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Shiratsuchi, Akiko,Shimizu, Kaori,Watanabe, Ikuko,Hashimoto, Yumi,Kurokawa, Kenji,Razanajatovo, Iony M.,Park, Keun H.,Park, Hae K.,Lee, Bok L.,Sekimizu, Kazuhisa,Nakanishi, Yoshinobu Blackwell Publishing Ltd 2010 Immunology Vol.129 No.2
<P>Summary</P><P>We previously reported that <I>Staphylococcus aureus</I> avoids killing within macrophages by exploiting the action of Toll-like receptor 2 (TLR2), which leads to the c-Jun N-terminal kinase (JNK)-mediated inhibition of superoxide production. To search for bacterial components responsible for this event, a series of <I>S. aureus</I> mutants, in which the synthesis of the cell wall was interrupted, were screened for the level of JNK activation in macrophages. In addition to a mutant lacking the lipoproteins that have been suggested to act as a TLR2 ligand, two mutant strains were found to activate the phosphorylation of JNK to a lesser extent than the parental strain, and this defect was recovered by acquisition of the corresponding wild-type genes. Macrophages that had phagocytosed the mutant strains produced more superoxide than those engulfing the parental strain, and the mutant bacteria were more efficiently killed in macrophages than the parent. The genes mutated, <I>dltA</I> and <I>tagO</I>, encoded proteins involved in the synthesis of <SMALL>D</SMALL>-alanylated wall teichoic acid. Unlike a cell wall fraction rich in lipoproteins, <SMALL>D</SMALL>-alanine-bound wall teichoic acid purified from the parent strain by itself did not activate JNK phosphorylation in macrophages. These results suggest that the <SMALL>D</SMALL>-alanylated wall teichoic acid of <I>S. aureus</I> modulates the cell wall milieu for lipoproteins so that they effectively serve as a ligand for TLR2.</P>
Signalling Pathway Involving GULP, MAPK and Rac1 for SR-BI-Induced Phagocytosis of Apoptotic Cells
Osada, Y.,Sunatani, T.,Kim, I.-S.,Nakanishi, Y.,Shiratsuchi, A. Oxford University Press 2009 The Journal of biochemistry Vol.145 No.3
<P>Class B scavenger receptor type I (SR-BI) is a phosphatidylserine (PS)-recognizing receptor of testicular Sertoli cells responsible for the phagocytosis of spermatogenic cells undergoing apoptosis. Here, we determined signal mediators that compose a signalling pathway for SR-BI-induced phagocytosis. Results of a yeast two-hybrid analysis and a cell-free binding assay indicated that SR-BI binds to engulfment adapter protein (GULP) using the C-terminal intracellular domain. A co-immunoprecipitation analysis showed the existence of a complex of GULP and SR-BI in cells prior to the activation of SR-BI by PS. A reduction of GULP expression in phagocytes decreased the SR-BI-mediated phagocytosis of apoptotic cells. Administration to phagocytes of PS-containing liposomes increased the levels of the GTP-bound form of Rac1 and the phosphorylated forms of mitogen-activated protein kinases (MAPK) p38 and extracellular signal-related kinase 1 and 2. Finally, lowering the expression of GULP abrogated MAPK phosphorylation, and the presence of MAPK inhibitors reduced the level of GTP-bound Rac1 in PS-activated phagocytes. These results collectively suggested the following signalling pathway for the SR-BI-induced phagocytosis: (i) PS-recognizing SR-BI activates associated GULP; (ii) activated GULP induces MAPK phosphorylation; (iii) activated MAPK increases GTP-bound Rac1; and (iv) activated Rac1 induces a rearrangement of the actin cytoskeleton.</P>
Kurokawa, Kenji,Lee, Hanna,Roh, Kyung-Baeg,Asanuma, Miwako,Kim, Young Sook,Nakayama, Hiroshi,Shiratsuchi, Akiko,Choi, Youngnim,Takeuchi, Osamu,Kang, Hee Jung,Dohmae, Naoshi,Nakanishi, Yoshinobu,Akira, American Society for Biochemistry and Molecular Bi 2009 The Journal of biological chemistry Vol.284 No.13
<P>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.</P>