The Triacylated ATP Binding Cluster Transporter Substrate-binding Lipoprotein of Staphylococcus aureus Functions as a Native Ligand for Toll-like Receptor 2.
Some synthetic lipopeptides, in addition to native lipoproteins derived from both Gram-negative bacteria and mycoplasmas, are known to activate TLR2 (Toll-like receptor 2). However, the native lipoproteins inherent to Gram-positive bacteria, which function as TLR2 ligands, have not been characterized. Here, we have purified a native lipoprotein to homogeneity from Staphylococcus aureus to study as a native TLR2 ligand. The purified 33-kDa lipoprotein was capable of stimulating TLR2 and was identified as a triacylated SitC lipoprotein, which belongs to a family of ATP binding cluster (ABC) transporter substrate-binding proteins. Analyses of the SitC-mediated production of cytokine using mouse peritoneal macrophages revealed that the SitC protein (3 nm) induced the production of tumor necrosis factor-alpha and interleukin-6. Moreover, analysis of knock-out mice showed that SitC required TLR2 and MyD88, but not TLR1 or TLR6, for the induction of cytokines. In addition to the S. aureus SitC lipoprotein, we purified two other native ABC transporter substrate-binding lipoproteins from Bacillus subtilis and Micrococcus luteus, which were both shown to stimulate TLR2. These results demonstrate that S. aureus SitC lipoprotein is triacylated and that the ABC transporter substrate-binding lipoproteins of Gram-positive bacteria function as native ligands for TLR2.
Kurokawa
Kenji
K
National Research Laboratory of Defense Proteins, College of Pharmacy, Pusan National University, Busan 609-735, Korea.
Lee
Hanna
H
Roh
Kyung-Baeg
KB
Asanuma
Miwako
M
Kim
Young Sook
YS
Nakayama
Hiroshi
H
Shiratsuchi
Akiko
A
Choi
Youngnim
Y
Takeuchi
Osamu
O
Kang
Hee Jung
HJ
Dohmae
Naoshi
N
Nakanishi
Yoshinobu
Y
Akira
Shizuo
S
Sekimizu
Kazuhisa
K
Lee
Bok Luel
BL
D018528:ATP-Binding Cassette Transporters / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D000107:Acetylation; D000818:Animals; D001412:Bacillus subtilis / Q000378:metabolism; D001426:Bacterial Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D016982:Micrococcus luteus / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D008024:Ligands; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha