TLR1- and TLR6-independent Recognition of Bacterial Lipopeptides

• Published in: The Journal of biological chemistry Vol. 281; no. 14; pp. 9049 - 9057
• Main Authors: Buwitt-Beckmann, Ute, Heine, Holger, Wiesmüller, Karl-Heinz, Jung, Günther, Brock, Roland, Akira, Shizuo, Ulmer, Artur J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.04.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Bacteria; Bacteria - chemistry; Fatty Acids - metabolism; Immunity, Innate; Ligands; Lipoproteins - chemistry; Lipoproteins - metabolism; Mice; Mice, Knockout; Phosphorylation; Signal Transduction; Toll-Like Receptor 1 - genetics; Toll-Like Receptor 1 - physiology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - physiology; Toll-Like Receptor 6 - genetics; Toll-Like Receptor 6 - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M512525200

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. Pam2C-SK4, Pam3C-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 PamOct2C-SSNASK4), 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.