Affinage

TLR1

Toll-like receptor 1 · UniProt Q15399

Length
786 aa
Mass
90.3 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 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

TLR1 is a pattern-recognition co-receptor that operates as an obligate partner of TLR2, forming a heterodimer that detects tri-acylated bacterial lipopeptides and lipoproteins at the cell surface and initiates innate immune signaling (PMID:17889651, PMID:12091878). TLR1 and TLR2 physically associate co-translationally, independent of ligand, and the crystal structure of the TLR1-TLR2-Pam3CSK4 complex shows an 'm'-shaped heterodimer in which the amide-bound lipid chain of the ligand inserts into a hydrophobic channel in TLR1 while the ester-bound chains occupy a pocket in TLR2, bringing the intracellular TIR domains into proximity for signaling (PMID:17889651, PMID:12935358, PMID:12975352). Ligand specificity is conferred by the TLR1 extracellular leucine-rich-repeat region (LRR 9-17), which discriminates tri-acylated from di-acylated agonists and distinguishes TLR1- from TLR6-dependent ligands (PMID:18079113, PMID:16455646), while a defined TIR-domain interface (TLR1 Gly-676 contacting the TLR2 DD loop) mediates the productive intracellular interaction (PMID:16893894). CD14, LBP and soluble CD14 act upstream as mobile carriers that capture lipopeptides and deliver them to the heterodimer, promoting ternary-complex assembly without remaining associated with the final complex (PMID:15714590, PMID:23430250). Engaged TLR1/2 signals through a MyD88-dependent NF-κB and MAPK (ERK1/2, p38) cascade to drive pro-inflammatory cytokine production (PMID:18056480, PMID:25969543, PMID:24437488). The receptor recognizes a broad range of microbial ligands—mycobacterial lipoarabinomannan and lipomannan, Francisella and Mycoplasma lipoproteins, Borrelia OspA, meningococcal porin PorB and enterotoxin LT-IIb-B5—and is genetically required for lipoprotein but not peptidoglycan responses (PMID:12935358, PMID:16455995, PMID:18079113, PMID:12091878, PMID:19234193, PMID:16177394, PMID:18474641). TLR1 cell-surface trafficking depends on a short cytoplasmic motif adjacent to the transmembrane domain and on the ER chaperones PRAT4A (positive) and PRAT4B (negative); the common I602S transmembrane polymorphism disrupts this motif, impairing surface expression and innate responses, an association linked to leprosy susceptibility and rescued by IFN-γ-induced PRAT4A (PMID:17548585, PMID:22447933, PMID:18461142). Beyond innate sensing, TLR1/2 engagement shapes adaptive and tissue immunity—driving intestinal TH17 differentiation and IgA via epithelial IL-6/IL-23 and CCL20-dependent dendritic-cell recruitment, and maintaining colonic crypt homeostasis through recognition of microbiota ligands (PMID:22778390, PMID:23443468, PMID:29794015).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 Medium

    Before TLR1's activating role was defined, its first characterized effect was to negatively modulate TLR2 signaling, establishing that TLR1 is a context-dependent modifier of TLR2 responses rather than a uniform amplifier.

    Evidence Transfection-based NF-κB reporter and cytokine assays with phenol-soluble modulin

    PMID:11123271

    Open questions at the time
    • Does not define the ligands for which TLR1 is activating versus inhibitory
    • Mechanism of the dampening effect unresolved
  2. 2002 High

    Genetic deletion established TLR1 as specifically required for recognition of tri-acylated lipoproteins while dispensable for peptidoglycan, separating its ligand class from other TLR2 functions.

    Evidence TLR1-/- and TLR2-/- mouse immunization with OspA and macrophage cytokine assays

    PMID:12091878

    Open questions at the time
    • Did not define the structural basis of ligand discrimination
    • Downstream pathway not dissected
  3. 2003 High

    Co-IP, imaging and domain-swap analyses showed TLR1 and TLR2 form a ligand-independent heterodimer whose TIR domains are the crucial intracellular interaction surface, defining the receptor as an obligate dimer rather than two independent sensors.

    Evidence Co-immunoprecipitation, confocal microscopy, receptor cross-linking, chimeric domain-swap and complementation assays

    PMID:12935358 PMID:12975352

    Open questions at the time
    • Atomic geometry of the dimer not yet resolved
    • How ligand binding repositions the TIR domains not directly shown
  4. 2005 High

    Live-cell biophysics placed CD14 upstream as the initial lipopeptide-binding step that recruits the ligand to a TLR1/TLR2 low-mobility signaling complex, ordering the recognition cascade.

    Evidence FRET/FRAP imaging and flow cytometry in human cells with Pam3CSK4

    PMID:15714590

    Open questions at the time
    • Stoichiometry of the CD14-TLR complex not defined
    • Whether CD14 dissociates from the final complex not addressed here
  5. 2006 High

    Mutagenesis and docking identified the specific TIR-domain interface residues (TLR1 Gly-676 / TLR2 DD loop) required for productive signaling, localizing the intracellular interaction at amino-acid resolution.

    Evidence Alanine-scanning mutagenesis, computational docking and NF-κB reporter assays

    PMID:16893894

    Open questions at the time
    • Interface mapped computationally rather than by structure
    • Recruitment of MyD88 to this interface not directly shown
  6. 2006 Medium

    Structure-activity analysis with lipopeptide variants and TLR-KO cells refined the acylation model, showing TLR1 dependence requires sufficiently long ester-bound chains and that some di-acylated ligands signal independently of TLR1/TLR6.

    Evidence Cytokine assays in TLR1-/- and TLR6-/- mouse cells with synthetic lipopeptide analogs

    PMID:16455646

    Open questions at the time
    • Structural explanation for chain-length requirement provided later by crystallography
    • Generality across natural ligands not established
  7. 2007 High

    The crystal structure of the TLR1-TLR2-Pam3CSK4 complex provided the atomic basis for heterodimer assembly and lipid discrimination, showing the amide-bound chain inserts into a hydrophobic channel in TLR1 to bridge the TIR domains.

    Evidence X-ray crystallography of the ternary ectodomain complex with functional validation

    PMID:17889651

    Open questions at the time
    • Does not capture the transmembrane or intracellular conformational changes
    • CD14/LBP delivery step not in the structure
  8. 2007 High

    Domain-exchange analysis localized ligand recognition to TLR1 extracellular LRR 9-17, the region that confers specificity for tri-acylated lipopeptides and Francisella lipoproteins.

    Evidence Chimeric TLR1/TLR6 domain-exchange and NF-κB reporter assays

    PMID:18079113

    Open questions at the time
    • Individual contact residues within the region not all mapped
    • Affinity contributions of the LRR region not quantified
  9. 2007 High

    Identification of the I602S transmembrane polymorphism linked a natural human variant to defective TLR1 surface trafficking and diminished agonist responses, connecting receptor cell biology to disease susceptibility.

    Evidence Flow cytometry, NF-κB reporter, whole-blood cytokine assays and a leprosy genetic association study

    PMID:17548585

    Open questions at the time
    • Molecular trafficking machinery not yet identified
    • Mechanism by which a transmembrane residue controls surface delivery unresolved
  10. 2008 High

    Functional and clinical analysis tied the I602S (1805G) allele to impaired NF-κB responses to M. leprae and to altered leprosy reversal-reaction risk, extending the trafficking defect to adaptive Th1 immunity.

    Evidence NF-κB reporter in HEK293, PBMC cytokine assays and a clinical genetic cohort

    PMID:18461142

    Open questions at the time
    • Causal chain from reduced surface TLR1 to Th1 outcome correlative
    • Effect sizes vary across pathogen contexts
  11. 2012 High

    Mechanistic dissection identified the short cytoplasmic trafficking motif disrupted by I602S and the opposing ER chaperones PRAT4A and PRAT4B, and showed IFN-γ rescues surface expression in variant monocytes, defining the regulatory logic of TLR1 surface delivery.

    Evidence Point mutagenesis, PRAT4A/B overexpression and knockdown, and IFN-γ treatment of primary human monocytes

    PMID:22447933

    Open questions at the time
    • Direct chaperone-TLR1 contact sites not mapped
    • How the cytoplasmic motif is read by the trafficking machinery unresolved
  12. 2013 High

    In vitro reconstitution defined LBP and soluble CD14 as independent mobile carriers that transfer lipopeptides to the receptor and enhance ternary-complex formation without remaining bound, refining the ligand-delivery model.

    Evidence Size-exclusion chromatography of recombinant soluble TLR ectodomains with cell activation assays

    PMID:23430250

    Open questions at the time
    • Kinetics of carrier handoff not quantified
    • Relative contributions of LBP versus sCD14 in vivo unclear
  13. 2019 High

    Crystallography of the synthetic agonist Diprovocim showed a non-lipopeptide ligand can drive TLR2/TLR1 dimerization through the TLR2 ectodomain pocket, establishing that the receptor can be activated by non-canonical chemistries.

    Evidence Crystal structure and in vitro biophysical assays of the TLR2-Diprovocim complex

    PMID:30829478

    Open questions at the time
    • TLR1's contribution to the Diprovocim-bound complex less defined than in the lipopeptide structure
    • In vivo activity not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TLR1's defined molecular recognition is translated into the divergent tissue- and disease-specific outcomes (TH17 versus regulatory responses, leukemic apoptosis, anti-tumor macrophage reprogramming, crypt homeostasis) at the level of signaling specificity remains unresolved.
  • Whether identical NF-κB/MAPK output can account for divergent cell-type outcomes is unexplained
  • No structural model linking ligand identity to differential downstream programs
  • Mechanism of the receptor-level TLR1/TLR2 functional dichotomy in pDCs not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
CD14LBPMYD88PRAT4APRAT4BTLR2
Complex memberships
TLR1-TLR2 heterodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Crystal structure of the human TLR1-TLR2 heterodimer bound to the tri-acylated lipopeptide Pam3CSK4 revealed an 'm'-shaped heterodimer: the two ester-bound lipid chains insert into a hydrophobic pocket in TLR2, while the amide-bound lipid chain inserts into a hydrophobic channel in TLR1, with an extensive hydrogen-bonding and hydrophobic network stabilizing the heterodimer and bringing the intracellular TIR domains into proximity to initiate signaling. X-ray crystallography of TLR1-TLR2-Pam3CSK4 ternary complex Cell High 17889651
2003 TLR1 and TLR2 are physically associated by co-immunoprecipitation independently of ligand; mycobacterial lipoarabinomannan (LAM) and phosphatidylinositol mannosides activate NF-κB only through the combined actions of TLR1 and TLR2. A protein fragment complementation assay showed that LAM alters the physical interaction between the intracellular TIR domains of TLR1 and TLR2 to initiate signaling. Co-immunoprecipitation; NF-κB luciferase reporter transfection assay; protein fragment complementation assay Journal of endotoxin research High 12935358
2003 TLR1 and TLR2 co-translationally form heterodimeric complexes on the cell surface and in the cytosol, as shown by confocal microscopy. Simultaneous cross-linking of both receptors produces ligand-independent signal transduction. Chimeric TLR domain-swap analysis demonstrated that both extracellular and intracellular (TIR) domains of both TLR1 and TLR2 are required for functional signaling, and that the TIR domain is the area of crucial intracellular TLR1-TLR2 interaction. Confocal microscopy; receptor cross-linking; chimeric TLR domain-swap analysis; cytokine secretion assay The Journal of cell biology High 12975352
2006 Alanine scanning mutagenesis of the TLR2 DD loop identified four residues (Arg-748, Phe-749, Leu-752, Arg-753) crucial for TLR2/TLR1 signaling. Computational docking predicted that Arg-748 and Phe-749 contact Gly-676 in the TLR1 BB loop; rational mutation of TLR1 Gly-676 to Ala or Leu reduced Pam3CSK4-mediated NF-κB activation, confirming this TIR-domain interface. Random and alanine-scanning mutagenesis; NF-κB reporter assay; computational energy minimization and docking The Journal of biological chemistry High 16893894
2005 Binding of the tri-acylated lipopeptide Pam3CSK4 to CD14 is the initial step in lipopeptide recognition, after which CD14 and the lipopeptide associate with TLR2 and TLR1, targeting TLR2 to a low-mobility signaling complex. This was demonstrated by FRET and FRAP imaging in human cells. FRET and FRAP imaging; flow cytometry; confocal microscopy European journal of immunology High 15714590
2013 Lipopolysaccharide-binding protein (LBP) and soluble CD14 independently act as mobile carriers that deliver triacylated lipopeptides/lipoproteins to TLR1 and TLR2, enhancing formation of the TLR1·TLR2·lipopeptide ternary complex as measured by size exclusion chromatography; neither LBP nor sCD14 remains physically associated with the final ternary complex. Size exclusion chromatography of recombinant soluble TLR ectodomains; cell activation assay with synthetic lipopeptide and natural lipoprotein OspA The Journal of biological chemistry High 23430250
2007 The I602S single nucleotide polymorphism within the TLR1 transmembrane domain causes aberrant trafficking of TLR1 to the cell surface and diminished functional responses to bacterial agonists in blood monocytes; the 602S variant but not 602I shows these trafficking and signaling deficiencies when expressed in heterologous systems. The 602S allele is associated with decreased leprosy incidence. Flow cytometry for surface expression; NF-κB reporter assay in transfected cells; whole-blood cytokine assay; genetic association study Journal of immunology High 17548585
2012 A short 6-amino-acid cytoplasmic region adjacent to the transmembrane domain is required for TLR1 cell-surface trafficking; a serine at position 602 (I602S) disrupts this trafficking motif. ER-resident chaperones PRAT4A and PRAT4B act as positive and negative regulators of TLR1 surface trafficking, respectively. IFN-γ treatment of monocytes from 602S homozygotes rescues TLR1 surface expression via induction of PRAT4A. Receptor deletion and point mutagenesis; flow cytometry; PRAT4A/B overexpression and knockdown; IFN-γ treatment of primary human monocytes The Journal of biological chemistry High 22447933
2006 Meningococcal outer membrane porin PorB binds directly to TLR2 (demonstrated by labeled-PorB binding assay in vitro and on HEK293 cells overexpressing TLR2) and selectively signals through the TLR2/TLR1 heterodimer rather than TLR2/TLR6; TLR1 is required for PorB-induced cell activation in transfected HEK293 cells and murine B cells. Labeled-protein binding assay; chimeric TLR2/TLR1 and TLR2/TLR6 transfection; NF-κB reporter assay; murine B cell activation assay Journal of immunology High 16455995
2007 Domain-exchange analysis showed that LRR 9-17 in the extracellular domain of TLR1 mediates responses to Francisella lipoproteins TUL4/FTT1103 and to triacylated lipopeptide; substituting the corresponding TLR6 LRR region with TLR1 LRR 9-17 enables TLR6 to recognize these TLR1-specific ligands. Chimeric TLR domain-exchange assay; NF-κB reporter assay in transfected cells The Journal of biological chemistry High 18079113
2007 TLR heterodimerization of TLR2 with TLR1 or TLR6 expands the lipopeptide ligand spectrum but leads to an identical NF-κB/MAPK signaling pattern; all TLR2 dimers use the same downstream cascade and produce the same gene activation profile. Dominant-negative signaling molecule expression; immunoblotting of MAPKs; microarray gene expression analysis Journal of leukocyte biology Medium 18056480
2006 Triacylated lipopeptides require TLR1 for cellular responses only when the ester-bound fatty acid chains are of sufficient length; short ester-bound chains render triacylated lipopeptides TLR1-independent. Diacylated lipopeptides can be recognized by TLR2 in a TLR1- and TLR6-independent manner, contradicting the strict acylation-pattern model. Cytokine production assay in TLR1-deficient and TLR6-deficient mouse cells; structure-activity analysis of synthetic lipopeptide analogs The Journal of biological chemistry Medium 16455646
2001 TLR1 inhibits TLR2-mediated responses to phenol-soluble modulin from Staphylococcus epidermidis; co-expression of TLR1 with TLR2 dampens signaling relative to TLR2 alone or TLR2/TLR6, showing a negative modulatory role for TLR1 in certain TLR2 ligand contexts. Transfection-based NF-κB reporter assay; cytokine measurement Journal of immunology Medium 11123271
2002 TLR1-deficient mice produce low anti-OspA antibody titers after vaccination and their macrophages fail to respond to OspA (a triacylated lipoprotein) but respond normally to peptidoglycan, establishing TLR1 as required for lipoprotein recognition but dispensable for PGN recognition. TLR1-/- and TLR2-/- mouse immunization; macrophage cytokine production assay; flow cytometry for TLR1 surface expression on human monocytes Nature medicine High 12091878
2015 Higher-order oligomeric α-synuclein directly engages the TLR1/2 heterodimer at the microglial cell membrane, triggering MyD88-dependent NF-κB nuclear translocation and production of TNF-α and IL-1β; blocking TLR1/2 with the small-molecule inhibitor CU-CPT22 or inhibiting TLR2 expression with candesartan reduces these responses. TLR1/2 blocking with CU-CPT22; candesartan treatment; NF-κB translocation assay; cytokine ELISA; primary mouse microglia culture Science signaling Medium 25969543
2012 The small molecule CU-CPT22 competes with Pam3CSK4 for binding to the TLR1/2 complex with high inhibitory activity and specificity, suppressing downstream TNF-α and IL-1β signaling, establishing TLR1/2 as a druggable target with a defined lipopeptide-binding site. Competitive binding assay; NF-κB reporter assay; cytokine ELISA in THP-1 cells Angewandte Chemie Medium 22969053
2015 A small molecule CU-T12-9 directly binds to both TLR1 and TLR2 (demonstrated by fluorescence anisotropy showing competitive binding with Pam3CSK4 at IC50 = 54.4 nM), facilitates TLR1/2 heterodimeric complex formation, and activates downstream NF-κB signaling leading to TNF-α, IL-10, and iNOS production; specificity was confirmed by antibody blocking of TLR1 or TLR2 but not TLR6. Fluorescence anisotropy competitive binding assay; NF-κB reporter assay; anti-TLR antibody blocking; cytokine ELISA Science advances Medium 26101787
2019 Crystal structure of the TLR2/TLR1 agonist Diprovocim revealed two Diprovocim molecules bound in the ligand-binding pocket formed between two TLR2 ectodomains; Diprovocim induces both TLR2/TLR1 heterodimers and TLR2 homodimers in vitro, via extensive hydrophobic interactions and hydrogen bonding, providing structural insight into TLR2/TLR1 activation by a noncanonical non-lipopeptide agonist. Crystal structure determination; in vitro biophysical assays; computational approaches Journal of medicinal chemistry High 30829478
2009 The pentameric B subunit of type IIb E. coli enterotoxin (LT-IIb-B5) activates TLR2/TLR1; four residues in the upper pore region of LT-IIb-B5 (M69E, A70D, L73E, S74D) are critical for binding TLR2 or TLR1, and mutations at the TLR2/1 dimer interface reduce activation by both Pam3CSK4 and LT-IIb-B5. LRR motifs 9-12 in the TLR1 central domain are critical for cooperative activation, and the LT-IIb-B5 binding site partially overlaps with that of Pam3CSK4. Site-directed mutagenesis of ligand and receptor; NF-κB reporter assay; binding assay; docking analysis Journal of immunology Medium 19234193
2008 The TLR1 I602S (T1805G) polymorphism impairs NF-κB signaling in HEK293 cells stimulated with M. leprae extracts; individuals homozygous for 1805G have significantly reduced cytokine responses to irradiated M. leprae and cell wall extracts in PBMCs, and the 1805G allele is associated with protection from leprosy reversal reaction (OR 0.51), linking TLR1 deficiency to impaired Th1-mediated adaptive immunity. NF-κB reporter assay in transfected HEK293 cells; PBMC cytokine assay; clinical genetic association study PLoS neglected tropical diseases High 18461142
2019 TLR1/2 activation by Pam3CSK4 in AML cells induces apoptosis via p38 MAPK-dependent Caspase-3 activation and myeloid differentiation via NF-κB; these effects are p53-independent (shown using Trp53-null AML cells) and selective for leukemic vs. normal hematopoietic stem/progenitor cells. Agonist treatment of primary AML and murine AML cells; p38 MAPK/Caspase-3 assay; NF-κB activation assay; Trp53-/- AML model; in vivo mouse model Blood advances Medium 29296851
2012 TLR1 activation in intestinal epithelium is required for induction of TH17 immunity during oral Yersinia enterocolitica infection; TLR2/TLR1-induced IL-6 and IL-23 combined with intestinal TGF-β drives TH17 differentiation, while TLR2/TLR6 drives IL-10+ regulatory T cell responses during both oral and systemic infection. TLR1-/- and TLR6-/- mouse infection model; cytokine measurement; T cell phenotyping The Journal of experimental medicine Medium 22778390
2013 TLR1 activation in intestinal epithelium upregulates CCL20, recruiting CCR6+ dendritic cells that produce innate cytokines driving TH17 cells and IgA production during oral Y. enterocolitica infection; neutralization of CCL20 or TLR1 deletion both impair CCR6+ DC recruitment and anti-Yersinia TH17/IgA responses. TLR1-/- mouse infection model; CCL20 antibody neutralization; dendritic cell phenotyping; IgA measurement Mucosal immunology Medium 23443468
2005 Mycobacterial lipomannan (LM) induces MMP-9 expression and secretion in human macrophages through a TLR1/TLR2- and CD14-dependent mechanism; LM simultaneously down-regulates TIMP-1, the major endogenous MMP-9 inhibitor. Anti-TLR1 and anti-TLR2 neutralizing antibody blocking; anti-CD14 blocking; ELISA and zymography for MMP-9; RT-PCR for TIMP-1 Infection and immunity Medium 16177394
2008 The triacylated lipoprotein MG149 from Mycoplasma genitalium activates NF-κB through TLR1 and TLR2; dominant-negative TLR1 but not dominant-negative TLR6 blocks MG149-induced NF-κB activation, and a synthetic triacylated lipopeptide derived from MG149 also signals through TLR1/2. Dominant-negative TLR constructs; NF-κB reporter assay; Triton X-114 protein fractionation Infection and immunity Medium 18474641
2008 TLR1/2 signaling in cystic fibrosis airway neutrophils upregulates TLR5 surface expression through a mechanism dependent on TLR1 and TLR2 cooperation; antibody blocking of TLR1 or TLR2 abrogates the Pam3CSK4-induced TLR5 upregulation, and elevated TLR5 enhances phagocytosis and respiratory burst via IL-8/CXCR1 signaling. Antibody-blocking experiments; confocal microscopy; flow cytometry; in vitro neutrophil stimulation Journal of immunology Medium 18684966
2018 Defective TLR1 recognition of microbiota-derived ligands by colonic epithelial cells disrupts crypt homeostasis (mucus layer defects, ectopic Paneth cells, increased crypt-base proliferation), increases mucosal-associated and translocating commensal bacteria, and promotes chronic low-grade inflammation mediated by innate lymphoid-like cells that worsen colonic injury. TLR1-/- mouse model; histology; bacterial culture; innate lymphoid cell phenotyping; colitis injury model Journal of immunology Medium 29794015
2019 In human primary plasmacytoid dendritic cells (pDCs), TLR1 and TLR2 are expressed and respond to gram-positive bacterial lipoproteins via TLR1/2; upregulation of costimulatory molecules and pro-inflammatory cytokines is TLR1-dependent via MAPK and NF-κB pathways, whereas type I IFN secretion is TLR2-dependent via PI3K, revealing a functional dichotomy within the same heterodimer. Antibody blocking of TLR1 vs TLR2; pathway inhibitors (MAPK, NF-κB, PI3K); cytokine/IFN ELISA; primary human pDC culture PLoS biology Medium 31017904
2015 siRNA knockdown of TLR1 (but not TLR6) in bovine endometrial epithelial and stromal cells reduces IL-6 and IL-8 accumulation in response to triacylated lipopeptides, and inhibitors of ERK1/2 or p38 limit IL-6 production; both lipopeptides rapidly induce phosphorylation of ERK1/2, p38, and NF-κB through TLR2/TLR1 heterodimers in endometrial cells. siRNA knockdown; cytokine ELISA; MAPK/NF-κB phosphorylation assay; kinase inhibitors Endocrinology Medium 24437488
2015 miR-15a/16 directly binds the 3'-UTR of TLR1 mRNA and reduces TLR1 protein expression in non-small cell lung cancer cells, thereby downregulating NF-κB signaling pathway activity and enhancing radiosensitivity. Luciferase reporter assay (3'-UTR); miRNA mimic overexpression; immunoblot; NF-κB reporter; in vivo xenograft model International journal of radiation oncology, biology, physics Medium 25442346
2020 The spacing of TLR1/2 ligand nanoclusters on an artificial 'phagocytic synapse' array dictates the proximity of TLR1/2 receptor clusters on macrophage surfaces and consequently the magnitude of pro-inflammatory responses; cell responses plateau when ligand spacing is small enough for receptor nanoclusters to become adjacent, demonstrating a physical integration of spatial ligand cues into TLR1/2 signaling. DNA nanoarray platform mimicking cell-microbe interface; fluorescence imaging of receptor clustering; cytokine assay Science advances Medium 33268354
2019 TLR1/2 activation by Pam3CSK4 increases Fcγ receptor IV (FcγRIV) expression on macrophages, leading to antibody-dependent macrophage-mediated depletion of regulatory T cells in the tumor microenvironment; this mechanism enhances efficacy of anti-CTLA-4 antibody and requires CD4 T cells, CD8 T cells, FcγRIV, and macrophages. In vivo mouse melanoma model; intratumoral injection; flow cytometry for FcγRIV expression; T cell depletion; tumor-infiltrating leukocyte analysis PNAS Medium 31076558

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 1073 17889651
2001 Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. Journal of immunology (Baltimore, Md. : 1950) 346 11123271
2002 Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nature medicine 321 12091878
2007 Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. Journal of leukocyte biology 252 18056480
2015 Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Science signaling 240 25969543
2007 Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. Journal of immunology (Baltimore, Md. : 1950) 213 17548585
2006 TLR1- and TLR6-independent recognition of bacterial lipopeptides. The Journal of biological chemistry 204 16455646
2022 Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation. Gut microbes 176 36398889
2005 TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation. Annals of the New York Academy of Sciences 166 16461792
2007 A common human TLR1 polymorphism regulates the innate immune response to lipopeptides. European journal of immunology 161 17595679
2012 Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angewandte Chemie (International ed. in English) 125 22969053
2010 TLR1/2, TLR7, and TLR9 signals directly activate human peripheral blood naive and memory B cell subsets to produce cytokines, chemokines, and hematopoietic growth factors. Journal of clinical immunology 124 20821041
2005 Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. Journal of the National Cancer Institute 124 15812078
2005 Binding of lipopeptide to CD14 induces physical proximity of CD14, TLR2 and TLR1. European journal of immunology 120 15714590
2014 Epithelial and stromal cells of bovine endometrium have roles in innate immunity and initiate inflammatory responses to bacterial lipopeptides in vitro via Toll-like receptors TLR2, TLR1, and TLR6. Endocrinology 116 24437488
2006 Meningococcal porin PorB binds to TLR2 and requires TLR1 for signaling. Journal of immunology (Baltimore, Md. : 1950) 115 16455995
2008 Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS neglected tropical diseases 111 18461142
2009 The TLR1/2 agonist PAM(3)CSK(4) instructs commitment of human hematopoietic stem cells to a myeloid cell fate. Leukemia 106 19641520
2018 Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice. Proceedings of the National Academy of Sciences of the United States of America 100 30150374
2006 Structural and functional evidence for the role of the TLR2 DD loop in TLR1/TLR2 heterodimerization and signaling. The Journal of biological chemistry 96 16893894
2003 Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling. The Journal of cell biology 95 12975352
2013 Human lipopolysaccharide-binding protein (LBP) and CD14 independently deliver triacylated lipoproteins to Toll-like receptor 1 (TLR1) and TLR2 and enhance formation of the ternary signaling complex. The Journal of biological chemistry 92 23430250
2008 Toll-like receptors TLR1, TLR2 and TLR4 gene mutations and natural resistance to Mycobacterium avium subsp. paratuberculosis infection in cattle. Veterinary immunology and immunopathology 90 19131114
2003 Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling. Journal of endotoxin research 87 12935358
2007 Identification of Francisella tularensis lipoproteins that stimulate the toll-like receptor (TLR) 2/TLR1 heterodimer. The Journal of biological chemistry 84 18079113
2015 TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis. PloS one 82 26430737
2011 Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS pathogens 81 21852947
2007 Role of TLR1 and TLR6 in the host defense against disseminated candidiasis. FEMS immunology and medical microbiology 81 18036178
2008 Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk. International journal of cancer 79 18752252
2015 Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists. Science advances 76 26101787
2008 TLR expression on neutrophils at the pulmonary site of infection: TLR1/TLR2-mediated up-regulation of TLR5 expression in cystic fibrosis lung disease. Journal of immunology (Baltimore, Md. : 1950) 73 18684966
2019 Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim. Journal of medicinal chemistry 71 30829478
2008 Distinct intracellular signaling pathways control the synthesis of IL-8 and RANTES in TLR1/TLR2, TLR3 or NOD1 activated human airway epithelial cells. Cellular signalling 68 19121387
2008 A triacylated lipoprotein from Mycoplasma genitalium activates NF-kappaB through Toll-like receptor 1 (TLR1) and TLR2. Infection and immunity 66 18474641
2016 Identification and characteristic analysis of TLR28: A novel member of the TLR1 family in teleost. Developmental and comparative immunology 65 27155354
2011 Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression. Journal of leukocyte biology 64 21642391
2015 Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunologic research 61 25784622
2019 TLR1/2 ligand enhances antitumor efficacy of CTLA-4 blockade by increasing intratumoral Treg depletion. Proceedings of the National Academy of Sciences of the United States of America 60 31076558
2019 TLR1/2 Specific Small-Molecule Agonist Suppresses Leukemia Cancer Cell Growth by Stimulating Cytotoxic T Lymphocytes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 60 31131189
2012 A specific role for TLR1 in protective T(H)17 immunity during mucosal infection. The Journal of experimental medicine 60 22778390
2011 Molecular evolution of the vertebrate TLR1 gene family--a complex history of gene duplication, gene conversion, positive selection and co-evolution. BMC evolutionary biology 59 21619680
2013 TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro. Journal of immunology (Baltimore, Md. : 1950) 58 24227786
2012 Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses. Genes and immunity 55 23151486
2012 Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) influences disease course in sarcoidosis. Tissue antigens 53 22150367
2017 House Dust Mite Increases pro-Th2 Cytokines IL-25 and IL-33 via the Activation of TLR1/6 Signaling. The Journal of investigative dermatology 51 28684329
2015 B cell TLR1/2, TLR4, TLR7 and TLR9 interact in induction of class switch DNA recombination: modulation by BCR and CD40, and relevance to T-independent antibody responses. Autoimmunity 51 25536171
2015 Molecular cloning of Salmo salar Toll-like receptors (TLR1, TLR22, TLR5M and TLR5S) and expression analysis in SHK-1 cells during Piscirickettsia salmonis infection. Journal of fish diseases 51 25903926
2014 miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-κB signaling pathway. International journal of radiation oncology, biology, physics 51 25442346
2011 TLR1/TLR2 heterodimers play an important role in the recognition of Borrelia spirochetes. PloS one 50 21998742
2017 Role of TLR1, TLR2 and TLR6 in the modulation of intestinal inflammation and Candida albicans elimination. Gut pathogens 49 28289440
2010 Identification, characterization and genetic mapping of TLR1 loci in rainbow trout (Oncorhynchus mykiss). Fish & shellfish immunology 48 20153434
2012 Atherosclerosis induced by endogenous and exogenous toll-like receptor (TLR)1 or TLR6 agonists. Journal of lipid research 46 22822027
2011 TLR1/2 activation during heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T Cell responses providing protection against Leishmania (Viannia). PLoS neglected tropical diseases 46 21695103
2007 Gene conversion limits divergence of mammalian TLR1 and TLR6. BMC evolutionary biology 45 17727694
2013 Innate immune receptors in human airway smooth muscle cells: activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 agonists. PloS one 44 23861935
2016 Up-regulated of miR-8159-5p and miR-217-5p by LPS stimulation negatively co-regulate TLR1 in miiuy croaker. Developmental and comparative immunology 43 27832948
2005 Mycobacterial lipomannan induces matrix metalloproteinase-9 expression in human macrophagic cells through a Toll-like receptor 1 (TLR1)/TLR2- and CD14-dependent mechanism. Infection and immunity 42 16177394
2019 TLR1/TLR2 signaling blocks the suppression of monocytic myeloid-derived suppressor cell by promoting its differentiation into M1-type macrophage. Molecular immunology 41 31212097
2008 Immunogenecity of modified alkane polymers is mediated through TLR1/2 activation. PloS one 41 18560588
2016 Comparative genomic evidence for duplication of TLR1 subfamily and miiuy croaker TLR1 perceives LPS stimulation via MyD88 and TIRAP. Fish & shellfish immunology 40 27431585
2014 TLR1, TLR2, and TLR6 gene polymorphisms are associated with increased susceptibility to complicated skin and skin structure infections. The Journal of infectious diseases 40 24511099
2017 Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells. Blood advances 39 29296851
2010 Common variants of TLR1 associate with organ dysfunction and sustained pro-inflammatory responses during sepsis. PloS one 38 21048935
2016 Molecular and functional characterization of Toll-like receptor (Tlr)1 and Tlr2 in common carp (Cyprinus carpio). Fish & shellfish immunology 37 27368535
2018 Innate Recognition of the Microbiota by TLR1 Promotes Epithelial Homeostasis and Prevents Chronic Inflammation. Journal of immunology (Baltimore, Md. : 1950) 36 29794015
2015 Vibrio cholerae porin OmpU mediates M1-polarization of macrophages/monocytes via TLR1/TLR2 activation. Immunobiology 36 26093918
2009 Mapping of a microbial protein domain involved in binding and activation of the TLR2/TLR1 heterodimer. Journal of immunology (Baltimore, Md. : 1950) 36 19234193
2021 Identification and expression analysis of sixteen Toll-like receptor genes, TLR1, TLR2a, TLR2b, TLR3, TLR5M, TLR5S, TLR7-9, TLR13a-c, TLR14, TLR21-23 in mandarin fish Siniperca chuatsi. Developmental and comparative immunology 35 33862097
2013 TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica. Mucosal immunology 35 23443468
2007 Association between Toll-like receptor gene cluster (TLR6, TLR1, and TLR10) and prostate cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 35 17932345
2022 The transcription factors TLR1 and TLR2 negatively regulate trichome density and artemisinin levels in Artemisia annua. Journal of integrative plant biology 34 35355415
2010 Correlation of TLR1-10 expression in peripheral blood mononuclear cells with chronic hepatitis B and chronic hepatitis B-related liver failure. Human immunology 34 20667457
2014 Toll-like receptor 1(TLR1) Gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children. Tuberculosis (Edinburgh, Scotland) 33 25544311
2013 The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6. Veterinary research 33 23826682
2016 miR-200a-3p regulates TLR1 expression in bacterial challenged miiuy croaker. Developmental and comparative immunology 32 27288848
2018 Genetic polymorphisms in TLR1, TLR2, TLR4, and TLR10 of Helicobacter pylori-associated gastritis: a prospective cross-sectional study in Thailand. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 31 28368946
2018 Genome wide analysis of TLR1/2- and TLR4-activated SZ95 sebocytes reveals a complex immune-competence and identifies serum amyloid A as a marker for activated sebaceous glands. PloS one 31 29927962
2021 Design, Synthesis, and Structure-Activity Relationship of N-Aryl-N'-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy. Journal of medicinal chemistry 30 34029463
2007 Genomic variants of TLR1--it takes (TLR-)two to tango. European journal of immunology 30 17654751
2012 Cell surface trafficking of TLR1 is differentially regulated by the chaperones PRAT4A and PRAT4B. The Journal of biological chemistry 29 22447933
2016 B Cell Anergy Modulated by TLR1/2 and the miR-17∼92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4. Journal of immunology (Baltimore, Md. : 1950) 28 27059597
2006 Genomic organization and transcript profiling of the bovine toll-like receptor gene cluster TLR6-TLR1-TLR10. Gene 28 16950576
2011 Functional characterization of naturally occurring genetic variants in the human TLR1-2-6 gene family. Human mutation 26 21618349
2020 Neonatal Stroke and TLR1/2 Ligand Recruit Myeloid Cells through the Choroid Plexus in a CX3CR1-CCR2- and Context-Specific Manner. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 32269105
2014 Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice. Clinical immunology (Orlando, Fla.) 25 24928324
2006 Borrelia burgdorferi Induces TLR1 and TLR2 in human microglia and peripheral blood monocytes but differentially regulates HLA-class II expression. Journal of neuropathology and experimental neurology 25 16783164
2018 TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer. Journal of gastrointestinal and liver diseases : JGLD 24 30574617
2022 RBD conjugate vaccine with a built-in TLR1/2 agonist is highly immunogenic against SARS-CoV-2 and variants of concern. Chemical communications (Cambridge, England) 23 35040862
2019 TLR1/2 orchestrate human plasmacytoid predendritic cell response to gram+ bacteria. PLoS biology 23 31017904
2013 Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A. PloS one 23 23844129
2021 COVID-19 Subunit Vaccine with a Combination of TLR1/2 and TLR3 Agonists Induces Robust and Protective Immunity. Vaccines 22 34579194
2005 Sublethal infection of C57BL/6 mice with Salmonella enterica Serovar Typhimurium leads to an increase in levels of Toll-like receptor 1 (TLR1), TLR2, and TLR9 mRNA as well as a decrease in levels of TLR6 mRNA in infected organs. Infection and immunity 22 15731092
2020 Macrophage activation on "phagocytic synapse" arrays: Spacing of nanoclustered ligands directs TLR1/2 signaling with an intrinsic limit. Science advances 21 33268354
2016 A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis. Journal of immunology (Baltimore, Md. : 1950) 21 26729809
2017 TLR1-10, NF-κB and p53 expression is increased in oral lichenoid disease. PloS one 20 28715461
2016 Identification and characterization of three TLR1 subfamily members from the orange-spotted grouper, Epinephelus coioides. Developmental and comparative immunology 20 27037219
2016 Diabetic pregnancy activates the innate immune response through TLR5 or TLR1/2 on neonatal monocyte. Journal of reproductive immunology 20 27351455
2010 Non-acylated Mycobacterium bovis glycoprotein MPB83 binds to TLR1/2 and stimulates production of matrix metalloproteinase 9. Biochemical and biophysical research communications 20 20800577
1997 Alternate junctions and microheterogeneity of Tlr1, a developmentally regulated DNA rearrangement in Tetrahymena thermophila. The Journal of eukaryotic microbiology 20 9304822
2015 TLR1 expression in mouse brain was increased in a KA-induced seizure model. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 19 26021825

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