Molecular basis for lipopolysaccharide mimetic action of Taxol and flavolipin.
We previously reported that Taxol, which mimics the action of LPS on murine macrophages, induces signals via mouse TLR4/MD-2, but not via human TLR4/MD-2. Here we investigated the molecular basis for this species-specific action of Taxol. Expression of mouse MD-2 conferred both LPS and Taxol responsiveness on HEK293 cells expressing mouse TLR4, whereas expression of human MD-2 conferred LPS responsiveness alone, suggesting that MD-2 is responsible for the species-specificity of Taxol responsiveness. Furthermore, mouse MD-2 mutants, in which Gln-22 was changed to other amino acids, showed dramatically reduced ability to confer Taxol responsiveness, although their ability to confer LPS responsiveness was not affected. These results indicated that Gln-22 of mouse MD-2 is essential for Taxol signaling, but not for LPS signaling. In this study, we also found that the TLR4/MD-2 complex, together with CD14, mediated signal transduction induced by flavolipin, an amino acid-containing lipid unique to Flavobacterium meningosepticum.
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Tokyo, Japan.
Kiyoshi
K
Kawasaki
Kazunori
K
Gomi
Yohko
Y
Kawai
Masao
M
Shiozaki
Masahiro
M
Nishijima
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D017931:DNA Primers / Q000737:chemistry; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008074:Lipoproteins / Q000494:pharmacology*; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection
D000954:Antigens, Surface; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D008074:Lipoproteins; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C451497:flavolipin; D005973:Glutamine; D017239:Paclitaxel