Toll-like receptor 9

Function

Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also acts via ADCY7, leading to cyclic di-AMP (c-di-AMP) synthesis and activation of the NLRP3 inflammasome (By similarity). Plays a role in defense against systemic mouse cytomegalovirus infection (By similarity). Controls lymphocyte response to Helicobacter infection (By similarity). Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production.

Classification

Family (Pfam)

PF18837 LRR_12, PF13516 LRR_6, PF13855 LRR_8, PF01582 TIR

InterPro

Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_12, LRR_dom_sf, TIR_dom, Toll_tir_struct_dom_sf

Functional cluster

Secreted Growth Factors & Cytokines

Experimental structures · PDB · 3

• 8AR3 NMR
• 9L48 X-ray 1.90A
• 9L49 X-ray 3.00A

A predicted model is available from AlphaFold.

Gene Ontology · 60

• GO:0016324 apical plasma membrane
• GO:0016323 basolateral plasma membrane
• GO:0005737 cytoplasm
• GO:0031901 early endosome membrane
• GO:0032009 early phagosome
• GO:0036019 endolysosome
• GO:0036020 endolysosome membrane
• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0005768 endosome
• GO:0010008 endosome membrane
• GO:0005576 extracellular region
• GO:0000139 Golgi membrane
• GO:0005764 lysosome
• GO:0005886 plasma membrane
• GO:0005149 interleukin-1 receptor binding
• GO:0038187 pattern recognition receptor activity
• GO:0042803 protein homodimerization activity
• GO:0035197 siRNA binding
• GO:0045322 unmethylated CpG binding
• GO:0007249 canonical NF-kappaB signal transduction
• GO:0071222 cellular response to lipopolysaccharide
• GO:0071248 cellular response to metal ion
• GO:0042742 defense response to bacterium
• GO:0050829 defense response to Gram-negative bacterium
• GO:0051607 defense response to virus
• GO:0032490 detection of molecule of bacterial origin
• GO:0045087 innate immune response
• GO:0030277 maintenance of gastrointestinal epithelium
• GO:0008584 male gonad development
• GO:0001774 microglial cell activation
• GO:0002755 MyD88-dependent toll-like receptor signaling pathway
• GO:1901895 negative regulation of ATPase-coupled calcium transmembrane transporter activity
• GO:0010508 positive regulation of autophagy
• GO:0050871 positive regulation of B cell activation
• GO:0030890 positive regulation of B cell proliferation
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction
• GO:0032722 positive regulation of chemokine production
• GO:0010628 positive regulation of gene expression
• GO:0032725 positive regulation of granulocyte macrophage colony-stimulating factor production
• GO:0002639 positive regulation of immunoglobulin production
• GO:0050729 positive regulation of inflammatory response
• GO:0032727 positive regulation of interferon-alpha production
• GO:0032728 positive regulation of interferon-beta production
• GO:0032733 positive regulation of interleukin-10 production
• GO:0032735 positive regulation of interleukin-12 production
• GO:0032741 positive regulation of interleukin-18 production
• GO:0032755 positive regulation of interleukin-6 production
• GO:0032757 positive regulation of interleukin-8 production
• GO:1905300 positive regulation of intestinal epithelial cell development
• GO:0046330 positive regulation of JNK cascade
• GO:0043410 positive regulation of MAPK cascade
• GO:1900227 positive regulation of NLRP3 inflammasome complex assembly
• GO:0034165 positive regulation of toll-like receptor 9 signaling pathway
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0032760 positive regulation of tumor necrosis factor production
• GO:0032729 positive regulation of type II interferon production
• GO:0045577 regulation of B cell differentiation
• GO:0034162 toll-like receptor 9 signaling pathway
• GO:0002224 toll-like receptor signaling pathway

Drugs targeting this protein · 2

• HYDROXYCHLOROQUINE SULFATE antagonist
• AGATOLIMOD SODIUM agonist

Related proteins · sequence + function similarity

• Toll-like receptor 9 0.99
• Toll-like receptor 9 0.98
• Toll-like receptor 9 0.98
• Toll-like receptor 9 0.98
• Toll-like receptor 9 0.97
• Toll-like receptor 9 0.97
• Toll-like receptor 9 0.96
• Transforming growth factor beta activator LRRC32 0.88
• Transforming growth factor beta activator LRRC33 0.88
• Transforming growth factor beta activator LRRC32 0.88
• Transforming growth factor beta activator LRRC32 0.88
• Transforming growth factor beta activator LRRC33 0.87

Co-cited proteins · studied together in the literature

• Toll-like receptor 8 5 shared papers
• Macrophage scavenger receptor types I and II 1 shared papers
• Toll-like receptor 7 3 shared papers
• Fc receptor-like protein 3 1 shared papers
• Palmitoyltransferase ZDHHC3 1 shared papers
• Toll-like receptor 9 2 shared papers
• Toll-like receptor 10 2 shared papers
• Tyrosine-protein kinase BTK 1 shared papers
• Toll-like receptor 11 1 shared papers
• Toll-like receptor 5 2 shared papers
• Protein canopy homolog 3 1 shared papers
• Toll-like receptor 1 2 shared papers

Literature · 15 cited papers

• TLR9 signaling requires ligand-induced phosphorylation of two specific tyrosine residues by EGFR and Syk. MBio · 2025
• Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice. Nat. Commun. · 2024
• FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation. Eur. J. Immunol. · 2013
• Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat. Commun. · 2010
• The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes. PLoS ONE · 2009
• Natural selection in the TLR-related genes in the course of primate evolution. Immunogenetics · 2008
• Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase. J. Biol. Chem. · 2007
• The consensus coding sequences of human breast and colorectal cancers. Science · 2006
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. · 2004
• The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. · 2003
• Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J. Immunol. · 2001
• … and 3 more in the literature graph