional interpretation, independently resolved in same year by a second group\",\n      \"pmids\": [\"37863913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of SLC15A4 (PHT1) in the outward-open conformation combined with biochemical and structural modeling defines the inward-open cavity as the TASL-binding site; the first 16 N-terminal residues of TASL fold into a helix that inserts into this cavity.\",\n      \"method\": \"Cryo-EM, biochemical binding assays, structural modeling of PHT1-TASL complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent cryo-EM structure corroborating Chen et al. 2023, with biochemical validation\",\n      \"pmids\": [\"37709742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Feeblin, a small-molecule inhibitor, binds SLC15A4 in a lysosomal outward-open conformation that is incompatible with TASL binding on the cytoplasmic side; this conformation-locking mechanism prevents TASL recruitment and leads to TASL proteostatic degradation, thereby blocking TLR7/8-IRF5 signaling.\",\n      \"method\": \"Cryo-EM structure of feeblin-SLC15A4 complex, phenotypic assay for TASL degradation, TLR pathway activity assays in human immune cells including SLE patient cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with mechanistic pharmacological validation and functional readouts\",\n      \"pmids\": [\"37863876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of SLC15A3 (apo) and SLC15A4 (apo and dipeptide-bound) define the specific dipeptide recognition mechanism; each protomer adopts an outward-facing conformation, and the N-terminal helix of TASL inserts deeply into the inward-facing cavity of SLC15A4 in the complex structure.\",\n      \"method\": \"Cryo-EM structure determination of SLC15A3 apo, SLC15A4 apo, SLC15A4+substrate, and SLC15A4-TASL complex\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple cryo-EM structures revealing substrate recognition and TASL recruitment mechanism\",\n      \"pmids\": [\"39719710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SLC15A4 loss in macrophages causes insufficient pyruvate biotransformation to the TCA cycle while increasing glutaminolysis; SLC15A4 is required for M1-prone metabolic shift and inflammatory IL-12 production after TLR9 stimulation. SLC15A4 was found in close proximity to AMPK and mTOR, and its deficiency impaired TLR-mediated AMPK activation. SLC15A4-intact macrophages resist nutrient fluctuations by limiting glutamine use, protecting respiratory homeostasis.\",\n      \"method\": \"Proximity-dependent biotin identification (BioID), fluxome analysis (metabolic flux), macrophage KO, AMPK/mTOR activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — BioID proximity proteomics plus quantitative fluxome analysis with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"34385317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human SLC15A4 exhibits pH- and temperature-dependent transport activity for dipeptides and tripeptides; it localizes to LAMP1+ compartments and constitutively associates with Raptor and LAMTORs (mTORC1 regulatory complex components). Knockdown in human pDC line CAL-1 impairs TLR7/8/9-triggered IFN-I production and mTORC1 activity, and impairs autophagy sustainability and mitochondrial membrane potential under starvation.\",\n      \"method\": \"Transport activity assays in human cells, LAMP1 co-localization, co-immunoprecipitation with Raptor/LAMTORs, SLC15A4 KD in CAL-1 cells with IFN-I/mTORC1/autophagy/mitochondrial readouts\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct transport assay, reciprocal co-IP, clean KD with multiple defined cellular phenotypes\",\n      \"pmids\": [\"33560415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLC15A4 is required for mast cell secretory-granule (lysosome-derived) homeostasis; its loss diminishes mTORC1 activity, increasing nuclear translocation of TFEB, which causes hyperdegranulation. SLC15A4 controls the mTORC1-TFEB signaling axis to limit FcεRI-mediated and IL-33-triggered inflammatory responses both in vitro and in vivo.\",\n      \"method\": \"Slc15a4 KO mast cells, mTORC1 activity assays, TFEB localization imaging, degranulation assays, FcεRI and IL-33 stimulation in vitro and in vivo\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined molecular pathway (mTORC1-TFEB) and multiple functional readouts in vitro and in vivo\",\n      \"pmids\": [\"29155995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC15A4 (PHT1) is expressed on endosomal membranes of macrophages (whereas PEPT2 is on the plasma membrane); both transporters transport bacterially derived di/tripeptides (including muramyl dipeptide) to facilitate NOD-dependent cytokine production. Pht1 KO mice show reduced proinflammatory cytokine responses to bacterial peptide ligands.\",\n      \"method\": \"Fluorescent MDP-rhodamine imaging, Pht1 KO mice cytokine assays, subcellular fractionation/localization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by live imaging, KO animal model with defined cytokine phenotype\",\n      \"pmids\": [\"29784761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chemoproteomic (activity-based protein profiling) approach identified first-in-class covalent inhibitors of SLC15A4 that suppress SLC15A4-mediated endolysosomal TLR and NOD signaling in human and mouse immune cells and suppress inflammation in vivo; mechanistically the inhibitors target SLC15A4 transporter function to block downstream immune signaling.\",\n      \"method\": \"Chemical proteomics/ABPP, functional inhibitor characterization in multiple human/mouse immune cell types, in vivo inflammation models, clinical ex vivo validation\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chemoproteomic target engagement combined with functional pathway assays in vivo and ex vivo\",\n      \"pmids\": [\"38191941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PHT1 (SLC15A4) plays an important role in histidine transport in brain parenchyma; ablation of Pht1 reduces L-histidine uptake in brain slices by ~50% and reduces brain parenchyma L-histidine levels in vivo, with compensatory upregulation of PEPT2 (~2-fold) in Pht1 null mice.\",\n      \"method\": \"In vitro brain slice uptake assays, in vivo pharmacokinetics, biodistribution studies, PCR and immunoblot in Pht1 null vs wildtype mice\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO model with direct transport functional readout, but single lab and no reconstitution\",\n      \"pmids\": [\"27845049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PHT1 (SLC15A4) mediates carnosine uptake in glioblastoma cells; siRNA-mediated knockdown of PHT1 significantly reduces carnosine uptake, and competitive inhibition with L-histidine (PHT1/2 inhibitor) blocks carnosine entry.\",\n      \"method\": \"siRNA knockdown, HPLC-MS carnosine uptake assay, competitive inhibition with substrate analogs\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific transport substrate readout, but single lab\",\n      \"pmids\": [\"31073693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-31-5p directly targets the 3'UTR of SLC15A4 and negatively regulates SLC15A4 expression; inhibition of miR-31-5p in pDC-like cells increases IRF5 phosphorylation and IFN-stimulated gene induction upon TLR stimulation, while overexpression of miR-31-5p reverses this effect.\",\n      \"method\": \"Luciferase reporter assay (miRNA-target validation), miR-31-5p mimic/inhibitor transfection, IRF5 phosphorylation immunofluorescence, ISG expression by RT-qPCR\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct luciferase validation of miRNA targeting, functional rescue experiments, but single lab\",\n      \"pmids\": [\"36510495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conformation-selective antibodies against SLC15A4 reveal two functional states: clone 107 binds the TASL-binding-incompetent luminal-open (outward-facing) state, while clone 235 stabilizes the TASL-binding-competent cytoplasmic-open (inward-facing) state, demonstrating that TASL recruitment depends on a conformational switch in SLC15A4.\",\n      \"method\": \"Antibody screening, cryo-EM validation of conformational states, functional assays for TASL binding competence, TLR pathway activity readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and antibody-based conformational trapping with functional validation of TASL recruitment mechanism\",\n      \"pmids\": [\"40781080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC15A4 (PHT1) is an endolysosomal proton-coupled transporter of histidine and di/tripeptides that localizes to LAMP1+ lysosomes via an AP-3-dependent trafficking pathway; upon inward-facing conformational change it recruits the adaptor TASL (via TASL's N-terminal helix inserting into its central cavity), which then activates IRF5 to drive type I interferon production downstream of endolysosomal TLR7/8/9 — while its transporter activity additionally optimizes lysosomal pH, mTORC1/AMPK signaling, and macrophage metabolic reprogramming required for full innate immune responses.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC15A4 (PHT1) is an endolysosomal proton-coupled transporter of histidine, di/tripeptides, and bacterially derived peptides that functions as a central signaling hub coupling endosomal innate immune sensing to type I interferon production and metabolic reprogramming in immune cells. Its transporter activity maintains endolysosomal pH and supports mTORC1 activation, AMPK signaling, and the mTORC1-TFEB axis that controls secretory granule homeostasis and metabolic fitness in macrophages, mast cells, and plasmacytoid dendritic cells [PMID:25238095, PMID:29155995, PMID:34385317]. A conformational switch from outward-facing to inward-facing state creates a cytoplasmic cavity into which the N-terminal helix of the adaptor TASL inserts, enabling TASL-mediated IRF5 activation downstream of TLR7/8/9 without affecting NF-κB or MAPK branches [PMID:32433612, PMID:37863913, PMID:40781080]. SLC15A4 traffics to LAMP1+/LAMP2+ endolysosomes via an AP-3-dependent pathway and is required for proper colocalization of nucleic acid-sensing TLRs with their ligands, and also transports muramyl dipeptide to facilitate NOD-dependent innate responses [PMID:35349343, PMID:29784761].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"A forward genetic screen established that SLC15A4 is selectively required for TLR7/9-mediated IFN-I production in pDCs but not conventional DCs, and linked it genetically to the AP-3/BLOC trafficking pathway — resolving whether this transporter has a non-redundant immune function.\",\n      \"evidence\": \"ENU mutagenesis (feeble mutant), positional cloning, cell-type-specific cytokine assays, epistasis with AP-3/BLOC mutants in mouse\",\n      \"pmids\": [\"21045126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SLC15A4 supports IFN-I was unknown\", \"Whether transporter activity per se is required was untested\", \"Downstream signaling pathway not delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that SLC15A4's transport activity — not merely its physical presence — is required for TLR-triggered cytokine production resolved a key mechanistic question: transporter-dead mutants failed to restore pH regulation, v-ATPase integrity, and mTOR/IRF7 signaling.\",\n      \"evidence\": \"Transporter activity assays, endolysosomal pH measurements, transporter-dead mutant rescue experiments in B cells and pDCs, mouse lupus model\",\n      \"pmids\": [\"25238095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How transport activity couples to mTOR activation was unclear\", \"Identity of direct signaling interactors remained unknown\", \"Role in non-pDC immune cells unexplored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extension of SLC15A4 function beyond pDCs revealed that it governs the mTORC1-TFEB axis in mast cells, controlling secretory granule homeostasis and limiting FcεRI/IL-33-driven inflammatory responses.\",\n      \"evidence\": \"Slc15a4 KO mast cells, mTORC1 activity assays, TFEB nuclear translocation imaging, degranulation assays in vitro and in vivo\",\n      \"pmids\": [\"29155995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SLC15A4 transporter activity feeds into mTORC1 regulation mechanistically\", \"Whether SLC15A4 physically associates with mTORC1 machinery\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localization of SLC15A4 to endosomal membranes of macrophages and demonstration that it transports bacterially derived muramyl dipeptide established a role in NOD-dependent innate sensing beyond TLR pathways.\",\n      \"evidence\": \"Fluorescent MDP-rhodamine imaging, Pht1 KO mice cytokine assays, subcellular fractionation\",\n      \"pmids\": [\"29784761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NOD and TLR functions of SLC15A4 are mechanistically separable\", \"Structural basis of peptide recognition unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of TASL as a direct lysosomal binding partner of SLC15A4 answered the long-standing question of how SLC15A4 specifically activates the IRF pathway: TASL's pLxIS motif recruits and activates IRF5, decoupling IFN-I signaling from NF-κB/MAPK.\",\n      \"evidence\": \"Co-immunoprecipitation, extensive TASL mutagenesis, SLC15A4/TASL deletion with pathway-specific readouts, primary and transformed human immune cells\",\n      \"pmids\": [\"32433612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SLC15A4-TASL interaction unknown\", \"Whether SLC15A4 conformational state governs TASL recruitment\", \"How transporter function relates to adaptor recruitment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"BioID and fluxome analyses revealed that SLC15A4 constitutively associates with Raptor and LAMTOR components, and that its loss rewires macrophage metabolism (reduced pyruvate-to-TCA flux, increased glutaminolysis), establishing SLC15A4 as a metabolic sensor coupling lysosomal transport to mTORC1/AMPK signaling.\",\n      \"evidence\": \"Proximity-dependent biotin identification (BioID), metabolic flux analysis, macrophage KO, AMPK/mTOR activity assays; co-IP with Raptor/LAMTORs in CAL-1 human pDC line\",\n      \"pmids\": [\"34385317\", \"33560415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect nature of SLC15A4-mTORC1 association not resolved\", \"Whether metabolic reprogramming and TASL/IRF5 signaling are independent outputs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Live-cell imaging established that SLC15A4 is required for formation of the LAMP2+VAMP3+ hybrid compartment where IFN-I production initiates, and confirmed AP-3-dependent trafficking; functional divergence from paralog SLC15A3 was demonstrated genetically.\",\n      \"evidence\": \"Live-cell fluorescence imaging/colocalization, SLC15A3 vs SLC15A4 mutant comparison, AP-3 genetic epistasis in mouse models\",\n      \"pmids\": [\"35349343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of AP-3 recognition on SLC15A4 not identified\", \"Whether SLC15A3 and SLC15A4 have overlapping substrates in immune contexts\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cryo-EM structures resolved the conformational cycle of SLC15A4 and the unprecedented mechanism of TASL recruitment: TASL's N-terminal helix inserts into the inward-facing cavity, while a cholesterol-stabilized dimer represents the outward-facing apo state. The inhibitor feeblin locks SLC15A4 in the outward-open conformation incompatible with TASL binding, causing TASL degradation and blocking TLR-IRF5 signaling.\",\n      \"evidence\": \"Multiple independent cryo-EM structures (apo monomeric/dimeric, TASL-bound, feeblin-bound), biochemical binding assays, TLR pathway assays including SLE patient cells\",\n      \"pmids\": [\"37863913\", \"37709742\", \"37863876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lysosomal luminal conditions trigger the outward-to-inward conformational switch in vivo\", \"Whether transport and TASL recruitment are simultaneous or sequential\", \"Substrate-bound inward-facing structure not yet captured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Substrate-bound cryo-EM structures defined the dipeptide recognition mechanism in the outward-facing state, and covalent inhibitors identified by chemoproteomics validated SLC15A4 as a druggable target suppressing both TLR and NOD signaling in vivo.\",\n      \"evidence\": \"Cryo-EM of SLC15A4+dipeptide and SLC15A4-TASL complex; activity-based protein profiling with functional inhibitor validation in human/mouse immune cells and in vivo models\",\n      \"pmids\": [\"39719710\", \"38191941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full transport cycle structures (inward-open with substrate) not available\", \"In vivo pharmacokinetics and selectivity of covalent inhibitors in disease models\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conformation-selective antibodies that distinguish the luminal-open (TASL-incompetent) from cytoplasmic-open (TASL-competent) states provided direct evidence that TASL recruitment is gated by a conformational switch, validating the structural model.\",\n      \"evidence\": \"Antibody screening, cryo-EM conformational trapping, functional TASL binding and TLR pathway readouts\",\n      \"pmids\": [\"40781080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals that bias SLC15A4 toward the inward-facing, TASL-competent conformation remain unidentified\", \"Whether conformational equilibrium differs across immune cell types\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how luminal substrate sensing triggers the conformational switch that enables TASL recruitment, whether transport and TASL-mediated signaling are temporally coupled or independent outputs, and how SLC15A4's metabolic (mTORC1/AMPK) and signaling (IRF5) functions are coordinated in different immune cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational trigger mechanism in vivo unknown\", \"Temporal relationship between transport and signaling unresolved\", \"Cell-type-specific regulation of dual functions not systematically addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 9, 11, 13, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 3, 9, 10, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 3, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3, 8, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 9, 13, 14]}\n    ],\n    \"complexes\": [\n      \"SLC15A4-TASL signaling complex\"\n    ],\n    \"partners\": [\n      \"TASL\",\n      \"RPTOR\",\n      \"LAMTOR1\",\n      \"LAMTOR2\",\n      \"PRKAA1\",\n      \"IRF5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}