{"gene":"TASL","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2020,"finding":"TASL (encoded by CXorf21) physically interacts with the endolysosomal transporter SLC15A4 and localizes to the lysosome; this interaction is required for TASL's function, as extensive mutagenesis demonstrated that both localization and function depend on SLC15A4 binding.","method":"Co-immunoprecipitation, mutagenesis, subcellular localization imaging","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction confirmed with extensive mutagenesis and localization studies; foundational study replicated by multiple subsequent structural studies","pmids":["32433612"],"is_preprint":false},{"year":2020,"finding":"TASL contains a conserved pLxIS motif that mediates the recruitment and activation of IRF5, placing TASL as the endolysosomal TLR adaptor connecting TLR7, TLR8, and TLR9 signaling to IRF5 activation (analogous to how STING, MAVS, and TRIF recruit IRF3).","method":"Mutagenesis of pLxIS motif, loss-of-function (TASL knockout/deletion), IRF pathway reporter assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of defined motif with functional readout, replicated independently across multiple labs and model systems","pmids":["32433612"],"is_preprint":false},{"year":2020,"finding":"Loss of TASL specifically abrogates IRF pathway activation downstream of endolysosomal TLR7, TLR8, and TLR9, without affecting NF-κB or MAPK signaling, indicating TLR ligand recognition and endolysosomal engagement occur normally but IRF5 activation is selectively blocked.","method":"TASL gene deletion in primary and transformed human immune cells, IRF/NF-κB/MAPK pathway reporter and phosphorylation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with selective pathway readouts, replicated in multiple cell types and by independent groups","pmids":["32433612","39856058","39856038"],"is_preprint":false},{"year":2019,"finding":"CXORF21 (TASL) protein co-localizes with TLR7 in immune cells, consistent with its endolysosomal localization.","method":"Immunofluorescence co-localization in primary immune cells","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-localization experiment in one lab, consistent with multiple subsequent structural and functional studies","pmids":["31092820"],"is_preprint":false},{"year":2019,"finding":"CXorf21 (TASL) knockdown increases lysosomal pH in female monocytes, demonstrating that TASL regulates endolysosomal pH, with female cells expressing more TASL showing lower lysosomal pH than male cells.","method":"CRISPR-Cas9 knockdown, lysosomal pH measurement (LysoSensor, pHrodo assays) in primary monocytes","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pH measurement after CRISPR knockout, replicated across two independent papers from same group","pmids":["31001245","31695690"],"is_preprint":false},{"year":2019,"finding":"CXorf21 (TASL) knockdown abrogates TLR7-driven IFNA1 mRNA expression and reduces secretion of TNF-alpha and IL-6 in healthy female monocytes, establishing a functional role in TLR7-driven cytokine production.","method":"CRISPR-Cas9 knockdown, qPCR, BioPlex cytokine immunoassay in primary monocytes","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cytokine phenotype, single lab, two orthogonal readouts","pmids":["31695690"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structures of human SLC15A4 in apo (monomeric and dimeric) states and in complex with TASL reveal that the N-terminal helix of TASL inserts into the inward-facing cavity of SLC15A4, which undergoes a conformational change from outward-facing to inward-facing state upon TASL binding; the dimeric apo form involves an interface with four cholesterol molecules.","method":"Cryo-EM structure determination of SLC15A4 alone and SLC15A4-TASL complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures with functional validation, independently replicated by two separate structural studies in the same year","pmids":["37863913"],"is_preprint":false},{"year":2023,"finding":"A small molecule inhibitor (feeblin) binds SLC15A4 in an outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to proteostatic degradation of TASL and blocking TLR7/8-IRF5 signaling; this demonstrates that the TASL-SLC15A4 interaction is required for TASL stability.","method":"Cryo-EM structure of feeblin-SLC15A4 complex, phenotypic TASL degradation assay, TLR7/8-IRF5 pathway assays in human immune cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus functional mechanistic assays, direct demonstration of conformational incompatibility with TASL binding","pmids":["37863876"],"is_preprint":false},{"year":2023,"finding":"PHT1 (SLC15A3) can also recruit TASL; cryo-EM structure of PHT1 in outward-open conformation combined with structural modeling predicts that the first 16 N-terminal residues of TASL form a helix that binds in the central cavity of PHT1's inward-open conformation, analogous to SLC15A4-TASL interaction.","method":"Cryo-EM structure of PHT1, biochemical binding assays, structural modeling of PHT1-TASL complex","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 1 for PHT1 structure / Moderate — complex model is computational, not directly resolved by cryo-EM; single lab","pmids":["37709742"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of SLC15A3 (apo) and SLC15A4 (apo and substrate-bound) confirm the N-terminal region of TASL forms a helical structure inserting deeply into the inward-facing cavity of SLC15A4, and reveal the specific dipeptide recognition mechanism that distinguishes SLC15A3 from SLC15A4 substrate binding.","method":"Cryo-EM structure determination of SLC15A3, SLC15A4, and SLC15A4-TASL complex","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM with multiple structures, independently confirming TASL interaction mode resolved by two other groups","pmids":["39719710"],"is_preprint":false},{"year":2024,"finding":"STAT3 directly and positively regulates TASL transcription by binding to the TASL promoter region, as demonstrated by luciferase assay and chromatin immunoprecipitation (ChIP); inhibition of STAT3 reduces TASL expression and alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells.","method":"ChIP, luciferase reporter assay, STAT3 knockdown/overexpression, qRT-PCR, Western blot in HK2 cells","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP and luciferase evidence of transcriptional regulation, two orthogonal methods, single lab","pmids":["38184662"],"is_preprint":false},{"year":2025,"finding":"SLC15A3 can also enhance TASL recruitment, functioning similarly to SLC15A4, to augment IRF5 signaling; m6A modification (written by METTL3, erased by ALKBH5) of SLC15A3 mRNA regulates macrophage M1 polarization via the SLC15A3-TASL-IRF5 axis.","method":"Conditional knockout of Mettl3/Alkbh5 in macrophages in vivo and in vitro, m6A sequencing, functional IRF5 pathway assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro knockouts with defined pathway readout, single lab, m6A modification of SLC15A3 upstream of TASL","pmids":["40679079"],"is_preprint":false},{"year":2025,"finding":"In mice, a paralogue of TASL (Gm6377/TASL2) accounts for residual IRF5 activity when TASL alone is deleted; double knockout of TASL and TASL2 phenocopies SLC15A4-deficient feeble mice, demonstrating that TASL and TASL2 together mediate all SLC15A4-dependent IRF5 activation downstream of TLR7/9.","method":"Single and double knockout mouse models, genetic epistasis, IRF5 activation assays, LCMV infection model, pristane-induced SLE model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockout phenocopying SLC15A4 deficiency, multiple orthogonal functional readouts in vivo","pmids":["39856058"],"is_preprint":false},{"year":2025,"finding":"TASL-deficient mice lack TLR7/9 responses and are protected from autoimmune symptoms; an SLE-associated TASL risk variant increases TASL protein expression via altered codon usage, resulting in augmented cytokine production in human cells, providing a mechanism for genetic risk.","method":"TASL knockout mice, Aldara and pristane autoimmune models, IRF5 phosphorylation assays, codon usage analysis, overexpression of risk variant in human cells with cytokine readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with disease model, mechanistic variant analysis with orthogonal functional readout, single lab with multiple methods","pmids":["39856038"],"is_preprint":false},{"year":2024,"finding":"TASL deficiency in keratinocytes causes G1/S cell cycle arrest, impairs proliferation and migration, disrupts lysosomal function and proper differentiation, and impairs calcium modulation required for keratinocyte differentiation, demonstrating a non-immune role for TASL in keratinocyte biology.","method":"TASL knockout in HaCaT keratinocyte cell line (CRISPR), cell cycle analysis, proliferation/migration assays, lysosomal function assays, calcium-induced differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple cellular phenotype readouts, single lab, non-immune context distinct from established TASL function","pmids":["38744928"],"is_preprint":false},{"year":2025,"finding":"TASL is required for full activation of B cells via TLR9 stimulation, for emergence of age-associated B cells (ABCs), and for IgG2c antibody production; TASL deletion prevents autoimmunity onset in the B6.MRLlpr lupus model.","method":"TASL knockout mice in B6.MRLlpr background, B cell activation assays, flow cytometry for ABCs, ELISA for antibodies, interferon/cytokine assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout in disease model with multiple defined cellular and molecular phenotypes, independently replicated as preprint","pmids":["41785302"],"is_preprint":false}],"current_model":"TASL (CXorf21/FLJ11577) is a lysosome-resident innate immune adaptor that binds via its N-terminal helix to the inward-facing cavity of the endolysosomal transporter SLC15A4 (and also PHT1/SLC15A3), undergoes proteostatic stabilization through this interaction, and uses its conserved pLxIS motif to recruit and activate IRF5 downstream of endolysosomal TLR7, TLR8, and TLR9 signaling—selectively activating the IRF transcriptional pathway without affecting NF-κB or MAPK signaling—while also regulating endolysosomal pH; its transcription is directly activated by STAT3, and a mouse paralogue TASL2 shares redundant IRF5-activating function in vivo."},"narrative":{"mechanistic_narrative":"TASL (CXorf21/FLJ11577) is a lysosome-resident innate immune adaptor that couples endolysosomal Toll-like receptor signaling to IRF5 activation [PMID:32433612, PMID:39856058, PMID:39856038]. It is recruited to the lysosome through direct binding to the endolysosomal transporter SLC15A4, an interaction required for both its localization and function; its conserved N-terminal helix inserts into the inward-facing cavity of SLC15A4 and drives a conformational shift of the transporter from an outward- to an inward-facing state [PMID:32433612, PMID:37863913, PMID:39719710]. This interaction is also proteostatic: disrupting it with a small molecule that locks SLC15A4 in an outward-open conformation triggers TASL degradation and blocks TLR7/8–IRF5 signaling [PMID:37863876]. Through a conserved pLxIS motif, TASL recruits and activates IRF5 downstream of TLR7, TLR8, and TLR9, selectively driving the IRF transcriptional arm without affecting NF-κB or MAPK signaling [PMID:32433612, PMID:39856058, PMID:39856038]. The closely related transporters PHT1/SLC15A3 can likewise recruit TASL to augment IRF5 signaling [PMID:37709742, PMID:40679079]. TASL transcription is directly activated by STAT3 [PMID:38184662], and in mice a paralogue, TASL2, provides redundant SLC15A4-dependent IRF5-activating function in vivo [PMID:39856058]. TASL is required for TLR7/9-driven cytokine and interferon responses and for B-cell activation, and its loss protects mice from autoimmunity, while an SLE-associated risk variant elevates TASL protein and augments cytokine production [PMID:31695690, PMID:39856038, PMID:41785302]. Beyond immunity, TASL also regulates endolysosomal pH and supports keratinocyte proliferation and differentiation [PMID:31001245, PMID:31695690, PMID:38744928].","teleology":[{"year":2019,"claim":"Before TASL had a defined molecular role, it was unclear whether the protein operated at the endolysosome; co-localization with TLR7 and an effect on lysosomal pH placed it in the endolysosomal compartment and linked it to TLR7-driven cytokine output.","evidence":"Immunofluorescence co-localization, CRISPR knockdown with lysosomal pH measurement and cytokine assays in primary monocytes","pmids":["31092820","31001245","31695690"],"confidence":"Medium","gaps":["No molecular partner or signaling mechanism identified at this stage","pH regulation mechanism not resolved","Sex-biased expression effect not mechanistically explained"]},{"year":2020,"claim":"The central question of how endolysosomal TLRs activate IRF5 was answered by showing TASL binds SLC15A4 to localize at the lysosome and uses a pLxIS motif to recruit and activate IRF5, defining it as the missing TLR7/8/9-to-IRF5 adaptor.","evidence":"Co-IP, extensive mutagenesis, subcellular imaging, pLxIS motif mutagenesis, and IRF/NF-κB/MAPK reporter and phosphorylation assays in human immune cells","pmids":["32433612","39856058","39856038"],"confidence":"High","gaps":["Structural basis of the TASL-SLC15A4 interaction not yet resolved","How IRF5 is phosphorylated downstream of TASL recruitment not detailed","Selectivity for IRF over NF-κB/MAPK not mechanistically explained"]},{"year":2023,"claim":"The structural and proteostatic basis of the interaction was established by cryo-EM, showing the TASL N-terminal helix inserts into the inward-facing SLC15A4 cavity and that disrupting this binding (via the inhibitor feeblin) destabilizes TASL and blocks TLR7/8-IRF5 signaling.","evidence":"Cryo-EM of apo and TASL-bound SLC15A4 and of the feeblin-SLC15A4 complex, with TASL degradation and pathway assays","pmids":["37863913","37863876"],"confidence":"High","gaps":["How conformational state of SLC15A4 controls TASL stability at the molecular level not fully defined","Role of the cholesterol-mediated dimer interface unclear","Whether transporter activity per se is required for signaling not resolved"]},{"year":2023,"claim":"The question of adaptor specificity was extended by showing the related transporter PHT1/SLC15A3 can also recruit TASL via an analogous N-terminal helix interaction, indicating TASL recruitment is not unique to SLC15A4.","evidence":"Cryo-EM of PHT1, biochemical binding assays, and structural modeling of the PHT1-TASL complex","pmids":["37709742"],"confidence":"Medium","gaps":["PHT1-TASL complex is a computational model, not directly resolved by cryo-EM","Physiological contribution of PHT1 versus SLC15A4 to TASL function not established"]},{"year":2024,"claim":"The high-resolution interaction mode and substrate recognition were independently confirmed, and an upstream transcriptional input was defined by showing STAT3 directly activates TASL transcription, connecting TASL levels to inflammatory signaling.","evidence":"Cryo-EM of SLC15A3/SLC15A4 with the TASL complex; ChIP, luciferase reporter, and STAT3 perturbation in HK2 cells","pmids":["39719710","38184662"],"confidence":"Medium","gaps":["Whether STAT3-driven TASL expression operates in immune cells not shown","Link between dipeptide-recognition mechanism and TASL signaling unresolved"]},{"year":2024,"claim":"A non-immune role was uncovered by showing TASL loss in keratinocytes causes cell cycle arrest and impairs differentiation, lysosomal function, and calcium handling, indicating broader cellular functions beyond innate immunity.","evidence":"CRISPR knockout in HaCaT keratinocytes with cell cycle, proliferation/migration, lysosomal, and calcium-induced differentiation assays","pmids":["38744928"],"confidence":"Medium","gaps":["Mechanism linking TASL to cell cycle and calcium signaling unknown","Whether the keratinocyte phenotype depends on SLC15A4 or IRF5 not tested","Single cell line, single lab"]},{"year":2025,"claim":"In vivo genetics resolved the redundancy and disease relevance: TASL and the paralogue TASL2 together account for all SLC15A4-dependent IRF5 activation, TASL deficiency abolishes TLR7/9 responses and protects against autoimmunity, and an SLE risk variant elevates TASL to augment cytokine production.","evidence":"Single and double knockout mice, genetic epistasis, autoimmune (Aldara/pristane/B6.MRLlpr) and infection models, B-cell assays, codon-usage variant analysis","pmids":["39856058","39856038","41785302"],"confidence":"High","gaps":["Human TASL2 orthologue contribution not addressed","Therapeutic targeting of the TASL-SLC15A4 axis in patients not established"]},{"year":2025,"claim":"An upstream regulatory layer on the transporter was defined by showing m6A modification of SLC15A3 mRNA tunes the SLC15A3-TASL-IRF5 axis to control macrophage M1 polarization.","evidence":"Conditional Mettl3/Alkbh5 macrophage knockouts in vivo and in vitro, m6A sequencing, and IRF5 pathway assays","pmids":["40679079"],"confidence":"Medium","gaps":["Whether SLC15A4-dependent TASL signaling is similarly regulated by m6A not tested","Direct effect of SLC15A3 levels on TASL stability not quantified"]},{"year":null,"claim":"How TASL recruitment to its transporter is converted into IRF5 phosphorylation, and what kinase or scaffold completes the pLxIS-dependent activation step, remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Kinase acting on TASL/IRF5 not identified","Structural basis for IRF5 selectivity over IRF3 unknown","Mechanism coupling TASL to lysosomal pH regulation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,10]}],"complexes":[],"partners":["SLC15A4","SLC15A3","IRF5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HAI6","full_name":"TLR adapter interacting with SLC15A4 on the lysosome","aliases":[],"length_aa":301,"mass_kda":33.9,"function":"Innate immune adapter that mediates the recruitment and activation of IRF5 downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9 (PubMed:32433612). Following recruitment to endolysosome by SLC15A4 downstream of TLR7, TLR8 and TLR9, specifically recruits IRF5 transcription factor via its pLxIS motif, leading to IRF5 activation and subsequent expression of type I interferons (PubMed:32433612). Plays a role in the regulation of endolysosomal pH in immune cells such as B-cells, dendritic cells and monocytes (PubMed:31001245)","subcellular_location":"Lysosome membrane; Endosome membrane; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9HAI6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TASL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TASL","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":"301049","title":"TLR ADAPTOR INTERACTING WITH ENDOLYSOSOMAL SLC15A4; TASL","url":"https://www.omim.org/entry/301049"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":18.4},{"tissue":"lymphoid tissue","ntpm":10.2}],"url":"https://www.proteinatlas.org/search/TASL"},"hgnc":{"alias_symbol":["FLJ11577"],"prev_symbol":["CXorf21"]},"alphafold":{"accession":"Q9HAI6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAI6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAI6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAI6-F1-predicted_aligned_error_v6.png","plddt_mean":58.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TASL","jax_strain_url":"https://www.jax.org/strain/search?query=TASL"},"sequence":{"accession":"Q9HAI6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAI6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAI6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAI6"}},"corpus_meta":[{"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":178,"is_preprint":false},{"pmid":"31092820","id":"PMC_31092820","title":"Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31092820","citation_count":87,"is_preprint":false},{"pmid":"31001245","id":"PMC_31001245","title":"Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31001245","citation_count":43,"is_preprint":false},{"pmid":"31695690","id":"PMC_31695690","title":"Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31695690","citation_count":39,"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":"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":"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":"39856058","id":"PMC_39856058","title":"The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39856058","citation_count":10,"is_preprint":false},{"pmid":"39856038","id":"PMC_39856038","title":"An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39856038","citation_count":8,"is_preprint":false},{"pmid":"38184662","id":"PMC_38184662","title":"Inhibition of STAT3 alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells by transcriptionally down-regulating TASL.","date":"2024","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/38184662","citation_count":6,"is_preprint":false},{"pmid":"40679079","id":"PMC_40679079","title":"METTL3/ALKBH5-Mediated N6-Methyladenosine Modification Drives Macrophage M1 Polarization via the SLC15A3-TASL-IRF5 Signaling Axis in Psoriasis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40679079","citation_count":5,"is_preprint":false},{"pmid":"38744928","id":"PMC_38744928","title":"TASL mediates keratinocyte differentiation by regulating intracellular calcium levels and lysosomal function.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38744928","citation_count":1,"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":"41785302","id":"PMC_41785302","title":"The adaptor protein TASL is required for age-related B cell emergence and lupus-like disease development in mice.","date":"2026","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/41785302","citation_count":0,"is_preprint":false},{"pmid":"41833412","id":"PMC_41833412","title":"Tracer-assisted shotgun lipidomics (TASL): A quantitative workflow integrating stable-isotope tracing with global lipidome profiling.","date":"2026","source":"Analytica chimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/41833412","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.01.668068","title":"TASL is required for age-related B cell formation and autoimmunity","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.01.668068","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9811,"output_tokens":3796,"usd":0.043187,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11380,"output_tokens":3419,"usd":0.071188,"stage2_stop_reason":"end_turn"},"total_usd":0.114375,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TASL (encoded by CXorf21) physically interacts with the endolysosomal transporter SLC15A4 and localizes to the lysosome; this interaction is required for TASL's function, as extensive mutagenesis demonstrated that both localization and function depend on SLC15A4 binding.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, subcellular localization imaging\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction confirmed with extensive mutagenesis and localization studies; foundational study replicated by multiple subsequent structural studies\",\n      \"pmids\": [\"32433612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TASL contains a conserved pLxIS motif that mediates the recruitment and activation of IRF5, placing TASL as the endolysosomal TLR adaptor connecting TLR7, TLR8, and TLR9 signaling to IRF5 activation (analogous to how STING, MAVS, and TRIF recruit IRF3).\",\n      \"method\": \"Mutagenesis of pLxIS motif, loss-of-function (TASL knockout/deletion), IRF pathway reporter assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of defined motif with functional readout, replicated independently across multiple labs and model systems\",\n      \"pmids\": [\"32433612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of TASL specifically abrogates IRF pathway activation downstream of endolysosomal TLR7, TLR8, and TLR9, without affecting NF-κB or MAPK signaling, indicating TLR ligand recognition and endolysosomal engagement occur normally but IRF5 activation is selectively blocked.\",\n      \"method\": \"TASL gene deletion in primary and transformed human immune cells, IRF/NF-κB/MAPK pathway reporter and phosphorylation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with selective pathway readouts, replicated in multiple cell types and by independent groups\",\n      \"pmids\": [\"32433612\", \"39856058\", \"39856038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXORF21 (TASL) protein co-localizes with TLR7 in immune cells, consistent with its endolysosomal localization.\",\n      \"method\": \"Immunofluorescence co-localization in primary immune cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-localization experiment in one lab, consistent with multiple subsequent structural and functional studies\",\n      \"pmids\": [\"31092820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXorf21 (TASL) knockdown increases lysosomal pH in female monocytes, demonstrating that TASL regulates endolysosomal pH, with female cells expressing more TASL showing lower lysosomal pH than male cells.\",\n      \"method\": \"CRISPR-Cas9 knockdown, lysosomal pH measurement (LysoSensor, pHrodo assays) in primary monocytes\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pH measurement after CRISPR knockout, replicated across two independent papers from same group\",\n      \"pmids\": [\"31001245\", \"31695690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CXorf21 (TASL) knockdown abrogates TLR7-driven IFNA1 mRNA expression and reduces secretion of TNF-alpha and IL-6 in healthy female monocytes, establishing a functional role in TLR7-driven cytokine production.\",\n      \"method\": \"CRISPR-Cas9 knockdown, qPCR, BioPlex cytokine immunoassay in primary monocytes\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cytokine phenotype, single lab, two orthogonal readouts\",\n      \"pmids\": [\"31695690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structures of human SLC15A4 in apo (monomeric and dimeric) states and in complex with TASL reveal that the N-terminal helix of TASL inserts into the inward-facing cavity of SLC15A4, which undergoes a conformational change from outward-facing to inward-facing state upon TASL binding; the dimeric apo form involves an interface with four cholesterol molecules.\",\n      \"method\": \"Cryo-EM structure determination of SLC15A4 alone and SLC15A4-TASL complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures with functional validation, independently replicated by two separate structural studies in the same year\",\n      \"pmids\": [\"37863913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A small molecule inhibitor (feeblin) binds SLC15A4 in an outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to proteostatic degradation of TASL and blocking TLR7/8-IRF5 signaling; this demonstrates that the TASL-SLC15A4 interaction is required for TASL stability.\",\n      \"method\": \"Cryo-EM structure of feeblin-SLC15A4 complex, phenotypic TASL degradation assay, TLR7/8-IRF5 pathway assays in human immune cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus functional mechanistic assays, direct demonstration of conformational incompatibility with TASL binding\",\n      \"pmids\": [\"37863876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHT1 (SLC15A3) can also recruit TASL; cryo-EM structure of PHT1 in outward-open conformation combined with structural modeling predicts that the first 16 N-terminal residues of TASL form a helix that binds in the central cavity of PHT1's inward-open conformation, analogous to SLC15A4-TASL interaction.\",\n      \"method\": \"Cryo-EM structure of PHT1, biochemical binding assays, structural modeling of PHT1-TASL complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for PHT1 structure / Moderate — complex model is computational, not directly resolved by cryo-EM; single lab\",\n      \"pmids\": [\"37709742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of SLC15A3 (apo) and SLC15A4 (apo and substrate-bound) confirm the N-terminal region of TASL forms a helical structure inserting deeply into the inward-facing cavity of SLC15A4, and reveal the specific dipeptide recognition mechanism that distinguishes SLC15A3 from SLC15A4 substrate binding.\",\n      \"method\": \"Cryo-EM structure determination of SLC15A3, SLC15A4, and SLC15A4-TASL complex\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM with multiple structures, independently confirming TASL interaction mode resolved by two other groups\",\n      \"pmids\": [\"39719710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STAT3 directly and positively regulates TASL transcription by binding to the TASL promoter region, as demonstrated by luciferase assay and chromatin immunoprecipitation (ChIP); inhibition of STAT3 reduces TASL expression and alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells.\",\n      \"method\": \"ChIP, luciferase reporter assay, STAT3 knockdown/overexpression, qRT-PCR, Western blot in HK2 cells\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP and luciferase evidence of transcriptional regulation, two orthogonal methods, single lab\",\n      \"pmids\": [\"38184662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC15A3 can also enhance TASL recruitment, functioning similarly to SLC15A4, to augment IRF5 signaling; m6A modification (written by METTL3, erased by ALKBH5) of SLC15A3 mRNA regulates macrophage M1 polarization via the SLC15A3-TASL-IRF5 axis.\",\n      \"method\": \"Conditional knockout of Mettl3/Alkbh5 in macrophages in vivo and in vitro, m6A sequencing, functional IRF5 pathway assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro knockouts with defined pathway readout, single lab, m6A modification of SLC15A3 upstream of TASL\",\n      \"pmids\": [\"40679079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mice, a paralogue of TASL (Gm6377/TASL2) accounts for residual IRF5 activity when TASL alone is deleted; double knockout of TASL and TASL2 phenocopies SLC15A4-deficient feeble mice, demonstrating that TASL and TASL2 together mediate all SLC15A4-dependent IRF5 activation downstream of TLR7/9.\",\n      \"method\": \"Single and double knockout mouse models, genetic epistasis, IRF5 activation assays, LCMV infection model, pristane-induced SLE model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockout phenocopying SLC15A4 deficiency, multiple orthogonal functional readouts in vivo\",\n      \"pmids\": [\"39856058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TASL-deficient mice lack TLR7/9 responses and are protected from autoimmune symptoms; an SLE-associated TASL risk variant increases TASL protein expression via altered codon usage, resulting in augmented cytokine production in human cells, providing a mechanism for genetic risk.\",\n      \"method\": \"TASL knockout mice, Aldara and pristane autoimmune models, IRF5 phosphorylation assays, codon usage analysis, overexpression of risk variant in human cells with cytokine readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with disease model, mechanistic variant analysis with orthogonal functional readout, single lab with multiple methods\",\n      \"pmids\": [\"39856038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TASL deficiency in keratinocytes causes G1/S cell cycle arrest, impairs proliferation and migration, disrupts lysosomal function and proper differentiation, and impairs calcium modulation required for keratinocyte differentiation, demonstrating a non-immune role for TASL in keratinocyte biology.\",\n      \"method\": \"TASL knockout in HaCaT keratinocyte cell line (CRISPR), cell cycle analysis, proliferation/migration assays, lysosomal function assays, calcium-induced differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple cellular phenotype readouts, single lab, non-immune context distinct from established TASL function\",\n      \"pmids\": [\"38744928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TASL is required for full activation of B cells via TLR9 stimulation, for emergence of age-associated B cells (ABCs), and for IgG2c antibody production; TASL deletion prevents autoimmunity onset in the B6.MRLlpr lupus model.\",\n      \"method\": \"TASL knockout mice in B6.MRLlpr background, B cell activation assays, flow cytometry for ABCs, ELISA for antibodies, interferon/cytokine assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout in disease model with multiple defined cellular and molecular phenotypes, independently replicated as preprint\",\n      \"pmids\": [\"41785302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TASL (CXorf21/FLJ11577) is a lysosome-resident innate immune adaptor that binds via its N-terminal helix to the inward-facing cavity of the endolysosomal transporter SLC15A4 (and also PHT1/SLC15A3), undergoes proteostatic stabilization through this interaction, and uses its conserved pLxIS motif to recruit and activate IRF5 downstream of endolysosomal TLR7, TLR8, and TLR9 signaling—selectively activating the IRF transcriptional pathway without affecting NF-κB or MAPK signaling—while also regulating endolysosomal pH; its transcription is directly activated by STAT3, and a mouse paralogue TASL2 shares redundant IRF5-activating function in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TASL (CXorf21/FLJ11577) is a lysosome-resident innate immune adaptor that couples endolysosomal Toll-like receptor signaling to IRF5 activation [#1, #2]. It is recruited to the lysosome through direct binding to the endolysosomal transporter SLC15A4, an interaction required for both its localization and function; its conserved N-terminal helix inserts into the inward-facing cavity of SLC15A4 and drives a conformational shift of the transporter from an outward- to an inward-facing state [#0, #6, #9]. This interaction is also proteostatic: disrupting it with a small molecule that locks SLC15A4 in an outward-open conformation triggers TASL degradation and blocks TLR7/8–IRF5 signaling [#7]. Through a conserved pLxIS motif, TASL recruits and activates IRF5 downstream of TLR7, TLR8, and TLR9, selectively driving the IRF transcriptional arm without affecting NF-κB or MAPK signaling [#1, #2]. The closely related transporters PHT1/SLC15A3 can likewise recruit TASL to augment IRF5 signaling [#8, #11]. TASL transcription is directly activated by STAT3 [#10], and in mice a paralogue, TASL2, provides redundant SLC15A4-dependent IRF5-activating function in vivo [#12]. TASL is required for TLR7/9-driven cytokine and interferon responses and for B-cell activation, and its loss protects mice from autoimmunity, while an SLE-associated risk variant elevates TASL protein and augments cytokine production [#5, #13, #15]. Beyond immunity, TASL also regulates endolysosomal pH and supports keratinocyte proliferation and differentiation [#4, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Before TASL had a defined molecular role, it was unclear whether the protein operated at the endolysosome; co-localization with TLR7 and an effect on lysosomal pH placed it in the endolysosomal compartment and linked it to TLR7-driven cytokine output.\",\n      \"evidence\": \"Immunofluorescence co-localization, CRISPR knockdown with lysosomal pH measurement and cytokine assays in primary monocytes\",\n      \"pmids\": [\"31092820\", \"31001245\", \"31695690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular partner or signaling mechanism identified at this stage\", \"pH regulation mechanism not resolved\", \"Sex-biased expression effect not mechanistically explained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The central question of how endolysosomal TLRs activate IRF5 was answered by showing TASL binds SLC15A4 to localize at the lysosome and uses a pLxIS motif to recruit and activate IRF5, defining it as the missing TLR7/8/9-to-IRF5 adaptor.\",\n      \"evidence\": \"Co-IP, extensive mutagenesis, subcellular imaging, pLxIS motif mutagenesis, and IRF/NF-κB/MAPK reporter and phosphorylation assays in human immune cells\",\n      \"pmids\": [\"32433612\", \"39856058\", \"39856038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TASL-SLC15A4 interaction not yet resolved\", \"How IRF5 is phosphorylated downstream of TASL recruitment not detailed\", \"Selectivity for IRF over NF-κB/MAPK not mechanistically explained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The structural and proteostatic basis of the interaction was established by cryo-EM, showing the TASL N-terminal helix inserts into the inward-facing SLC15A4 cavity and that disrupting this binding (via the inhibitor feeblin) destabilizes TASL and blocks TLR7/8-IRF5 signaling.\",\n      \"evidence\": \"Cryo-EM of apo and TASL-bound SLC15A4 and of the feeblin-SLC15A4 complex, with TASL degradation and pathway assays\",\n      \"pmids\": [\"37863913\", \"37863876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformational state of SLC15A4 controls TASL stability at the molecular level not fully defined\", \"Role of the cholesterol-mediated dimer interface unclear\", \"Whether transporter activity per se is required for signaling not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The question of adaptor specificity was extended by showing the related transporter PHT1/SLC15A3 can also recruit TASL via an analogous N-terminal helix interaction, indicating TASL recruitment is not unique to SLC15A4.\",\n      \"evidence\": \"Cryo-EM of PHT1, biochemical binding assays, and structural modeling of the PHT1-TASL complex\",\n      \"pmids\": [\"37709742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PHT1-TASL complex is a computational model, not directly resolved by cryo-EM\", \"Physiological contribution of PHT1 versus SLC15A4 to TASL function not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The high-resolution interaction mode and substrate recognition were independently confirmed, and an upstream transcriptional input was defined by showing STAT3 directly activates TASL transcription, connecting TASL levels to inflammatory signaling.\",\n      \"evidence\": \"Cryo-EM of SLC15A3/SLC15A4 with the TASL complex; ChIP, luciferase reporter, and STAT3 perturbation in HK2 cells\",\n      \"pmids\": [\"39719710\", \"38184662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3-driven TASL expression operates in immune cells not shown\", \"Link between dipeptide-recognition mechanism and TASL signaling unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A non-immune role was uncovered by showing TASL loss in keratinocytes causes cell cycle arrest and impairs differentiation, lysosomal function, and calcium handling, indicating broader cellular functions beyond innate immunity.\",\n      \"evidence\": \"CRISPR knockout in HaCaT keratinocytes with cell cycle, proliferation/migration, lysosomal, and calcium-induced differentiation assays\",\n      \"pmids\": [\"38744928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TASL to cell cycle and calcium signaling unknown\", \"Whether the keratinocyte phenotype depends on SLC15A4 or IRF5 not tested\", \"Single cell line, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vivo genetics resolved the redundancy and disease relevance: TASL and the paralogue TASL2 together account for all SLC15A4-dependent IRF5 activation, TASL deficiency abolishes TLR7/9 responses and protects against autoimmunity, and an SLE risk variant elevates TASL to augment cytokine production.\",\n      \"evidence\": \"Single and double knockout mice, genetic epistasis, autoimmune (Aldara/pristane/B6.MRLlpr) and infection models, B-cell assays, codon-usage variant analysis\",\n      \"pmids\": [\"39856058\", \"39856038\", \"41785302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human TASL2 orthologue contribution not addressed\", \"Therapeutic targeting of the TASL-SLC15A4 axis in patients not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"An upstream regulatory layer on the transporter was defined by showing m6A modification of SLC15A3 mRNA tunes the SLC15A3-TASL-IRF5 axis to control macrophage M1 polarization.\",\n      \"evidence\": \"Conditional Mettl3/Alkbh5 macrophage knockouts in vivo and in vitro, m6A sequencing, and IRF5 pathway assays\",\n      \"pmids\": [\"40679079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SLC15A4-dependent TASL signaling is similarly regulated by m6A not tested\", \"Direct effect of SLC15A3 levels on TASL stability not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TASL recruitment to its transporter is converted into IRF5 phosphorylation, and what kinase or scaffold completes the pLxIS-dependent activation step, remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase acting on TASL/IRF5 not identified\", \"Structural basis for IRF5 selectivity over IRF3 unknown\", \"Mechanism coupling TASL to lysosomal pH regulation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLC15A4\", \"SLC15A3\", \"IRF5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}