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Pathway Description
Toll-Like Receptor Pathway 2
Bos taurus
Category:
Protein Pathway
Sub-Categories:
Immunological
Pathogen-Activated Signaling
Gene Regulatory
Cellular Response
Created: 2018-09-20
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.
References
Toll-Like Receptor Pathway 2 References
Yamaji D, Kitamura H, Kimura K, Matsushita Y, Okada H, Shiina T, Morimatsu M, Saito M: Cloning of bovine MAIL and its mRNA expression in white blood cells of Holstein cows. Vet Immunol Immunopathol. 2004 Apr;98(3-4):175-84. doi: 10.1016/j.vetimm.2003.12.004.
Pubmed: 15010226
Doleschall M, Mayer B, Cervenak J, Cervenak L, Kacskovics I: Cloning, expression and characterization of the bovine p65 subunit of NFkappaB. Dev Comp Immunol. 2007;31(9):945-61. doi: 10.1016/j.dci.2006.12.007. Epub 2007 Jan 24.
Pubmed: 17306370
Zimin AV, Delcher AL, Florea L, Kelley DR, Schatz MC, Puiu D, Hanrahan F, Pertea G, Van Tassell CP, Sonstegard TS, Marcais G, Roberts M, Subramanian P, Yorke JA, Salzberg SL: A whole-genome assembly of the domestic cow, Bos taurus. Genome Biol. 2009;10(4):R42. doi: 10.1186/gb-2009-10-4-r42. Epub 2009 Apr 24.
Pubmed: 19393038
Ikeda A, Takata M, Taniguchi T, Sekikawa K: Molecular cloning of bovine CD14 gene. J Vet Med Sci. 1997 Aug;59(8):715-9. doi: 10.1292/jvms.59.715.
Pubmed: 9300371
Diamond G, Russell JP, Bevins CL: Inducible expression of an antibiotic peptide gene in lipopolysaccharide-challenged tracheal epithelial cells. Proc Natl Acad Sci U S A. 1996 May 14;93(10):5156-60. doi: 10.1073/pnas.93.10.5156.
Pubmed: 8643545
Seabury CM, Womack JE: Analysis of sequence variability and protein domain architectures for bovine peptidoglycan recognition protein 1 and Toll-like receptors 2 and 6. Genomics. 2008 Oct;92(4):235-45. doi: 10.1016/j.ygeno.2008.06.005. Epub 2008 Aug 9.
Pubmed: 18639626
Opsal MA, Vage DI, Hayes B, Berget I, Lien S: Genomic organization and transcript profiling of the bovine toll-like receptor gene cluster TLR6-TLR1-TLR10. Gene. 2006 Dec 15;384:45-50. doi: 10.1016/j.gene.2006.06.027. Epub 2006 Jul 29.
Pubmed: 16950576
Werling D, Piercy J, Coffey TJ: Expression of TOLL-like receptors (TLR) by bovine antigen-presenting cells-potential role in pathogen discrimination? Vet Immunol Immunopathol. 2006 Jul 15;112(1-2):2-11. doi: 10.1016/j.vetimm.2006.03.007. Epub 2006 May 15.
Pubmed: 16701904
Yang W, Zerbe H, Petzl W, Brunner RM, Gunther J, Draing C, von Aulock S, Schuberth HJ, Seyfert HM: Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder. Mol Immunol. 2008 Mar;45(5):1385-97. doi: 10.1016/j.molimm.2007.09.004. Epub 2007 Oct 22.
Pubmed: 17936907
Cates EA, Connor EE, Mosser DM, Bannerman DD: Functional characterization of bovine TIRAP and MyD88 in mediating bacterial lipopolysaccharide-induced endothelial NF-kappaB activation and apoptosis. Comp Immunol Microbiol Infect Dis. 2009 Nov;32(6):477-90. doi: 10.1016/j.cimid.2008.06.001. Epub 2008 Aug 28.
Pubmed: 18760477
Connor EE, Cates EA, Williams JL, Bannerman DD: Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-4) signaling molecules. Vet Immunol Immunopathol. 2006 Aug 15;112(3-4):302-8. doi: 10.1016/j.vetimm.2006.03.003. Epub 2006 Apr 18.
Pubmed: 16621030
Sauter KS, Brcic M, Franchini M, Jungi TW: Stable transduction of bovine TLR4 and bovine MD-2 into LPS-nonresponsive cells and soluble CD14 promote the ability to respond to LPS. Vet Immunol Immunopathol. 2007 Jul 15;118(1-2):92-104. doi: 10.1016/j.vetimm.2007.04.017. Epub 2007 May 3.
Pubmed: 17559944
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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