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FLASH GENE
Symbol TLR9 contributors: mct - updated : 28-06-2018
HGNC name toll-like receptor 9
HGNC id 15633
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • essential role for the N-terminal fragment of TLR9 in DNA sensing
  • an extracellular part composed of 18 leucine-rich repeats (LRR) that is necessary for ligand recognition
  • a cysteine rich region
  • a transmembrane segment
  • a cytoplasmic domain, the TOLL homology domain (TH), common to Toll and IL1 receptors (also called TIR domain)
  • three AAs in the C-terminus of the extracellular domain of TLR9 are required for ligand activation
  • both the C- and N-termini of the extracellular domain (ECD) are necessary for the function of TLR9
    • HOMOLOGY
    interspecies homolog to Drosophila transmembrane receptor Toll,9
    Homologene
    FAMILY
  • Toll-like receptor family
    • CATEGORY immunity/defense , receptor membrane
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • although ligand recognition occurs in endolysosomes, it has been reported that most, if not all, TLR9 resides in the endoplasmic reticulum (ER) of resting cells
  • sequestered in the endoplasmic reticulum (ER) in a resting state and traffic to endolysosomes upon ligand-induced stimulation
  • translocates from ER to endolysosomes through the Golgi complex and that Golgi export is required for optimal TLR9 signaling
  • primarily resides in the endoplasmic reticulum, traffics to endosomes, is proteolytically processed and responds to DNA
  • expressed on the surface of splenic dendritic cells
  • localized in the endolysosome
    • basic FUNCTION
  • pathogen recognition and activation of innate immunity
  • potential inducer of apoptosis and septic shock
  • activating NF-Kappa B signaling pathway
  • can recognize nucleic acids and trigger signaling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (thus contributing to the pathogenesis of systemic lupus erythematosus)
  • mediating cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response
  • required for effective innate immune responses against Gram-negative bacterial pathogens
  • blocks osteoclast differentiation through induction of phosphatase
  • initiate immune responses to infection by recognizing microbial nucleic acid
  • requirement for processing of TLR9 may represent an evolutionary strategy to ensure proper self/non-self discrimination based on nucleic acid recognition
  • recognize pathogen-derived nucleotides in intracellular compartments and respond to host-derived nucleotides as well, and they have been implicated in a variety of autoimmune diseases
  • TLR9-induced suppression of EBV lytic gene expression is dependent on the TLR9–MyD88 signaling axis
  • TLR9–MyD88 activation leading to histone modification might be the signaling event responsible for the interaction between the malaria parasite P. falciparum and EBV gene expression in B cells contributing to the pathogenesis of endemic Burkitt lymphoma
  • with TLR7, are required for plasmacytoid dendritic cells
  • senses DNA with unmethylated CpG motifs derived from bacteria and viruses
  • TLR9 signaling pathway is involved in inflammatory responses in failing hearts in response to pressure overload and plays an important role in the pathogenesis of heart failure
  • mitochondrial DNA that escapes from autophagy-mediated degradation cell-autonomously leads to TLR9-mediated inflammatory responses in cardiomyocytes, myocarditis, and dilated cardiomyopathy
  • cell death and injury result in the release of mtDNA (mitochondrial DNA) that acts via TLR9 (Toll-like receptor 9), a pattern recognition receptor of the immune system which detects bacterial and viral DNA
  • platelet TLR9 is a functional platelet receptor that links oxidative stress, innate immunity, and thrombosis
  • TLR9-mediated recognition of viral and bacterial DNA activates the innate immune system
  • would potentially signal in acidic pH as endolysosome/lysosome condition
  • has paradoxical roles in regulating anti-DNA B cells
  • initiates inflammatory response by recognizing DNA, imported by infection or released from tissue damage
  • role of TLR9 in energy metabolism and cellular protection in cardiomyocytes and neurons
  • component of the innate immune system, which recognizes the DNA of both pathogens and hosts, and can drive autoimmune diseases
  • TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses
  • distinct roles for TLR7 and TLR9 in the differentiation of autoreactive B cells that explain the capacity of TLR9 to limit, as well as TLR7 to promote, the clinical features of systemic erythematosus lupus
    • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS immunity/defense
    text apoptosis of infected cells
    PATHWAY
    metabolism
    signaling signal transduction
    a component
  • component in the recognition of immunostimulating bacterial CpG-DNA motifs, in different subsets of human peripheral blood mononuclear cells (PBMC)
  • TLR9–MyD88 signaling axis is implicated in TLR9-induced suppression of EBV lytic gene expression
  • forms a complex with AP3B1 and promotes association of TRAF3 and IRF7
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • late endosome/lysosome-localized RAB7B can down-regulate TLR9-triggered proinflammatory cytokine and type I IFN production by impairing TLR9 signaling via promotion of TLR9 degradation
  • ATG4B, a key enzyme in autophagy
  • potentiation of TLR9 responses for human na
    • ve B-cell growth through CD180 signaling
  • plasmacytoid dendritic cells (pDCs) play an important role in IFNA1 production during varicella-zoster virus (VZV) infection through TLR9-dependent and -independent pathways
  • upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, UNC93B1
  • HSP90B1 is critical for both TLR9 egress from the ER, and for protein conformational stability in the endosomal compartment
  • IRF5 is a transcription factor activated by toll like receptor TLR7 and TLR9 during innate immune responses
  • DOCK8 functions as an adaptor in a TLR9-MYD88 signaling pathway in B cells
  • is essential for dendritic cells (DC) activation caused by CpG oligonucleotides (ODN)
  • physical association of TLR9, ICAM1 and TRAF6 leads to activation of noncanonical NFKB1 signalling
  • ADRB2 stimulation suppresses TLR9-dependent IFNA1 secretion in human peripheral blood mononuclear cells
  • signaling cascades driven by the BCR and TLR9 have a newly identified meeting point at TBX21(
  • BTK is an important player for TLR9 but not TLR7 signaling in human Plasmacytoid dendritic cells (PDCs)
  • BTK regulates dendritic cell responses upon TLR9 engagement in terms of activation, cytokine production, and STAT1/3 upregulation
  • to restrict Nucleic acid (NA)-sensing in endolysosomes, TLR7/9 trafficking is tightly controlled by a multiple transmembrane protein UNC93B1
  • TRIM35 is a negative feedback regulator of TLR7/9-mediated type I IFN production due to its ability to suppress the stability of IRF7
  • critical role of RTN4 and GRAMD4 in trafficking of TLR9
  • SARM1, mediates TLR7/TLR9-induced apoptosis in neurons
  • TRAF6-mediated degradation of DOK3 is required for production of IL6 and TNF in TLR9 signaling
  • IRF8 inhibits TLR9-dependent gene expression by directly blocking the activity of IRF5
  • CAMP selectively modulated synthesis of TLR4 and TLR9 in intestinal epithelium, but only when cells were exposed to virulence factors, mostly from apical surfaces
  • critical role of CD180 in regulating TLR7- and TLR9-mediated activation of macrophages and Dendritics cells
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    in primary Sjogren syndrome
    constitutional       gain of function
    results in inhibition of TNFSF11-induced osteoclastogenesis
    tumoral     --other  
    aberrantly expressed in neuroblastoma (NB) cells
    tumoral     --over  
    associated with poor differentiation, a high proliferation rate and disseminated in oesophageal adenocarcinoma
    Susceptibility
  • to asthma
  • to systemic lupus erythematosus (SLE)
    • Variant & Polymorphism SNP
  • 1237 C increases risk for asthma in Europeans
  • TLR9 C > T (rs352140) polymorphism might contribute to renal and immunologic disorders in SLE patients and to the presence of anti-dsDNA Ab
    • Candidate gene
    Marker
  • circulating mtDNA may be potential markers of early detection of pre-eclampsia
    • Therapy target
    SystemTypeDisorderPubmed
    cancerbrainglioma/neuroblstoma
    may represent a novel theranostic target in this disease
    reproductionpregnancy 
    anti-TLR9 treatments may be promising in the management of the pre-eclampsia
    ANIMAL & CELL MODELS