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J. Biol. Chem., Vol. 279, Issue 19, 20044-20048, May 7, 2004

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3-O-Deacylation of Lipid A by PagL, a PhoP/PhoQ-regulated Deacylase of Salmonella typhimurium, Modulates Signaling through Toll-like Receptor 4^*

Kiyoshi Kawasaki, Robert K. Ernst¶, and Samuel I. Miller¶||**

From the Departments of Microbiology,,^¶Medicine, and ^||Genome Sciences, University of Washington, Seattle, Washington 98195

Toll-like receptor 4 (TLR4)-mediated responses, which are induced by the lipid A portion of lipopolysaccharide, are important for host defense against Salmonellae infection. A variety of different data indicate that the acylation state of lipid A can alter TLR4-mediated responses. The S. typhimurium virulence gene product PhoP/PhoQ signals the presence of host microenvironments to regulate the expression of a lipid A 3-O-deacylase, PagL, and a lipid A palmitoyltransferase, PagP. We now demonstrate that 3-O-deacylation and palmitoylation of lipid A decreases its ability to induce TLR4-mediated signaling. Deacylated lipid A, deacylated and palmitoylated lipid A, palmitoylated lipid A, and unmodified lipid A species were purified from Escherichia coli heterologously expressing PagL and/or PagP. The purified lipid A preparations showed spectra of a single lipid A species on mass spectrometry and gave a single band on thin layer chromatography. The activity of purified lipid A species was examined using human and mouse cell lines that express recombinant human TLR4. Compared with unmodified lipid A, the modified lipid A species are 30–100-fold less active in the ability to induce NF-B-dependent reporter activation. These results suggest that the lipid A modifications reduce TLR4-signaling as part of Salmonellae adaptation to host environments.

Received for publication, February 4, 2004

^* This work was funded by National Institutes of Health Grant AI-30479 (to S. I. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Uehara Memorial Foundation.

^** To whom correspondence should be addressed. Tel.: 206-616-5107; Fax: 206-616-5109; E-mail: millersi{at}u.washington.edu.

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