Details for: TLR9

Gene ID: 54106

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TLR9

Ensembl ID: ENSG00000239732

Description: toll like receptor 9

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • plasmacytoid dendritic cell, human CL0001058
    CSI 3.43
    rCSI 2.39%
    PRS 99.48
  • intestinal tuft cell CL0019032
    CSI 2.83
    rCSI 4.33%
    PRS 98.51
  • dendritic cell CL0000451
    CSI 2.6
    rCSI 3.21%
    PRS 98.51
  • plasmacytoid dendritic cell CL0000784
    CSI 2.31
    rCSI 2.34%
    PRS 99.22

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Toll-like receptor 9 ([TLR9](/details-gene/54106)) is a critical protein-coding gene located on chromosome 3. It functions as an endosomal pattern recognition receptor and a key component of the innate immune system. As described by Hemmi et al. (2000), [TLR9](/details-gene/54106) is specialized to recognize unmethylated CpG dinucleotides, a molecular signature common in bacterial and viral DNA but rare in vertebrates [Link](https://doi.org/10.1038/35047123). This recognition event, occurring within endolysosomes, triggers potent downstream signaling pathways, culminating in robust inflammatory and antiviral responses. **Overall**, expression data reveals that [TLR9](/details-gene/54106) is a highly significant marker for specialized immune cells, most notably [plasmacytoid dendritic cell, human](/details-cell/CL0001058), positioning it as a primary sensor for microbial nucleic acids. ## Cellular Roles and Expression Landscape The expression profile of [TLR9](/details-gene/54106) underscores its specialized role as a sentinel of the innate immune system. Its significance is highest in professional antigen-presenting cells that are pivotal for orchestrating immune responses. * **Dendritic Cell Lineages:** The gene shows the highest significance in [plasmacytoid dendritic cell, human](/details-cell/CL0001058) (CSI: 3.43), a cell type renowned for its capacity to produce vast amounts of type I interferon in response to viral infections. High significance is also noted in the broader categories of [dendritic cell](/details-cell/CL0000451) (CSI: 2.60) and [plasmacytoid dendritic cell](/details-cell/CL0000784) (CSI: 2.31), confirming its central role in initiating antiviral immunity and bridging the innate and adaptive systems. * **Mucosal Immunity:** Intriguingly, [TLR9](/details-gene/54106) also displays high significance in the [intestinal tuft cell](/details-cell/CL0019032) (CSI: 2.83). These are specialized chemosensory epithelial cells in the gut, suggesting a role for [TLR9](/details-gene/54106) in detecting microbial DNA within the intestinal lumen and potentially initiating local mucosal immune responses. This is consistent with its annotated function in the [maintenance of gastrointestinal epithelium](/details-gene/54106) ([GO:0030277](https://www.ebi.ac.uk/QuickGO/term/GO:0030277)). Collectively, the cellular landscape of [TLR9](/details-gene/54106) expression highlights its function as a specialized sensor predominantly active in immune cells stationed at key environmental interfaces and within circulation, poised to detect pathogenic invasion. ## Pathways and Molecular Function Functionally, [TLR9](/details-gene/54106) operates as a [pattern recognition receptor activity](/details-gene/54106) ([GO:0038187](https://www.ebi.ac.uk/QuickGO/term/GO:0038187)) with a specific affinity for [unmethylated cpg binding](/details-gene/54106) ([GO:0045322](https://www.ebi.ac.uk/QuickGO/term/GO:0045322)). Upon ligand binding within the endosome, it initiates the [Toll-like receptor 9 signaling pathway](/details-gene/54106) ([GO:0034162](https://www.ebi.ac.uk/QuickGO/term/GO:0034162)), a process extensively detailed within the Reactome database as the [Toll like receptor 9 (tlr9) cascade](/details-gene/54106) ([R-HSA-168138](https://reactome.org/content/detail/R-HSA-168138)). This signaling is primarily mediated through the MyD88 adaptor protein, as captured by the [Myd88-dependent toll-like receptor signaling pathway](/details-gene/54106) ([GO:0002755](https://www.ebi.ac.uk/QuickGO/term/GO:0002755)). Activation leads to the recruitment and activation of downstream kinases, engaging pathways such as [Traf6 mediated induction of nfkb and map kinases upon tlr7/8 or 9 activation](/details-gene/54106) ([R-HSA-975138](https://reactome.org/content/detail/R-HSA-975138)). The ultimate consequences of this cascade are profoundly pro-inflammatory and antiviral, including: * **NF-κB Activation:** Positive regulation of [Canonical nf-kappab signal transduction](/details-gene/54106) ([GO:0043123](https://www.ebi.ac.uk/QuickGO/term/GO:0043123)) drives the expression of numerous inflammatory cytokines, such as TNF ([GO:0032760](https://www.ebi.ac.uk/QuickGO/term/GO:0032760)), IL-6 ([GO:0032755](https://www.ebi.ac.uk/QuickGO/term/GO:0032755)), and IL-12 ([GO:0032735](https://www.ebi.ac.uk/QuickGO/term/GO:0032735)). * **Interferon Production:** In pDCs, [TLR9](/details-gene/54106) signaling strongly promotes the [positive regulation of interferon-alpha production](/details-gene/54106) ([GO:0032727](https://www.ebi.ac.uk/QuickGO/term/GO:0032727)), a hallmark of the antiviral response. * **B Cell Activation:** [TLR9](/details-gene/54106) is also a key co-stimulatory receptor on B cells, where its activation leads to the [positive regulation of b cell activation](/details-gene/54106) ([GO:0050871](https://www.ebi.ac.uk/QuickGO/term/GO:0050871)) and [positive regulation of immunoglobulin production](/details-gene/54106) ([GO:0002639](https://www.ebi.ac.uk/QuickGO/term/GO:0002639)). These pathways collectively demonstrate that [TLR9](/details-gene/54106) is a central hub in the innate immune system, translating the detection of microbial DNA into a multi-faceted defense program. ## Research Directions The specific expression pattern and critical function of [TLR9](/details-gene/54106) make it a gene of intense interest for both basic immunology and clinical applications. Its dysregulation is implicated in autoimmune diseases where the immune system mistakenly reacts to self-DNA. For instance, recent work highlights how post-translational modifications like palmitoylation can regulate [TLR9](/details-gene/54106) signaling and contribute to systemic autoimmunity [Link](https://doi.org/10.1038/s41467-023-43650-z). ### Proposed Hypotheses: 1. Given its high significance in [intestinal tuft cell](/details-cell/CL0019032), [TLR9](/details-gene/54106) signaling in these cells may act as a primary sensor of gut dysbiosis or specific enteric pathogens, initiating local epithelial and immune responses that contribute to either protective immunity or the pathology of inflammatory bowel disease. 2. The regulatory mechanisms controlling [TLR9](/details-gene/54106) translocation from the endoplasmic reticulum to the endosome ([Link](https://doi.org/10.1038/ni1028)) may be defective in B cells and pDCs from patients with systemic lupus erythematosus (SLE), leading to increased cell-surface expression and heightened sensitivity to self-DNA-containing immune complexes. ### Experimental Approach: To test the first hypothesis regarding the role of [TLR9](/details-gene/54106) in intestinal tuft cells, a conditional knockout mouse model could be generated using a tuft cell-specific Cre driver (e.g., *Dclk1*-Cre). These mice, alongside littermate controls, could be subjected to a model of infectious colitis (e.g., *Citrobacter rodentium* infection) or sterile inflammation (e.g., DSS-induced colitis). The impact of [TLR9](/details-gene/54106) deletion would be assessed by quantifying disease severity, analyzing immune cell infiltration via flow cytometry, and performing single-cell RNA sequencing on sorted epithelial cells to define the specific [TLR9](/details-gene/54106)-dependent transcriptional programs in tuft cells. ### Therapeutic Potential: [TLR9](/details-gene/54106) is a dual-faceted therapeutic target. * **Agonism:** Synthetic CpG oligonucleotides that activate [TLR9](/details-gene/54106) are potent immune adjuvants used to enhance vaccine efficacy and in cancer immunotherapy to stimulate anti-tumor responses. In this context, **activation** is the therapeutic strategy. * **Antagonism:** For autoimmune diseases like SLE and psoriasis, where pathological activation of [TLR9](/details-gene/54106) by self-DNA drives inflammation, **inhibition** is the goal. Development of specific antagonists, such as inhibitory oligonucleotides or small molecules that block endosomal signaling, represents a promising therapeutic avenue to suppress aberrant immune activation while potentially preserving systemic immunity.

Genular Protein ID: 1665298148

Symbol: TLR9_HUMAN

Name: Toll-like receptor 9

UniProtKB Accession Codes:

Q9NR96 B3Y661 D1CS56 Q6UVZ2 Q9HD68 Q9HD69 Q9HD70 Q9NYC2 Q9NYC3

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 6 ChEMBL 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 6 DrugCentral 1 EMBL 21 Ensembl 1 GO 65 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 5 RNAct 1 Reactome 7 RefSeq 1 SIGNOR 1 SMART 4 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 2 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 11022119

Title: Three novel mammalian Toll-like receptors: gene structure, expression, and evolution.

PubMed ID: 11022119

PubMed ID: 11022120

Title: Cloning and characterization of a sub-family of human Toll-like receptors: hTLR7, hTLR8 and hTLR9.

PubMed ID: 11022120

PubMed ID: 11130078

Title: A Toll-like receptor recognizes bacterial DNA.

PubMed ID: 11130078

DOI: 10.1038/35047123

PubMed ID: 18810425

Title: Natural selection in the TLR-related genes in the course of primate evolution.

PubMed ID: 18810425

DOI: 10.1007/s00251-008-0332-0

PubMed ID: 19924287

Title: The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes.

PubMed ID: 19924287

DOI: 10.1371/journal.pone.0007803

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11564765

Title: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells.

PubMed ID: 11564765

DOI: 10.4049/jimmunol.167.7.3555

PubMed ID: 14716310

Title: TLR9 signals after translocating from the ER to CpG DNA in the lysosome.

PubMed ID: 14716310

DOI: 10.1038/ni1028

PubMed ID: 17932028

Title: Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase.

PubMed ID: 17932028

DOI: 10.1074/jbc.m707682200

PubMed ID: 20865800

Title: Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone.

PubMed ID: 20865800

DOI: 10.1038/ncomms1070

PubMed ID: 23857366

Title: FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation.

PubMed ID: 23857366

DOI: 10.1002/eji.201243068

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 38169466

Title: Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice.

PubMed ID: 38169466

DOI: 10.1038/s41467-023-43650-z

Sequence Information:

  • Length: 1032
  • Mass: 115860
  • Checksum: 71280AA9680EDCE2
  • Sequence:
    • MGFCRSALHP LSLLVQAIML AMTLALGTLP AFLPCELQPH GLVNCNWLFL KSVPHFSMAA 
PRGNVTSLSL SSNRIHHLHD SDFAHLPSLR HLNLKWNCPP VGLSPMHFPC HMTIEPSTFL 
AVPTLEELNL SYNNIMTVPA LPKSLISLSL SHTNILMLDS ASLAGLHALR FLFMDGNCYY 
KNPCRQALEV APGALLGLGN LTHLSLKYNN LTVVPRNLPS SLEYLLLSYN RIVKLAPEDL 
ANLTALRVLD VGGNCRRCDH APNPCMECPR HFPQLHPDTF SHLSRLEGLV LKDSSLSWLN 
ASWFRGLGNL RVLDLSENFL YKCITKTKAF QGLTQLRKLN LSFNYQKRVS FAHLSLAPSF 
GSLVALKELD MHGIFFRSLD ETTLRPLARL PMLQTLRLQM NFINQAQLGI FRAFPGLRYV 
DLSDNRISGA SELTATMGEA DGGEKVWLQP GDLAPAPVDT PSSEDFRPNC STLNFTLDLS 
RNNLVTVQPE MFAQLSHLQC LRLSHNCISQ AVNGSQFLPL TGLQVLDLSH NKLDLYHEHS 
FTELPRLEAL DLSYNSQPFG MQGVGHNFSF VAHLRTLRHL SLAHNNIHSQ VSQQLCSTSL 
RALDFSGNAL GHMWAEGDLY LHFFQGLSGL IWLDLSQNRL HTLLPQTLRN LPKSLQVLRL 
RDNYLAFFKW WSLHFLPKLE VLDLAGNQLK ALTNGSLPAG TRLRRLDVSC NSISFVAPGF 
FSKAKELREL NLSANALKTV DHSWFGPLAS ALQILDVSAN PLHCACGAAF MDFLLEVQAA 
VPGLPSRVKC GSPGQLQGLS IFAQDLRLCL DEALSWDCFA LSLLAVALGL GVPMLHHLCG 
WDLWYCFHLC LAWLPWRGRQ SGRDEDALPY DAFVVFDKTQ SAVADWVYNE LRGQLEECRG 
RWALRLCLEE RDWLPGKTLF ENLWASVYGS RKTLFVLAHT DRVSGLLRAS FLLAQQRLLE 
DRKDVVVLVI LSPDGRRSRY VRLRQRLCRQ SVLLWPHQPS GQRSFWAQLG MALTRDNHHF 
YNRNFCQGPT AE