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Human but not murine toll-like receptor 2 discriminates between tri-palmitoylated and tri-lauroylated peptides

Abstract

Toll-like receptors (TLRs) mediate activation of the immune system upon challenge with microbial agonists, components of disintegrating cells of the body, or metabolic intermediates of lipidic nature. Comparison of murine (m) and human (h) TLR2 primary sequences revealed 65% of identical residues within the extracellular domains in contrast to 84% in the intracellular domains. Comparative analysis of TLR2-driven cell activation by various TLR2 agonists showed that the tri-lauroylated lipopeptide analogue (Lau3CSK4) is recognized efficiently through mTLR2 but not hTLR2. Genetically complemented human embryonic kidney (HEK) 293 cells and murine TLR2-/- embryonic fibroblasts, as well as human and murine macrophage cells were used for this analysis. In contra st to cellular activation, which depended on blockable access of the TLR2-ligand to TLR2, cellular uptake of Lau3CSK4 and tri-palmitoylated peptide (P3CSK4) was independent of TLR2. A low-conserved region spanning from leucine rich repeat (LRR) motif 7 to 10 was found to control TLR2 species-specific cell activation. Exchange of mLRR8 for hLRR8 in mTLR2 abrogated mTLR2-typical cell activation upon cellular challenge with Lau3CSK4 but not P3CSK4 implicating mLRR8 as a central element of Lau3CSK4 recognitio n. The point mutation L112P within LRR3 abrogated hTLR2-dependent recognition of lipopeptides but merely attenuated mTLR2 function, while deletion of the N-terminal third of each LRR-rich domain (LRRs 1 to 7) had the opposite effect on P3CSK4 recognition. Despite similar domain structure of both TLR2 molecules, species-specific properties thus exist. Our results imply distinct susceptibilities of humans and mice to challenge with specific TLR2 ligands.

Authors: Grabiec A, Meng G, Fichte S, Bessler W, Wagner H, Kirschning CJ
Journal: J Biol Chem., 279(46):48004-48012
Year: 2004
PubMed: Find in PubMed