|Coordinate||167,308,286 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||toll-like receptor 7|
|Chromosomal Location||167,304,929-167,330,558 bp (-)|
|MGI Phenotype||The innate immune response to viral infection is affected in homozygous null mice. Mice homozygous or hemizygous for a point mutation produce little or no tumor necrosis factor (TNF) alpha in response to stimulation by a single stranded RNA analog.|
|Amino Acid Change||Threonine changed to Isoleucine|
|Institutional Source||Beutler Lab|
T68I in Ensembl: ENSMUSP00000061853 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Phenotypic Category||immune system, TLR signaling defect: TNF production by macrophages, TLR signaling defect: type I IFN production by macrophages|
|Alleles Listed at MGI|
|Mode of Inheritance||X-linked Recessive|
|Local Stock||Live Mice, Sperm, gDNA|
|Last Updated||03/28/2017 1:36 PM by Katherine Timer|
|Nature of Mutation|
The Tlr7 gene on the X chromosome of rsq1 mice was sequenced, and a C to T transition was identified in exon 3 (of 3 total exons) at position 391 of the Tlr7 transcript. The mutation was identified in a hemizygous male.
The mutated nucleotide is indicated in red lettering, and results in a conversion of threonine to isoleucine at residue 68 of the TLR7 protein.
TLR7 is a type I integral membrane glycoprotein containing 1050 amino acids. Like the other TLRs, its cytoplasmic domain (at its C terminus) shares similarity with the interleukin-1 and IL-18 receptors (IL-1R and IL-18R) in a conserved region of approximately 200 amino acids known as the Toll/IL-1R (TIR) domain (2-4), which mediates homo- and heterotypic protein interactions during signal transduction. TIR domains in TLRs and in IL receptors contain 3 conserved boxes (boxes 1, 2 and 3), which are required for signaling (5). In addition, TIR domains contain six α-helices (αA, αB, αC, αC’, αD and αE) and five β-strands (βA, βB, βC, βD and βE) which are connected by seven loops. The crystal structures of the TLR1 and TLR2 TIR domains revealed that they fold into a structure with a central five-stranded parallel β-sheet surrounded by five helices (6) (see the record for languid for a picture of the TLR2 TIR domain). Many of the α-helices and connecting loops are predicted to participate in binding partner recognition, and their mutation is expected to abrogate specific binding interactions. This is true of a proline to histidine mutation in the BB loop of TLR4 (see the record for lps3), which abolishes MyD88 binding (7) and LPS-induced signaling in mice (8).
The extracellular domains of TLRs, unlike those of the interleukin receptors, contain multiple leucine-rich repeats (LRRs), which mediate ligand recognition by TLRs and generally consist of 24-29 amino acids with two conserved leucine-rich sequences: XLXXLXLXXN (residues 1-10, present in all LRR subtypes) followed by XØXXØX4FXXLX (residues ~11-24, but variable in length, sequence and structure), where X is any amino acid and Ø is a hydrophobic amino acid [discussed in (9)]. Crystal structures of several TLRs reveal that each LRR forms a loop such that the juxtaposition of several LRR loops forms a horseshoe structure, with the hydrophobic residues of the LRR consensus sequence pointed inward (10-12). In addition, the XLXXLXLXX sequence folds into a β-strand, with the remaining LRR residues oriented on the convex side of the structure. TLR7 has 27 LRRs in its ectodomain encoded by the N-terminal portion of the protein (3;4). Some of these LRRs contain insertions of up to 16 amino acids following positions 10 or 15 in the LRR consensus sequence, a common occurrence among LRRs of many TLRs. In TLR3, insertions in two of the LRRs extend outward from the convex face of the protein (11;12) (Figure 4; PDB ID 3CIY). It has been suggested that insertions in LRRs provide contacts that mediate the ligand-binding specificity of TLRs (9). For TLR7, LRRs 2, 5 and 8 contain long insertions following the tenth residue. These insertions, along with an insertion in LRR11, are positioned proximal to the β-strands formed by the first ten residues. These four insertions may contribute to the ligand-binding site (9). The ectodomain of TLR9 has been shown to undergo proteolytic cleavage between LRR14 and LRR15, and a similar cleavage event also occurs in TLR7 (13;14).
A recent study using a VISA knockout mouse model found that the mitochondrial protein, VISA (i.e. IPS-1, MAVS, or CardIF), is necessary for B cell expression of TLR7 (15). Treatment of the VISA-deficient B cells with a TLR7 agonist found that TLR7-mediated induction of CD23 and CD69 did not occur; no change was observed after treatment with a TLR9 agonist (15). Furthermore, VISA-deficient B cells proliferated poorly and produced less cytokines in response to TLR7 agonists (15). Further examination the VISA-deficient B cells found that VISA is required for NF-κB activation after TLR7 agonist exposure; TLR9-mediated activation of NF-κB was not changed (15). TLR7-mediated MyD88 association with IRAK1 is essential for TLR7 signaling. In VISA-deficient B cells, the about of TLR7-mediated MyD88-IRAK1 association was decreased (15).
The rsq1 mutation results in a threonine to isoleucine substitution of amino acid 68 of TLR7, located within the first LRR b-strand (Figure 5). Threonine 68 is conserved among mammalian TLR7 orthologues and mouse paralogues. The rsq1 mutation disrupts a N-linked glycosylation consensus sequence [NXT/S, where X can be any amino acid]; the putative glycosylation site is at N66. An intact glycosylation consensus sequence is essential for the initiation of a signaling response to ssRNA and low molecular weight TLR7 agonists (1).
Northern blot and RT-PCR analysis detected Tlr7 transcript in heart, spleen, liver, kidney, small intestine, stomach and placenta (2-4). Tlr7 mRNA is also found in bone marrow and lymph node cells (2), in particular in plasmacytoid dendritic cells (pDC) (16;17), B cells (2;18), and eosinophils (19). TLR7 is localized intracellularly (20), in the endoplasmic reticulum (ER) (21), and at endosomal membranes (22;23).
TLRs are key sensors of invading microorganisms, recognizing conserved molecular motifs found in different pathogens and triggering host cell responses. There are 12 TLRs in mice and 10 in humans, and each receptor recognizes a distinct set of microbial ligand(s) (Figure 6). TLR7 was first shown to recognize imidazoquinolines, guanosine-based chemicals that are used as antiviral drugs (2). Peritoneal macrophages from mice with a targeted deletion of TLR7 produce normal amounts of TNF-α in response to LPS, peptidoglycan and zymosan (TLR2/6 ligands), MALP-2, Pam3CSK4 and CpG ODNs, but produced no detectable TNF-α or IL-12p40 in response to the imidazoquinolines imiquimod or R-848 (2). Splenic B lymphocyte proliferation and upregulation of costimulatory molecules (CD40, CD80, CD86) by bone marrow-derived dendritic cells, normal responses to imidazoquinolines, are also abrogated in Tlr7-/- mice (2).
Single-stranded (ss) RNA viruses are now known to be the natural microbial ligands for TLR7 (24-26). This was demonstrated using Tlr7-/- mice, which produce greatly reduced levels of serum IFN-α upon systemic infection with the ssRNA virus vesicular stomatitis virus (VSV) (24). In vitro, Tlr7-/- pDC or total bone marrow cells produce almost no IFN-α and IL-12p40 after infection with VSV or influenza virus, another ssRNA virus (24;26). GU-rich ssRNA oligonucleotides from HIV-1 also activate TLR7 on human myeloid cells and pDC to produce IFN-α, IL-6, TNF-α and IL-12p40 (25). Recent studies demonstrate that pDC recognition of some ssRNA viruses via TLR7 requires the transport of cytosolic viral replication intermediates into lysosomes by autophagy (27), a process by which cells engulf parts of their own cytoplasm to eliminate foreign material or recycle various molecules. This mechanism explains why certain ssRNA viruses, such as respiratory syncytial virus (28), elicit pDC responses only after live viral infection. In addition, the shape of viral ssRNAs may determine the potency of TLR7 signaling, since UV crosslinking of viral RNAs before transfection into TLR7-expressing HEK cells can affect the level of IFN-α production (29). Similar to TLR9, proteolytic cleavage of TLR7 within its ectodomain occurs in the endolysosome (13;14). Although full length and cleaved forms of TLR9 are capable of binding ligand, only the cleaved form can recruit MyD88 and lead to signaling. The cleavage mechanism has been postulated to restrict receptor activation to endolysosomal compartments and prevent responses to self nucleic acids (13). TLR7 signaling requires proper localization of the receptor in the endosomal/lysosomal compartment as well as lysosomal acidification, which permits viral-lysosomal membrane fusion (22-24;26). Because not only viral-derived ssRNA, but ssRNA in general, can activate TLR7, it is thought that compartmentalization of TLR7 helps to prevent activation of signaling by self-ssRNA (26). The ER-resident twelve transmembrane-spanning protein Unc93b1 is required for signaling by all of the nucleic acid-sensing intracellular TLRs (TLRs 3, 7, 9 in mice), as evidenced by the lack of cytokine production by 3d cells (which harbor a mutation in Unc93b1) when stimulated with poly I:C, R-848 or CpG ODN (30). Unc93b1 physically interacts with TLRs 3, 7 and 9 (21), an interaction that may be required for proper targeting of these TLRs from the ER to the endosome (Figure 7).
Once activated, TLR7 signaling requires the adapter MyD88 and, like other MyD88-dependent TLRs, recruits IL-1R-associated kinase 1 (IRAK1), IRAK4 and tumor necrosis factor receptor-associated factor 6 (TRAF6), leading to NF-κB and MAP kinase activation (2;25;26;31). MyD88, together with TRAF6 and IRAK4, has also been shown to bind interferon regulatory factor 7 (IRF7) directly in order to stimulate IFN-α production (32;33). Although TLR7 signaling (including IRAK-1 and NF-κB activation) leading to IFNα/β production is strictly IRAK-4-dependent, human patients with IRAK-4 deficiency are said to be resistant to common viruses, and peripheral blood mononuclear cells from such patients produce normal levels of IFN-α/β and –λ in response to a variety of viruses, including ssRNA viruses (31). It has been suggested that TLR7 induction of IFN-α/β and –λ via IRAK4 in humans may be redundant in protective immunity to viruses (31). However, this statement rests upon the fact that living IRAK4 deficient patients are not seen to have severe viral infections. This sampling approach would ignore premature deaths from viral infection that might occur among IRAK4 deficient individuals. Moreover, viral infection of blood cells was not confirmed in the experiments that were performed (31).
Several reports support a role for TLR7 in the pathogenesis of the autoimmune disease systemic lupus erythematosus. TLR7 deficiency results in lower titers of autoantibodies and less severe disease in the lupus-prone MRL-Faslpr mice (34). In addition, the Y chromosome-linked autoimmunity accelerator (Yaa) locus in male BXSB mice (that confers a high incidence of lupus with early onset when bred to lupus mouse models) is caused by an X to Y chromosome translocation of a group of genes including Tlr7, suggesting that its increased expression may contribute to the disease (35;36). This hypothesis has been recently confirmed in transgenic mice overexpressing TLR7, which spontaneously develop autoimmune disease characterized by autoantibody production, splenomegaly, glomerulonephritis, DC expansion, and liver and lung inflammation (37). These phenotypes apparently lead to death in Tlr7-transgenic mice, with the level of TLR7 overexpression correlating with the number of deaths among transgenic lines (37).
A recent study has shown that TLR7 is also involved in promoting autoimmune diabetes in the NOD mouse (38). Cytotoxic T lymphocytes in the NOD model are induced by TLR7 signaling (in conjunction with CD40-mediated activation of dendritic cells) (38). Treatment with a TLR7 agonist protomoted diabetes onset and activate NOD bone-derived dendritic cells and the secretion of proinflammatory cytokines and chemokines; inhibition of TLR7 leads to a delay in the early events of diabetes (38).
In an effort to understand the contributions of sex-associated factors on the immune system, a recent study examined the populations of leukocytes in young and old female and male mice (39). In aged female mice, B cells bearing CD11b and CD11c, but not CD21 were found at a much higher frequency in the older females when compared to the above-mentioned groups (39). When autoimmune-prone mice were examined at several ages, the number of the CD11b/c subset of B cells were elevated by as early as 3 months; the presence of autoantibodies could be observed by 6 months (39). Examination of the elevated population found that these cells secreted autoreactive antibodies (39). Gene expression analysis by microarray determined that the CD11b/c B cells share similarities to peritoneal B1 cells, however, there are over 500 genes that are differentially expressed in the CD11b/c cells. The CD11b/c cells express many genes that are expressed by cytotoxic cells (e.g. T-bet, perforin, and granzyme A). Changes to TLR7 signaling (in both MyD88 and TLR7 knockout mice) prevented the accumulation of the B cells in aged female mice. Exposure to TLR3, TLR4, and TLR9 agonists did not lead to an accumulation of CD11b/c B cells or the secretion of autoantibodies.
The exact molecular defect that is caused by the T68I rsq1 mutation in TLR7 is unknown. Expression analysis revealed that the defect in TLR7 signaling was not due to impaired expression or localization of the rsq1 mutant. It is proposed that the loss of the putative N-glycosylation consensus sequence in the rsq1 mutant leads to loss of N-glycosylation at N66 (Figure 8) and analysis of a mutant TLR7 (N66A) resulted in a TLR7 protein that was unable to activate NF-kB (1). Although the mutation is in close proximity to the ligand binding site, the rsq1 mutant was able to bind ssRNA and interfere with TLR7 signaling as well as to colocalize and bind to wild-type TLR7, therefore, the loss of the purported glycosylation moiety at N66 seems to not cause a large change in the folding of TLR7 (1). Co-expression studies using the rsq1 TLR7 mutant and wild-type TLR7 found that although rsq1 associates with the wild-type TLR7, the mutant prevents the formation of a signaling-competent dimer (Figure 9) (1). Therefore, the loss of N-glycosylation at N66 could lead to a change in the structure that would subsequently disturb the function of TLR7 (1). It is proposed that the loss of N-glycosylation at N66 due to the rsq1 mutation could alter the ability of TLR7 to trigger the dimeric receptor complex or that it could change the ability of TLR7 to bind to a signaling partner such as a protease or a chaperone (1).
|Primers||Primers cannot be located by automatic search.|
Rsq1 genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
Primers for PCR amplification
Rsq1(F): 5’- AGCACTCTTCGCAGCAACTAATATGTAA-3’
Rsq1(R): 5’-CCAACTCAACAAGGTTGGGAAGAAAATG -3’
1) 94°C 2:00
2) 94°C 0:15
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 35X
6) 72°C 10:00
7) 4°C ∞
Primers for sequencing
Rsq1_seq(F): 5’- TACTTGTGGACAAGACTGATGACC -3’
Rsq1_seq(R): 5’- TTTCCATCCAGGTAAAGGGC -3’
The following sequence of 1911 nucleotides (from Genbank genomic region NC_000086 for linear DNA sequence of Tlr7) is amplified:
21166 agcac tcttcgcagc
21181 aactaatatg taatgctgct tctgtatctt aaaaactgtt tggggcagca agagacatgg
21241 ctcagtgggt aagtatggtg atgtgaatgt gaatgacccc gtaggctcat gtttgaatac
21301 ttggttccca gtcagtggaa cttttggcaa ggattaggag gtgtggcttt gttgaaagag
21361 gtgtgccact agaggtaggc tgtgagattt caaaagtcca tgcccatccc agtctcattc
21421 cttctctgcc tacaatttgc agataacatg tgagctctca gcagctgctc cagtgtcatg
21481 cctacctgtc tgctaccatg tttcctgtca tgatatcata aactaaccct ctaaaactct
21541 aggcaagaac cagagcaaat gctttgtttt ctaaggtgtt gtggtcatag tggttcatca
21601 cagcaataga aacagtaatg agacagtaag tgtacttgtg gacaagactg atgacctgcg
21661 tttgatctgc aggatccaca aggtggaagg agataacaga ctctcacaag ttatcctctg
21721 accgccacaa tcacgtcatg gtatgtgcac actcactgac atatgcaaag catactcaca
21781 caagacaaat aaataaatgt gaaaaaattc ttgaagtttg ttagaaagct aagatggtac
21841 aagcaaaaca taaaaccatt atcaaagtct tcagtggtta ataagtacag tcacagggac
21901 ggaggtgctg tttacactat tacaaacaag acctgtgttg tttagtttta ataatgtacc
21961 aaaagagagg aaataaatgg aacttctcaa tcattccttg atatatttta taacaataat
22021 ttttttctct cttttattta caggtgtttt cgatgtggac acggaagaga caaattttga
22081 tctttttaaa tatgctctta gtttctagag tctttgggtt tcgatggttt cctaaaactc
22141 taccttgtga agttaaagta aatatcccag aggcccatgt gatcgtggac tgcacagaca
22201 agcatttgac agaaatccct gagggcattc ccactaacac caccaatctt acccttacca
22261 tcaaccacat accaagcatc tctccagatt ccttccgtag gctgaaccat ctggaagaaa
22321 tcgatttaag atgcaattgt gtacctgttc tactggggtc caaagccaat gtgtgtacca
22381 agaggctgca gattagacct ggaagcttta gtggactctc tgacttaaaa gccctttacc
22441 tggatggaaa ccaacttctg gagataccac aggatctgcc atccagctta catcttctga
22501 gccttgaggc taacaacatc ttctccatca cgaaggagaa tctaacagaa ctggtcaaca
22561 ttgaaacact ctacctgggt caaaactgtt attatcgaaa tccttgcaat gtttcctatt
22621 ctattgaaaa agatgctttc ctagttatga gaaatttgaa ggttctctca ctaaaagata
22681 acaatgtcac agctgtcccc accactttgc cacctaattt actagagctc tatctttata
22741 acaatatcat taagaaaatc caagaaaatg attttaataa cctcaatgag ttgcaagttc
22801 ttgacctaag tggaaattgc cctcgatgtt ataatgtccc atatccgtgt acaccgtgtg
22861 aaaataattc ccccttacag atccatgaca atgctttcaa ttcattgaca gaattaaaag
22921 ttttacgttt acacagtaat tctcttcagc atgtgccccc aacatggttt aaaaacatga
22981 gaaacctcca ggaactagac ctctcccaaa actacttggc cagagaaatt gaggaggcca
23041 aatttttgca ttttcttccc aaccttgttg agttgg
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated C is shown in red text.
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|Science Writers||Eva Marie Y. Moresco, Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Owen M. Siggs, Bruce Beutler|