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J. Biol. Chem., Vol. 283, Issue 7, 3751-3760, February 15, 2008

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Identification of Francisella tularensis Lipoproteins That Stimulate the Toll-like Receptor (TLR) 2/TLR1 Heterodimer^*

From the Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163

The innate immune response to Francisella tularensis is primarily mediated by TLR2, though the bacterial products that stimulate this receptor remain unknown. Here we report the identification of two Francisella lipoproteins, TUL4 and FTT1103, which activate TLR2. We demonstrate that TUL4 and FTT1103 stimulate chemokine production in human and mouse cells in a TLR2-dependent way. Using an assay that relies on chimeric TLR proteins, we show that TUL4 and FTT1103 stimulate exclusively the TLR2/TLR1 heterodimer. Our results also show that yet unidentified Francisella proteins, possibly unlipi-dated, have the ability to stimulate the TLR2/TLR6 heterodimer. Through domain-exchange analysis, we determined that an extended region that comprises LRR 9–17 in the extra-cellular portion of TLR1 mediates response to Francisella lipoproteins and triacylated lipopeptide. Substitution of the corresponding LRR of TLR6 with the LRR derived from TLR1 enables TLR6 to recognize TUL4, FTT1103, and triacylated lipopeptide. This study identifies for the first time specific Fran-cisella products capable of stimulating a proinflammatory response and the cellular receptors they trigger.

Received for publication, August 16, 2007 , and in revised form, October 10, 2007.

^* This work was supported in part by National Institutes of Health Grants AI-05466501 (to F. R.), AI074582 (to J. E. B.), and AI061260 (to M. A. M.) and research grants from the UTHSC Bacterial Pathogenesis Center (to F. R. and J. E. B.). 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.

¹ To whom correspondence should be addressed: Dept. of Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Ave., Memphis, TN 38163. Tel.: 901-448-1775; Fax: 901-448-8462; E-mail: fre{at}utmem.edu.

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