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|Coordinate||56,271,339 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||toll-like receptor adaptor molecule 1|
|Chromosomal Location||56,269,319-56,276,786 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. [provided by RefSeq, Jan 2012]
PHENOTYPE: Homozygous null mice are viable but exhibit abnormalities of the innate immune system. [provided by MGI curators]
|Amino Acid Change||Isoleucine changed to Threonine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000055104]|
AA Change: I252T
|Predicted Effect||probably benign
PolyPhen 2 Score 0.063 (Sensitivity: 0.94; Specificity: 0.84)
|Phenotypic Category||Autosomal Dominant|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Dominant|
|Last Updated||2016-09-22 10:30 AM by Anne Murray|
|Record Created||2016-02-10 1:52 PM by Lei Sun|
The Yue phenotype was identified among G3 mice of the pedigree R4294, some of which showed reduced TNFα secretion from macrophages in response to the Toll-like receptor 3 (TLR3) ligand, poly(I:C) (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 43 mutations. The diminished TNFα secretion in response to poly(I:C) phenotype was linked by continuous variable mapping to a mutation in Ticam1: a T to C transition at base pair 56,271,339 (v38) on chromosome 17, or base pair 5,429 in the GenBank genomic region NC_000083 encoding the Ticam1 gene. Linkage was found with a dominant model of inheritance, wherein three variant homozygotes and 13 heterozygotes departed phenotypically from 12 homozygous reference mice with a P value of 4.33 x 10-4 (Figure 2).
The mutation corresponds to residue 953 in the mRNA sequence NM_174989 within exon 2 of 2 total exons.
The mutated nucleotide is indicated in red. The mutation results in an isoleucine (I) to threonine (T) substitution at position 252 (I252T) in the TRIF protein, and is strongly predicted by PolyPhen-2 to be benign (score = 0.063).
Ticam1 encodes the 732-amino acid protein TICAM-1 [Toll-interleukin 1 receptor (TIR) domain-containing adaptor molecule-1; hereafter TRIF (TIR domain-containing adaptor inducing IFN-β)], an adaptor in TLR3 and TLR4 signaling (Figure 3). Mouse TRIF contains a conserved C-terminal proline-rich domain. TRIF also contains a Toll/IL-1 receptor (TIR) domain, a conserved region of approximately 200 amino acids which mediates homo- and heterotypic protein interactions during signal transduction (1;2). TRIF reportedly harbors between one and three TNF receptor-associated factor-6 (TRAF6) binding motifs at its N-terminus (3;4), defined by the sequence P-X-E-X-X-acidic/aromatic (5).
The Yue mutation results in an isoleucine to threonine substitution at position 252 (I252T); amino acid 252 is predicted to be within one of the TRAF6 binding motifs.
Please see the record Lps2 for more information about Ticam1.
The twelve mouse TLRs and ten human TLRs recognize a wide range of structurally distinct molecules, and all signal through only four adaptor proteins known to date: MyD88, Tirap (Mal), TICAM-1 (TRIF) and TRAM (6). TRIF and MyD88, act in LPS-induced TLR4 signaling leading to NF-κB and IRF-3 activation, and upregulation of costimulatory molecules (7-9). TRIF is the only adaptor serving TLR3 (7;9). The TRIF-mediated MyD88-independent pathway induces a late-phase activation of NF-κB and MAP kinases. Lps2 or Trif-null macrophages fail to activate NF-κB or IRF-3, or induce IFN-β in response to poly I:C (7;9).
Similar to the Lps2 mice, Yue mice have reduced TNF-α production in response to poly(I:C), indicating reduced TRIFYue function. The Yue mice were not assessed for IFN-β induction in response to poly I:C. The mutated residue in Yue is in a putative TRAF6-binding motif (P-X-E-X-X-acidic/aromatic) (5). Mutation of the glutamate residues in the putative TRAF6 binding motifs to alanine results in loss of co-immunoprecipitated with TRAF6, and failure to activate an NF-κB luciferase reporter (3;4). However, recent data obtained using TRAF6-/- macrophages demonstrate that TRAF6 is not required for TRIF-dependent NF-κB activation (10), suggesting that the TRIF-TRAF6 interaction has a separate, yet unknown function, or that in TRAF6-/- cells another protein can fulfill this role.
Yue(F):5'- AACACTTTCTGTGGTGGACG -3'
Yue(R):5'- GACTGGAGTTGGGGACATAC -3'
Yue_seq(F):5'- ACTTTCTGTGGTGGACGTCAGG -3'
Yue_seq(R):5'- AGTTGGGGACATACGTTACACTCC -3'
1. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., and Seya, T. (2003) TICAM-1, an Adaptor Molecule that Participates in Toll-Like Receptor 3-Mediated Interferon-Beta Induction. Nat Immunol. 4, 161-171.
2. Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., and Akira, S. (2002) Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter that Preferentially Activates the IFN-Beta Promoter in the Toll-Like Receptor Signaling. J Immunol. 169, 6668-6672.
3. Sato, S., Sugiyama, M., Yamamoto, M., Watanabe, Y., Kawai, T., Takeda, K., and Akira, S. (2003) Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-Beta (TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-Kappa B and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling. J Immunol. 171, 4304-4310.
4. Jiang, Z., Mak, T. W., Sen, G., and Li, X. (2004) Toll-Like Receptor 3-Mediated Activation of NF-kappaB and IRF3 Diverges at Toll-IL-1 Receptor Domain-Containing Adapter Inducing IFN-Beta. Proc Natl Acad Sci U S A. 101, 3533-3538.
5. Ye, H., Arron, J. R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N. K., Segal, D., Dzivenu, O. K., Vologodskaia, M., Yim, M., Du, K., Singh, S., Pike, J. W., Darnay, B. G., Choi, Y., and Wu, H. (2002) Distinct Molecular Mechanism for Initiating TRAF6 Signalling. Nature. 418, 443-447.
6. Beutler, B., Jiang, Z., Georgel, P., Crozat, K., Croker, B., Rutschmann, S., Du, X., and Hoebe, K. (2006) Genetic Analysis of Host Resistance: Toll-Like Receptor Signaling and Immunity at Large. Annu Rev Immunol. 24, 353-389.
7. Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S. O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J., and Beutler, B. (2003) Identification of Lps2 as a Key Transducer of MyD88-Independent TIR Signaling. Nature. 424, 743-748.
8. Hoebe, K., Jannsen, E. M., Kim, S. O., Alexopoulou, L., Flavell, R. A., Han, J., and Beutler, B. (2003) Upregulation of Costimulatory Molecules Induced by Lipopolysaccharide and Double-Stranded RNA Occurs by Trif-Dependent and Trif-Independent Pathways. Nat Immunol. 4, 1223-1229.
9. Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., and Akira, S. (2003) Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway. Science. 301, 640-643.
10. Gohda, J., Matsumura, T., and Inoue, J. (2004) Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling, J Immunol. 173, 2913-2917.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Lei Sun and Bruce Beutler|
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