Affinage

TLR7

Toll-like receptor 7 · UniProt Q9NYK1

Length
1049 aa
Mass
120.9 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TLR7 is an endolysosomal pattern recognition receptor that detects single-stranded RNA and guanosine/deoxyguanosine nucleoside ligands to initiate innate and adaptive immune responses, with a central role in antiviral defense, B cell activation, and the pathogenesis of systemic lupus erythematosus. TLR7 possesses two ligand-binding pockets: one engages guanosine-derived nucleosides (including 2',3'-cGMP generated cooperatively by RNase T2 and PLD3/PLD4 exonucleases), while the other binds RNA oligonucleotides; ligand engagement drives a conformational shift from an open to a closed dimer state, triggering MyD88-dependent NF-κB activation and IRF5 activation via the SLC15A4–TASL adaptor axis (PMID:14976261, PMID:33060576, PMID:38697119, PMID:32433612). TLR7 trafficking and signaling thresholds are tightly controlled by UNC93B1, which recruits syntenin-1 to sort TLR7 into multivesicular bodies for signal termination and engages BORC/Arl8b for receptor turnover, while SHP2-mediated dephosphorylation of TLR7 Tyr1024 regulates Golgi-to-endosome transit; loss of these checkpoints—through UNC93B1 or TLR7 gain-of-function mutations—causes childhood-onset SLE (PMID:31546246, PMID:38207015, PMID:34936223, PMID:35477763). TLR7 escapes X chromosome inactivation in female immune cells, producing biallelic expression that enhances TLR7-driven responses and contributes to the female sex bias in autoimmunity and neuroinflammatory demyelination (PMID:29374079, PMID:39607927).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2004 High

    Identification of ssRNA as the natural TLR7 ligand and MyD88 as the obligate signaling adaptor established TLR7 as an endosomal nucleic acid sensor mediating antiviral type I IFN production.

    Evidence TLR7-/- and MyD88-/- mice failed to respond to ssRNA or influenza virus with cytokine production

    PMID:14976261

    Open questions at the time
    • Precise RNA sequence or structural motifs recognized by TLR7 not defined
    • Endosomal delivery mechanism of natural ligands unknown
  2. 2007 High

    Demonstration that 2'-O-methylation of RNA potently antagonizes TLR7 revealed a chemical basis for self/non-self RNA discrimination and provided the first tool compound for receptor inhibition.

    Evidence 2'OMe-modified RNA inhibited TLR7-dependent IFN-α and IL-6 in human PBMCs, murine DCs, and in vivo

    PMID:17579574

    Open questions at the time
    • Direct binding mode of 2'OMe RNA to TLR7 not resolved
    • Whether 2'OMe modification prevents TLR7 binding or signaling conformational change unclear
  3. 2009 High

    Discovery that LL37 shuttles self-RNA into endosomes to activate TLR7 explained how endogenous RNA—normally excluded from endosomal compartments—can breach tolerance and drive autoimmune IFN-α production in psoriasis.

    Evidence Co-culture/binding assays, TLR7-deficient cells, and in vivo psoriatic skin analysis

    PMID:19703986

    Open questions at the time
    • Whether other cationic carriers substitute for LL37 in different autoimmune contexts not tested
    • Relative contribution of TLR7 vs TLR8 in human pDC activation by LL37-RNA complexes unclear
  4. 2010 High

    Genetic epistasis between TLR7 and TLR9 in lupus-prone mice established that TLR9 restrains TLR7-driven autoimmunity, revealing an unexpected cross-regulatory hierarchy rather than simple redundancy.

    Evidence Tlr7-/-, Tlr9-/-, double-KO, and Myd88-/- MRL/lpr mice with autoantibody profiling and disease scoring

    PMID:20089701

    Open questions at the time
    • Molecular mechanism by which TLR9 suppresses TLR7 signaling not identified
    • Whether the TLR9-TLR7 hierarchy operates in human lupus unconfirmed
  5. 2012 Medium

    A genome-wide RNAi screen cataloged ~190 cofactors for TLR7/9 signaling, revealing dependence on ubiquitin ligases, sphingolipid metabolism, and chromatin modification, greatly expanding the known signaling network.

    Evidence Genome-wide siRNA screen with cross-profiling against multiple immunoreceptors; HRS validated for TLR9 endolysosomal targeting

    PMID:22423970

    Open questions at the time
    • Most TLR7-specific cofactors not individually validated
    • Mechanistic roles of sphingolipid and chromatin regulators in TLR7 signaling undefined
  6. 2014 High

    Proteome-wide phosphoproteomics and transcriptomics demonstrated that TLR7 can signal in two distinct modes—nucleoside versus oligoribonucleotide—triggering different downstream phosphorylation and transcriptional programs.

    Evidence Phosphoproteomics and transcriptomics in primary human monocyte-derived DCs with multiple ligand classes, plus ectodomain mapping

    PMID:24813206

    Open questions at the time
    • Structural basis for dual-mode signaling not yet resolved at this time
    • Relative physiological contribution of each mode during infection unknown
  7. 2015 High

    Identification of guanosine and deoxyguanosine as direct endogenous TLR7 ligands, with ITC-measured binding and cooperative enhancement by oligoribonucleotides, established TLR7 as a dual-ligand receptor with two binding sites.

    Evidence ITC binding, cytokine assays in mouse/human immune cells, Unc93b1 D34A macrophages

    PMID:26489884

    Open questions at the time
    • Structural identity of the two pockets not yet resolved at atomic level
    • Physiological source of free guanosine in endosomes unclear
  8. 2015 High

    Discovery that TREML4 is essential for TLR7-induced type I IFN through p38-STAT1 phosphorylation and MyD88 recruitment identified a cell-surface co-receptor that sets TLR7 signaling intensity.

    Evidence Genome-scale shRNA screen validated by Treml4-/- mice, phosphorylation and co-IP assays

    PMID:25848864

    Open questions at the time
    • Direct physical interaction between TREML4 and TLR7 not demonstrated
    • Whether TREML4 participates in TLR7 endosomal sorting unknown
  9. 2015 High

    Demonstration that B cell autophagy is required to deliver RNA ligands to endosomal TLR7, and that its ablation eliminates lupus in TLR7-transgenic mice, defined autophagy as a critical upstream ligand-delivery pathway.

    Evidence B cell-specific Atg5 KO crossed to TLR7-transgenic mice; autoantibodies and inflammation abolished

    PMID:26120731

    Open questions at the time
    • Whether autophagy delivers self-RNA, viral RNA, or both to TLR7 not distinguished
    • Specific autophagic cargo targeting mechanism for TLR7 ligand delivery undefined
  10. 2018 High

    Demonstration that TLR7 escapes X chromosome inactivation in female immune cells, yielding biallelic expression and enhanced TLR7 responses, provided a molecular explanation for the female sex bias in SLE.

    Evidence Single-cell allelic expression, flow cytometry protein quantification, B cell functional assays in women vs men and Klinefelter males

    PMID:29374079

    Open questions at the time
    • Epigenetic mechanism governing TLR7 XCI escape not defined
    • Whether biallelic expression is uniform across all immune cell subsets not fully mapped
  11. 2019 High

    Elucidation of the UNC93B1–syntenin-1 axis for TLR7-selective signal termination revealed a phosphorylation-dependent sorting mechanism that shuttles TLR7 into multivesicular body intralumenal vesicles, explaining how TLR7 (but not TLR9) is restrained.

    Evidence UNC93B1 mutagenesis, syntenin-1 binding, exosome fractionation, in vivo autoimmunity rescue

    PMID:31546246

    Open questions at the time
    • Kinase responsible for UNC93B1 phosphorylation not identified
    • Whether exosomal release of TLR7 has intercellular signaling consequences unknown
  12. 2019 High

    Functional demonstration that deoxyguanosine alone—without RNA—activates TLR7 in an endosomal maturation-dependent manner clarified that the nucleoside pocket can independently initiate signaling.

    Evidence TLR7-/- and MyD88-/- murine cells and human PBMCs treated with dG, with endosomal maturation inhibitors

    PMID:31608988

    Open questions at the time
    • Whether RNA-independent dG activation occurs physiologically in vivo not established
    • Relative potency of dG vs ssRNA+G synergy in natural infection undefined
  13. 2019 High

    Identification of TLR7-driven differentiation of monocytes into inflammatory hemophagocytes via IRF5 revealed a previously unknown pathogenic cellular output of excessive TLR7 signaling causing cytopenias.

    Evidence TLR7-overexpressing mice, lineage tracing, IRF5-KO and MyD88-KO mice, malarial anemia model

    PMID:30630901

    Open questions at the time
    • Transcriptional program downstream of IRF5 driving hemophagocyte fate not characterized
    • Relevance to human hemophagocytic syndromes not directly tested
  14. 2020 High

    Identification of TASL as an endolysosomal adaptor bridging SLC15A4 to IRF5 activation defined a dedicated signaling branch for TLR7-to-IRF pathway signaling that is independent of NF-κB and MAPK.

    Evidence TASL and SLC15A4 knockout, TASL pLxIS motif mutagenesis, co-IP, cytokine assays in human immune cells

    PMID:32433612

    Open questions at the time
    • How TASL is itself activated upon TLR7 engagement not resolved
    • Whether TASL contributes differentially to TLR7 vs TLR9 signaling outcomes unclear
  15. 2020 High

    Structural resolution of TLR7 open-to-closed conformational equilibrium by crystallography and cryo-EM explained the activation mechanism and showed that antagonists lock TLR7 in the open (inactive) state.

    Evidence X-ray crystallography, cryo-EM, small-molecule antagonist testing in vivo

    PMID:33060576

    Open questions at the time
    • Full-length TLR7–MyD88 signalosome structure not resolved
    • How dual ligand binding to the two pockets cooperatively triggers closing not atomically detailed
  16. 2021 High

    Demonstration that RNase T2 catalytic activity is required to generate TLR7 ligands from ssRNA in endolysosomes placed this nuclease as an obligate upstream processing step.

    Evidence RNase T2-deficient macrophages, RNA degradation assays, catalytic-site mutagenesis

    PMID:34161582

    Open questions at the time
    • Whether RNase T2 products are sufficient without further processing by exonucleases not addressed
  17. 2021 High

    Identification of SHP2-mediated Tyr1024 dephosphorylation as a mechanism controlling TLR7 Golgi-to-endosome trafficking revealed a phosphorylation-based checkpoint for receptor delivery and inflammatory signaling.

    Evidence Conditional SHP2 KO mice, TLR7 Y1024 knock-in, in vivo psoriasis model

    PMID:34936223

    Open questions at the time
    • Kinase that phosphorylates TLR7 Tyr1024 not identified
    • Whether this checkpoint operates in all TLR7-expressing cell types not tested
  18. 2022 High

    Discovery of a TLR7 gain-of-function variant (Y264H) that selectively enhances guanosine sensing and causes monogenic lupus—rescued by MyD88 deletion—provided definitive human genetic proof that TLR7 hyperactivation is sufficient to drive systemic autoimmunity.

    Evidence Patient mutation, knock-in mice, epistasis with MyD88-KO, B cell functional assays

    PMID:35477763

    Open questions at the time
    • Structural basis for Y264H selectivity toward guanosine vs RNA ligands not atomically resolved
    • Frequency of TLR7 gain-of-function alleles across lupus cohorts not determined
  19. 2022 High

    Demonstration that purine nucleoside phosphorylase (PNP) controls TLR7 activation by catabolizing guanosine/deoxyguanosine ligands linked metabolic purine salvage to TLR7 signaling threshold regulation.

    Evidence PNP inhibition in B cells/macrophages, nucleoside quantification, germinal center assays, autoimmune mouse model

    PMID:35653193

    Open questions at the time
    • Relative contribution of PNP-regulated dG vs RNA-derived ligands in disease not quantified
    • Whether PNP deficiency in humans activates TLR7 not directly shown
  20. 2023 High

    Cell-type-specific deletion established B cell-intrinsic TLR7 as the dominant driver of accelerated lupus in TLR9-deficient mice, confirming that the TLR9–TLR7 cross-regulatory axis operates within the B cell compartment.

    Evidence TLR7-floxed with CD19-Cre on MRL/lpr and TLR9-/- backgrounds, BM chimeras

    PMID:37606042

    Open questions at the time
    • Whether dendritic cell TLR7 contributes independently to the TLR9-deficient phenotype not excluded
    • Intracellular mechanism of TLR9-mediated TLR7 restraint still undefined
  21. 2024 High

    Biochemical reconstitution of the RNase T2–PLD3/PLD4 cooperative pathway demonstrated how endosomal nucleases generate both 2',3'-cGMP (pocket 1 ligand) and RNA fragments (pocket 2 ligand) for TLR7, solving the ligand-generation pathway.

    Evidence In vitro reconstitution, structural studies of PLD homodimers, mutagenesis of disease-associated PLD variants, cell-based validation

    PMID:38697119

    Open questions at the time
    • Whether additional endonucleases contribute in specific cell types not tested
    • Kinetics of ligand generation relative to TLR7 dwell time in endolysosomes unknown
  22. 2024 High

    Identification of the BORC–Arl8b axis interacting with UNC93B1 to control TLR7 receptor turnover, and validation via a childhood-onset SLE UNC93B1 mutation, defined a second UNC93B1-dependent checkpoint (turnover vs signal termination) for TLR7 dosage.

    Evidence UNC93B1–Arl8b direct interaction, patient mutation analysis, receptor turnover and endosomal fractionation

    PMID:38207015

    Open questions at the time
    • How BORC/Arl8b directs TLR7 to lysosomes for degradation at the molecular level not detailed
    • Relationship between syntenin-1 MVB sorting and BORC-mediated turnover not integrated
  23. 2024 High

    TLR7 was shown to mediate a non-canonical cancer cell-intrinsic signaling program in which ssRNA released from dying tumor cells activates TLR7 on neighboring cancer cells to promote invasion and metastasis, expanding TLR7 function beyond immune cells.

    Evidence 3D co-cultures, in vivo mammary tumor models, TLR7 genetic KO, defined signaling axis (SP→TACR1→death→ssRNA→TLR7)

    PMID:39112700

    Open questions at the time
    • Whether TLR7 pro-metastatic signaling uses canonical MyD88 or alternative adaptors not specified
    • Generalizability beyond breast cancer models not established
  24. 2024 High

    Demonstration that X-linked Tlr7 regulates sex-specific type I IFN responses to myelin and that its deletion or pharmacological inhibition mitigates demyelination extended the sex-biased TLR7 paradigm to neuroinflammatory disease.

    Evidence Single-nuclei transcriptomics, FCG sex-chromosome model, Tlr7 conditional KO, TLR7 inhibitor in demyelination and AD mouse models

    PMID:39607927

    Open questions at the time
    • Whether TLR7 acts in resident microglia, infiltrating monocytes, or both not fully dissected
    • Human translation of TLR7 inhibition for demyelinating disease not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full structural basis for cooperative dual-pocket ligand engagement triggering TLR7 dimer closure, the identity of kinases regulating UNC93B1 and TLR7 phosphorylation, and the molecular mechanism of TLR9-mediated TLR7 restraint within B cells remain unresolved.
  • Full-length TLR7–MyD88 signalosome structure not available
  • Kinases for UNC93B1 S550 phosphorylation and TLR7 Tyr1024 phosphorylation unknown
  • Molecular mechanism of TLR9 cross-regulation of TLR7 undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005768 endosome 5 GO:0005764 lysosome 3 GO:0031410 cytoplasmic vesicle 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 5
Partners
ARL8BIRF5MYD88PTPN11SLC15A4TASLTREML4UNC93B1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 TLR7 recognizes single-stranded RNA (ssRNA) as a ligand in endosomal compartments, signaling through MyD88 to induce type I IFN and inflammatory cytokines in plasmacytoid dendritic cells during viral infection. Genetic knockout mice (TLR7-/-, MyD88-/-), cell stimulation assays with ssRNA and influenza virus Science High 14976261
2009 The antimicrobial peptide LL37 binds self-RNA released by dying cells, protects it from extracellular degradation, and transports it into endosomal compartments of plasmacytoid dendritic cells where it activates TLR7 to trigger IFN-alpha secretion. Co-culture assays, co-IP/binding assays, TLR7/8-deficient cells, in vivo psoriatic skin analysis Journal of Experimental Medicine High 19703986
2018 TLR7 escapes X chromosome inactivation in immune cells (B lymphocytes, monocytes, plasmacytoid dendritic cells) from women and Klinefelter syndrome males, resulting in biallelic TLR7 expression, higher TLR7 protein levels, and enhanced functional responses to TLR7 ligands including preferential enrichment during TLR7-driven plasma cell proliferation and increased IgG class switching. Single-cell allelic expression analysis, protein quantification by flow cytometry, functional B cell differentiation assays Science Immunology High 29374079
2022 A gain-of-function TLR7 variant (Y264H) selectively increases sensing of guanosine and 2',3'-cGMP, drives aberrant survival of BCR-activated B cells, and causes lupus; deficiency of downstream adaptor MyD88 rescues all autoimmune phenotypes. Human genetic variant identification, knock-in mice, epistasis with MyD88 knockout, B cell functional assays Nature High 35477763
2010 TLR7 and TLR9 act in parallel but cross-regulatory pathways in lupus: TLR9 suppresses TLR7-dependent RNA-associated autoantibody production, and disease driven by TLR9 deficiency depends on TLR7 for its manifestation. Aspects of disease independent of both TLRs are mediated by MyD88-independent components. Genetic epistasis using Tlr7-/-, Tlr9-/-, Tlr7/9-double KO, and Myd88-/- MRL/lpr mice; autoantibody profiling; disease scoring Journal of Immunology High 20089701
2007 2'-O-methyl (2'OMe)-modified RNA acts as a potent TLR7 antagonist, inhibiting TLR7-dependent IFN-alpha and IL-6 induction by ssRNA and small-molecule TLR7 agonist loxoribine in human PBMCs, murine DCs, and in vivo, without requiring direct incorporation into immunostimulatory RNA. In vitro cytokine assays with human PBMCs and murine DCs, in vivo mouse experiments, competitive inhibition assays Molecular Therapy High 17579574
2020 TASL (encoded by CXorf21) interacts with the endolysosomal transporter SLC15A4 and contains a conserved pLxIS motif that mediates recruitment and activation of IRF5, functioning as an innate immune adaptor specifically required for TLR7, TLR8, and TLR9 signaling to the IRF pathway without affecting NF-κB or MAPK signaling. Genetic deletion of SLC15A4 and TASL, extensive TASL mutagenesis, co-immunoprecipitation, cytokine production assays in primary and transformed human immune cells Nature High 32433612
2019 UNC93B1 specifically limits TLR7 (but not TLR9) signaling by recruiting syntenin-1, which requires phosphorylation of UNC93B1, facilitating sorting of TLR7 into intralumenal vesicles of multivesicular bodies to terminate signaling. Both UNC93B1 and TLR7 are detected in exosomes. UNC93B1 mutagenesis, syntenin-1 binding assays, exosome fractionation/detection, TLR7-dependent autoimmunity mouse models Nature High 31546246
2015 Guanosine (G), 2'-deoxyguanosine (dG), and modified nucleosides including 7-methylguanosine, 8-hydroxyguanosine (8-OHG), and 8-hydroxydeoxyguanosine (8-OHdG) are endogenous ligands for TLR7; oligoribonucleotides (ORN) strengthen TLR7 interaction with G/dG, and 8-OHdG binds TLR7/ORN complex with measurable affinity by isothermal titration calorimetry. In vitro cytokine production assays in mouse and human immune cells, isothermal titration calorimetry, Unc93b1 D34A/D34A macrophage studies International Immunology High 26489884
2020 TLR7 structural analysis combining crystallography and cryo-EM revealed an equilibrium between open and closed conformations of TLR7; antagonists bind a specific pocket and stabilize the open conformation, preventing receptor activation. X-ray crystallography, cryo-electron microscopy, small-molecule antagonist development and in vivo testing Nature Communications High 33060576
2024 The lysosomal endonuclease RNase T2, together with 5' exonucleases PLD3 and PLD4, cooperatively generate TLR7 ligands: RNase T2 produces guanosine 2',3'-cyclic monophosphate-terminated RNA fragments, and PLD exonuclease activity releases 2',3'-cGMP to engage TLR7 pocket 1 and generates RNA fragments for pocket 2. PLD enzymes form homodimers with two ligand-binding sites required for activity. Biochemical reconstitution, structural studies, loss-of-function in cell lines and primary cells, mutagenesis of disease-associated PLD variants Immunity High 38697119
2024 The late endosomal BORC complex and small GTPase Arl8b control intracellular TLR7 levels by regulating receptor turnover through a direct interaction between the TLR7 trafficking factor UNC93B1 and Arl8b; an UNC93B1 mutation causing childhood-onset lupus reduces BORC interaction and leads to endosomal TLR7 accumulation and unrestricted signaling. Protein interaction studies (direct interaction between UNC93B1 and Arl8b), patient mutation analysis, receptor turnover assays, endosomal fractionation Science Immunology High 38207015
2015 TREML4 is an essential positive regulator of TLR7 signaling; macrophages from Treml4-/- mice are hyporesponsive to TLR7 agonists, failing to produce type I IFNs due to impaired phosphorylation of STAT1 by p38 MAPK and decreased recruitment of the adaptor MyD88 to TLR7. Genome-scale shRNA screen, Treml4-/- mice, phosphorylation assays (STAT1, p38), MyD88-TLR7 co-immunoprecipitation Nature Immunology High 25848864
2021 SHP2 promotes trafficking of TLR7 from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, which boosts TLR7 ubiquitination and NF-κB-mediated inflammation; SHP2 inhibition or TLR7 Tyr1024 point mutation attenuates psoriasis-like skin inflammation. Single-cell RNA sequencing, conditional SHP2 KO mice, TLR7 phosphorylation assays, Tlr7 point-mutant knock-in mice, in vivo psoriasis model EMBO Molecular Medicine High 34936223
2015 TRIM35 negatively regulates TLR7/9-mediated type I IFN production by interacting with IRF7 and promoting K48-linked ubiquitination and proteasome-dependent degradation of IRF7; TRIM35 expression is induced by TLR7/9 stimulation as a negative feedback mechanism. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, overexpression and knockdown FEBS Letters Medium 25907537
2019 TLR7 signaling drives differentiation of Ly6Chi monocytes into inflammatory hemophagocytes (iHPCs) that internalize red blood cells, causing anemia and thrombocytopenia; IRF5 participates in TLR7-driven iHPC differentiation, and endosomal TLR and MyD88 signaling is required for iHPC development during malarial anemia. TLR7-overexpressing mice, lineage tracing, IRF5 KO mice, MyD88 KO mice, cell fate mapping Science High 30630901
2015 B cell autophagy is required for TLR7 activation in B cells and for SLE development; B cell-specific ablation of autophagy (Atg5) in TLR7 transgenic mice eliminates antinuclear antibodies and inflammation, indicating that autophagy delivers RNA ligands to endosomal TLR7. TLR7 transgenic mice crossed with B cell-specific Atg5 conditional KO (Cd19-Cre Atg5f/f), autoantibody measurement, cytokine profiling, survival analysis Autophagy High 26120731
2019 TLR7 specifically increases expression of transcription factor FOSL1 in monocytes, which reduces IL-27 and TNF-alpha production; TLR7 (but not TLR8) activation of monocytes stimulates Ca2+ flux that prevents type I IFN responses, demonstrating distinct signaling cascades downstream of TLR7 vs. TLR8. RNA virus infection of human CD14+ monocytes, TLR7/8 agonists, siRNA knockdown, Ca2+ flux assays, cytokine profiling Science Signaling High 31662487
2014 TLR7 and TLR8 ectodomains recognize RNA oligoribonucleotides (ORN) and imidazoquinolines via overlapping and non-overlapping recognition sites; sensing of these two ligand classes triggers distinct downstream phosphorylation and transcriptional events, indicating TLR7/8 can signal in two different modes depending on ligand class. Proteome-wide phosphoproteomics, genome-wide transcriptomics in primary human monocyte-derived DCs, ectodomain mapping with murine loss-of-function mutations and human SNPs Journal of Immunology High 24813206
2012 Genome-wide RNAi screening identified 190 cofactors required for TLR7 and TLR9 signaling, including proteins involved in ubiquitin-protein ligase activities, sphingolipid metabolism, chromatin modifications, and ancient stress responses; HRS was characterized as necessary for ubiquitin-dependent TLR9 targeting to the endolysosome. Genome-wide RNAi screen, cross-profiling against multiple immunoreceptors, functional NF-κB pathway mapping Cell Host & Microbe Medium 22423970
2008 TLR7 and CD40 cooperate in B cells to produce synergistic IL-6 via enhanced JNK and AP-1 (cJun/cFos) activation; dual CD40+TLR7 stimulation markedly enhanced JNK activity and expanded the repertoire of AP-1 dimers compared to single receptor stimulation. Primary human and mouse B cell stimulation, JNK activity assays, AP-1 activity assays, cytokine measurement European Journal of Immunology Medium 18228247
2016 Structure-guided mutagenesis of human TLR7 identified molecular determinants of GS-9620 binding; TLR7 exists in a ligand-independent oligomeric state, and GS-9620 activation is associated with compound-induced conformational changes; NF-κB and Akt pathways are activated as immediate downstream responses in plasmacytoid DCs. Structure-guided mutagenesis, subcellular distribution assays, molecular modeling, primary pDC signaling assays PLoS ONE Medium 26784926
2017 Extracellular miRNAs (miR-34a, -122, -133a, -142, -146a, -208a) induce cytokine production and leukocyte migration through TLR7/MyD88 signaling; this activity requires intact RNA sequences (uridine→adenosine mutation abolishes it) and is absent in TLR7-/- or MyD88-/- cells but preserved in TLR3- or Trif-deficient cells. TLR7-/-, MyD88-/-, TLR3-/-, TRIF-/- knockout mice, in vivo leukocyte migration assays, sequence mutagenesis of miRNAs, RNase pretreatment controls Journal of Immunology High 28768728
2021 RNase T2 deficiency in macrophages impairs TLR7 responses while upregulating TLR3 responses; RNase T2 degrades ssRNAs in endosomes/lysosomes generating TLR7 ligands, and its catalytic activity (H122A and C188R but not H69A or E118V mutations impair both RNA degradation and TLR7 rescue) is required for this function. RNase T2-deficient macrophages, in vitro RNA degradation assays, RNase T2 mutagenesis, subcellular localization by confocal imaging International Immunology High 34161582
2024 UNC93B1 variants (E92G and R336L) cause selective TLR7 hyperactivation: E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to constitutive type I IFN signaling and early-onset SLE, establishing a direct mechanistic link between UNC93B1-TLR7 interaction and receptor activity. Patient variant identification, mouse macrophage functional assays with variant UNC93B1, protein stability measurements, co-immunoprecipitation of UNC93B1-TLR7 interaction Science Immunology High 38207055
2024 TLR7 gain-of-function interface mutations (F507S and L528I) at the TLR7 dimerization interface enhance TLR7 signaling, causing early-onset SLE and neurological disease; altered homo-dimerization is predicted to underlie enhanced signaling. Human genetic variant identification, structural modeling of dimerization interface, patient clinical phenotyping Journal of Clinical Immunology Medium 38324161
2019 Deoxyguanosine (dG) triggers cytokine production (including type I IFNs, TNF, IL-6) through TLR7 and its adaptor MyD88 in an endosomal maturation-dependent manner, without requiring concurrent provision of RNA, demonstrating that dG is an RNA-independent TLR7 agonist. Murine bone marrow macrophages and pDCs, human PBMCs, TLR7-/- and MyD88-/- cells, endosomal maturation inhibitors, cytokine assays European Journal of Immunology High 31608988
2023 The female-specific XIST lncRNA is a rich source of TLR7 ligands; XIST RNA stimulates IFN-alpha production by plasmacytoid DCs in a TLR7-dependent manner, and XIST deletion diminishes the ability of whole cellular RNA to activate TLR7. XIST deletion experiments, pDC stimulation assays with XIST RNA, TLR7-dependence validation, extracellular vesicle enrichment assays JCI Insight High 37733447
2017 TLR7 signaling in T cells inhibits Th17 cell differentiation from naive T cells and IL-17 production via downregulation of STAT3 signaling through induction of SOCS3 and SOCS5, independently of dendritic cell involvement. In vitro T cell differentiation assays, STAT3 signaling analysis, SOCS3/5 measurement, in vivo EAE model with imiquimod treatment Journal of Immunology Medium 28652396
2018 Bruton's tyrosine kinase (Btk) mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in TLR7/8-stimulated primary human macrophages; this mechanism is distinct from Btk's role in TLR4 signaling where it acts via p38 MAP kinase to stabilize TNF mRNA. Btk gene overexpression and siRNA knockdown, p65 phosphorylation assays, nuclear translocation assays in primary human macrophages Biochemical and Biophysical Research Communications Medium 29567473
2024 Neuronal substance P (SP) acts on tumoral TACR1 receptors to drive death of a TACR1-high cancer cell population; ssRNAs released from dying cells activate neighboring cancer cell TLR7 to non-canonically activate a pro-metastatic gene expression program, promoting breast tumor invasion and metastasis. 3D co-cultures, in vivo mouse mammary tumor models, genetic KO of TLR7, calcium imaging of neurons, TACR1 antagonist treatment Nature High 39112700
2022 Purine nucleoside phosphorylase (PNP) regulates TLR7 signaling in B lymphocytes and macrophages by controlling levels of (deoxy)guanosine nucleoside ligands; PNP inactivation increases these ligands, promotes germinal center formation without exogenous antigen, and accelerates autoimmune disease. PNP inhibition/inactivation in B cells and macrophages, TLR7 agonist (deoxyguanosine) level measurement, germinal center formation assays, mouse autoimmunity model Journal of Clinical Investigation High 35653193
2013 TLR7 drives accumulation of CD11c+ age-associated B cells (ABCs) and autoantibody production in autoimmune-prone mice; depletion of CD11c+ ABCs rapidly reduces autoantibodies, and Mer-/- mice lacking TLR7 fail to develop anti-chromatin IgG antibodies or ABCs. Genetic cross of Mer-/- with TLR7-/- mice, ABC depletion experiments, autoantibody quantification Immunologic Research Medium 22945807
2015 TLR7 expressed on the cell surface of immune cells (not only endolysosomes) can be targeted by an anti-TLR7 antibody that internalizes with TLR7 into endolysosomes, inhibiting TLR7 responses in dendritic cells, macrophages, and B cells both in vitro and in vivo. Cell surface TLR7 detection by antibody staining, antibody internalization tracking, in vivo cytokine inhibition assays, therapeutic treatment of Unc93b1 D34A/D34A mice Nature Communications High 25648980
2024 The X-linked gene Tlr7 regulates sex-specific type I IFN response to myelin; Tlr7 deletion dampens sex differences and protects against demyelination, while TLR7 inhibitor mitigates tau-induced motor impairment and demyelination in male mice. Single-nuclei transcriptomics, sex chromosome manipulation (FCG model), Tlr7 conditional KO mice, TLR7 inhibitor treatment in demyelination and AD mouse models Science High 39607927
2023 B cell-intrinsic TLR7 expression is a major driver of lupus in TLR9-deficient MRL/lpr mice; B cell-specific TLR7 deletion greatly improved disease in TLR9-deficient accelerated SLE, revealing a cis regulatory interaction between TLR9 (protective) and TLR7 (pathogenic) within the B cell compartment. TLR7-floxed allele crossed with CD11c-Cre or CD19-Cre, BM chimera strategy, on MRL/lpr and TLR9-deficient MRL/lpr backgrounds; disease scoring, proteinuria measurement JCI Insight High 37606042

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science (New York, N.Y.) 2569 14976261
2009 Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. The Journal of experimental medicine 578 19703986
2018 TLR7 escapes X chromosome inactivation in immune cells. Science immunology 494 29374079
2022 TLR7 gain-of-function genetic variation causes human lupus. Nature 432 35477763
2010 TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. Journal of immunology (Baltimore, Md. : 1950) 277 20089701
2007 2'-O-methyl-modified RNAs act as TLR7 antagonists. Molecular therapy : the journal of the American Society of Gene Therapy 271 17579574
2013 Aldara activates TLR7-independent immune defence. Nature communications 210 23463003
2017 Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. Journal of neuroinflammation 196 28118842
2008 The use of TLR7 and TLR8 ligands for the enhancement of cancer immunotherapy. The oncologist 177 18701762
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