TLR4 as the mammalian endotoxin sensor.
For more than a century, the ability to sense endotoxin (later known also as lipopolysaccharide; LPS) stood as the archetypal innate immune response: even before the phrase 'innate immunity' became popular. Yet the mechanism by which LPS initiated a signal remained unknown. The problem was solved in 1998 by positional cloning, which revealed that Toll-like receptor (TLR) 4, one of ten mammalian paralogues with homology to the Drosophila protein Toll, is the central component of the LPS receptor. During the 3 years that followed, gene knockout work supported the view that the TLRs perceive a number of indispensable molecular structures shared by diverse representatives of the microbial world. The highly specific LPS-sensing function of TLR4 is remarkable for its prevalence in Mammalia, which to the present time is the only class of the phylum Chordata known to have a gene encoding TLR4, and known to display exquisite sensitivity to LPS. The fact that LPS signals are elicited through a single biochemical pathway has raised important pharmacotherapeutic opportunities as well.
Beutler
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Department of Immunology, Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. brūce@scripps.edu
D000818:Animals; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D019143:Evolution, Molecular; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008322:Mammals; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors