TLR1- and TLR6-independent recognition of bacterial lipopeptides.
Bacterial cell walls contain lipoproteins/peptides, which are strong modulators of the innate immune system. Triacylated lipopeptides are assumed to be recognized by TLR2/TLR1-, whereas diacylated lipopeptides use TLR2/TLR6 heteromers for signaling. Following our initial discovery of TLR6-independent diacylated lipopeptides, we could now characterize di- and triacylated lipopeptides (e.g. Pam(2)C-SK(4), Pam(3)C-GNNDESNISFKEK), which have stimulatory activity in TLR1- and in TLR6-deficient mice. Furthermore, for the first time, we present triacylated lipopeptides with short length ester-bound fatty acids (like PamOct(2)C-SSNASK(4)), which induce no response in TLR1-deficient cells. No differences in the phosphorylation of MAP kinases by lipopeptide analogs having different TLR2-coreceptor usage were observed. Blocking experiments indicated that different TLR2 heteromers recognize their specific lipopeptide ligands independently from each other. In summary, a triacylation pattern is necessary but not sufficient to render a lipopeptide TLR1-dependent, and a diacylation pattern is necessary but not sufficient to render a lipopeptide TLR6-dependent. Contrary to the current model, distinct lipopeptides are recognized by TLR2 in a TLR1- and TLR6-independent manner.
Buwitt-Beckmann
Ute
U
Department of Immunology and Cell Biology, Research Center Borstel, 23845 Borstel, Germany.
Heine
Holger
H
Wiesmüller
Karl-Heinz
KH
Jung
Günther
G
Brock
Roland
R
Akira
Shizuo
S
Ulmer
Artur J
AJ
D000818:Animals; D001419:Bacteria / Q000737:chemistry; D005227:Fatty Acids / Q000378:metabolism; D007113:Immunity, Innate; D008024:Ligands; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000502:physiology*
D005227:Fatty Acids; D008024:Ligands; D008074:Lipoproteins; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6