Mycoplasma fermentans Lipoprotein M161Ag-Induced Cell Activation Is Mediated by Toll-Like Receptor 2: Role of N-Terminal Hydrophobic Portion in its Multiple Functions

M161Ag is a 43-kDa surface lipoprotein of Mycoplasma fermentans, serving as a potent cytokine inducer for monocytes/macrophages, maturing dendritic cells (DCs), and activating host complement on affected cells. It possesses a unique N-terminal lipo-amino acid, S:-diacylglyceryl cysteine. The 2-kDa m...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2001-02, Vol.166 (4), p.2610-2616
Main Authors: Nishiguchi, Miyuki, Matsumoto, Misako, Takao, Toshifumi, Hoshino, Masaru, Shimonishi, Yasutsugu, Tsuji, Shoutaro, Begum, Nasim A, Takeuchi, Osamu, Akira, Shizuo, Toyoshima, Kumao, Seya, Tsukasa
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Animals
Antigens, Bacterial - genetics
Antigens, Bacterial - metabolism
Antigens, Bacterial - physiology
Bacterial Outer Membrane Proteins - immunology
Bacterial Outer Membrane Proteins - metabolism
Cell Line
Cells, Cultured
Complement C3 - metabolism
Complement Pathway, Alternative - immunology
Drosophila Proteins
Humans
Lipoproteins - genetics
Lipoproteins - immunology
Lipoproteins - metabolism
Macrophage Activation - immunology
Macrophages, Peritoneal - immunology
Membrane Glycoproteins - physiology
Membrane Proteins - genetics
Membrane Proteins - metabolism
Membrane Proteins - physiology
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Mycoplasma fermentans
Mycoplasma fermentans - immunology
Peptide Fragments - immunology
Peptide Fragments - metabolism
Protein Sorting Signals - physiology
Receptors, Cell Surface - physiology
Recombinant Proteins - immunology
Recombinant Proteins - metabolism
TLR2 protein
Toll-Like Receptor 2
Toll-Like Receptors
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Summary:M161Ag is a 43-kDa surface lipoprotein of Mycoplasma fermentans, serving as a potent cytokine inducer for monocytes/macrophages, maturing dendritic cells (DCs), and activating host complement on affected cells. It possesses a unique N-terminal lipo-amino acid, S:-diacylglyceryl cysteine. The 2-kDa macrophage-activating lipopeptide-2 (MALP-2), recently identified as a ligand for Toll-like receptor 2 (TLR2), is derived from M161Ag. In this study, we identified structural motifs sustaining the functions of M161Ag using wild-type and unlipidated rM161Ag with (SP(+)) or without signal peptides (SP(-)). Because the SP(+) rM161Ag formed dimers via 25Cys, we obtained a monomeric form by mutagenesis (SP(+)C25S). Only wild type accelerated maturation of human DCs as determined by the CD83/86 criteria, suggesting the importance of the N-terminal fatty acids for this function. Wild-type and the SP(+) form of monomer induced secretion of TNF-alpha and IL-12 p40 by human monocytes and DCs. Either lipid or signal peptide at the N-terminal portion of monomer was required for expression of this function. In contrast, murine macrophages produced TNF-alpha in response to wild type, but not to any recombinant form of M161Ag, suggesting the species-dependent response to rM161Ag. Wild-type and both monomeric and dimeric SP(+) forms possessed the ability to activate complement via the alternative pathway. Again, the hydrophobic portion was associated with this function. These results, together with the finding that macrophages from TLR2-deficient mice did not produce TNF-alpha in response to M161Ag, infer that the N-terminal hydrophobic structure of M161Ag is important for TLR2-mediated cell activation and complement activation.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.166.4.2610