Discrimination of bacterial lipoproteins by Toll-like receptor 6

TLDR

Bacterial lipoproteins activate immunity through TLR2, with most being triacylated at the N‑terminus cysteine, whereas the mycoplasmal MALP‑2 is only diacylated. Co‑expression of TLR2 and TLR6 in TLR2–/– TLR6–/– embryonic fibroblasts is required for MALP‑2 responsiveness. TLR6‑deficient cells are unresponsive to MALP‑2 but respond normally to other lipopeptides, indicating that TLR6 cooperatively recognizes MALP‑2 with TLR2 and discriminates its N‑terminal lipoylated structure from other bacterial lipopeptides.

Abstract

Bacterial lipoproteins (BLP) trigger immune responses via Toll-like receptor 2 (TLR2) and their immunostimulatory properties are attributed to the presence of a lipoylated N-terminus. Most BLP are triacylated at the N-terminus cysteine residue, but mycoplasmal macrophage-activating lipopeptide-2 kD (MALP-2) is only diacylated. Here we show that TLR6-deficient (TLR6–/–) cells are unresponsive to MALP-2 but retain their normal responses to lipopeptides of other bacterial origins. Reconstitution experiments in TLR2–/– TLR6–/– embryonic fibroblasts reveal that co-expression of TLR2 and TLR6 is absolutely required for MALP-2 responsiveness. Taken together, these results show that TLR6 recognizes MALP-2 cooperatively with TLR2, and appears to discriminate between the N-terminal lipoylated structures of MALP-2 and lipopeptides derived from other bacteria.