Affinage

TASL

TLR adapter interacting with SLC15A4 on the lysosome · UniProt Q9HAI6

Length
301 aa
Mass
33.9 kDa
Annotated
2026-06-10
15 papers in source corpus 14 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2019 Medium

    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

    PMID:31001245 PMID:31092820 PMID:31695690

    Open questions at the time
    • No molecular partner or signaling mechanism identified at this stage
    • pH regulation mechanism not resolved
    • Sex-biased expression effect not mechanistically explained
  2. 2020 High

    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

    PMID:32433612 PMID:39856038 PMID:39856058

    Open questions at the time
    • 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
  3. 2023 High

    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

    PMID:37863876 PMID:37863913

    Open questions at the time
    • 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
  4. 2023 Medium

    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

    PMID:37709742

    Open questions at the time
    • PHT1-TASL complex is a computational model, not directly resolved by cryo-EM
    • Physiological contribution of PHT1 versus SLC15A4 to TASL function not established
  5. 2024 Medium

    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

    PMID:38184662 PMID:39719710

    Open questions at the time
    • Whether STAT3-driven TASL expression operates in immune cells not shown
    • Link between dipeptide-recognition mechanism and TASL signaling unresolved
  6. 2024 Medium

    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

    PMID:38744928

    Open questions at the time
    • 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
  7. 2025 High

    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

    PMID:39856038 PMID:39856058 PMID:41785302

    Open questions at the time
    • Human TASL2 orthologue contribution not addressed
    • Therapeutic targeting of the TASL-SLC15A4 axis in patients not established
  8. 2025 Medium

    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

    PMID:40679079

    Open questions at the time
    • Whether SLC15A4-dependent TASL signaling is similarly regulated by m6A not tested
    • Direct effect of SLC15A3 levels on TASL stability not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TASL recruitment to its transporter is converted into IRF5 phosphorylation, and what kinase or scaffold completes the pLxIS-dependent activation step, remains undefined.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 2
Pathway
R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
IRF5SLC15A3SLC15A4

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 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. Co-immunoprecipitation, mutagenesis, subcellular localization imaging Nature High 32433612
2020 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). Mutagenesis of pLxIS motif, loss-of-function (TASL knockout/deletion), IRF pathway reporter assays Nature High 32433612
2020 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. TASL gene deletion in primary and transformed human immune cells, IRF/NF-κB/MAPK pathway reporter and phosphorylation assays Nature High 32433612 39856038 39856058
2019 CXORF21 (TASL) protein co-localizes with TLR7 in immune cells, consistent with its endolysosomal localization. Immunofluorescence co-localization in primary immune cells Nature communications Medium 31092820
2019 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. CRISPR-Cas9 knockdown, lysosomal pH measurement (LysoSensor, pHrodo assays) in primary monocytes Frontiers in immunology Medium 31001245 31695690
2019 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. CRISPR-Cas9 knockdown, qPCR, BioPlex cytokine immunoassay in primary monocytes Frontiers in immunology Medium 31695690
2023 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. Cryo-EM structure determination of SLC15A4 alone and SLC15A4-TASL complex Nature communications High 37863913
2023 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. Cryo-EM structure of feeblin-SLC15A4 complex, phenotypic TASL degradation assay, TLR7/8-IRF5 pathway assays in human immune cells Nature communications High 37863876
2023 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. Cryo-EM structure of PHT1, biochemical binding assays, structural modeling of PHT1-TASL complex Nature communications Medium 37709742
2024 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. Cryo-EM structure determination of SLC15A3, SLC15A4, and SLC15A4-TASL complex Structure High 39719710
2024 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. ChIP, luciferase reporter assay, STAT3 knockdown/overexpression, qRT-PCR, Western blot in HK2 cells European journal of medical research Medium 38184662
2025 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. Conditional knockout of Mettl3/Alkbh5 in macrophages in vivo and in vitro, m6A sequencing, functional IRF5 pathway assays Advanced science Medium 40679079
2025 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. Single and double knockout mouse models, genetic epistasis, IRF5 activation assays, LCMV infection model, pristane-induced SLE model Nature communications High 39856058
2025 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. TASL knockout mice, Aldara and pristane autoimmune models, IRF5 phosphorylation assays, codon usage analysis, overexpression of risk variant in human cells with cytokine readout Nature communications High 39856038
2024 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. TASL knockout in HaCaT keratinocyte cell line (CRISPR), cell cycle analysis, proliferation/migration assays, lysosomal function assays, calcium-induced differentiation assays Scientific reports Medium 38744928
2025 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. TASL knockout mice in B6.MRLlpr background, B cell activation assays, flow cytometry for ABCs, ELISA for antibodies, interferon/cytokine assays PLoS biology High 41785302

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9. Nature 178 32433612
2019 Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus. Nature communications 87 31092820
2019 Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21. Frontiers in immunology 43 31001245
2019 Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis. Frontiers in immunology 39 31695690
2023 A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity. Nature communications 28 37863876
2023 Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling. Nature communications 25 37863913
2023 Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1. Nature communications 13 37709742
2025 The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse. Nature communications 10 39856058
2025 An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nature communications 8 39856038
2024 Inhibition of STAT3 alleviates LPS-induced apoptosis and inflammation in renal tubular epithelial cells by transcriptionally down-regulating TASL. European journal of medical research 6 38184662
2025 METTL3/ALKBH5-Mediated N6-Methyladenosine Modification Drives Macrophage M1 Polarization via the SLC15A3-TASL-IRF5 Signaling Axis in Psoriasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 40679079
2024 TASL mediates keratinocyte differentiation by regulating intracellular calcium levels and lysosomal function. Scientific reports 1 38744928
2026 The adaptor protein TASL is required for age-related B cell emergence and lupus-like disease development in mice. PLoS biology 0 41785302
2026 Tracer-assisted shotgun lipidomics (TASL): A quantitative workflow integrating stable-isotope tracing with global lipidome profiling. Analytica chimica acta 0 41833412
2024 The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL. Structure (London, England : 1993) 0 39719710

Missed literature

Know a paper Affinage missed for TASL? Flag it for the maintainers and the community.

No submissions yet.