Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response.
In mice (and by inference, in all mammals), a single pathway exists to serve lipopolysaccharide (LPS) signal transduction, and as such, allelic mutations at a single locus entirely abolish responses to LPS in C3H/HeJ and C57BL/10ScCr mice. Positional cloning of this locus, known as Lps, revealed that mutations of the Toll-like receptor 4 gene (Tlr4) are responsible for endotoxin resistance. A quick succession of studies have shown Tlr4 to be the critical transmembrane component of the LPS signal transduction complex. As LPS sensing by Tlr4 depends on physical contact between the two molecules, Tlr4 is a direct interface with the microbial world. Eight other molecules with strong similarity to Tlr4 are presently known in mammals, and taking Tlr4 as a model, all may be guessed to participate in the early detection of invasive pathogens. Acting together, the Toll-like receptors may be assumed to present macrophages with a comprehensive "picture" of the micobial world, and thus comprise the principal sensing molecules utilized by cells of the innate immune system.
Beutler
B
B
The Howard Hughes Medical Institute, 5323 Harry Hines Blvd., Y5.224, Dallas, TX 75235-9050, USA. beutler@howie.swmed.edu
Poltorak
A
A
D000818:Animals; D005075:Biological Evolution; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020931:ran GTP-Binding Protein
D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C102460:Ran protein, mouse; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020559:Monomeric GTP-Binding Proteins; D020931:ran GTP-Binding Protein