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Toll-Like Receptor Pathway 2
Last Updated: 2019-08-16
Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens. TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex. TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface. Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex. After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO). Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex. NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.
Toll-Like Receptor Pathway 2 References
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This pathway was propagated using PathWhiz - Pon, A. et al. Pathways with PathWhiz (2015) Nucleic Acids Res. 43(Web Server issue): W552–W559.
Propagated from SMP0069593
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