Identification of francisella tularensis lipoproteins that stimulate the Toll-like receptor (TLR) 2/TLR1 heterodimer

doi:10.1074/jbc.M706854200

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Papers In Press, published online ahead of print December 13, 2007
J. Biol. Chem, 10.1074/jbc.M706854200
Submitted on August 16, 2007
Revised on October 10, 2007
Accepted on December 13, 2007

Identification of francisella tularensis lipoproteins that stimulate the Toll-like receptor (TLR) 2/TLR1 heterodimer

Shalini Thakran, Hanfen Li, Christy L. Lavine, Mark A. Miller, James E. Bina, Xiaowen R. Bina, and Fabio Re

Molecular Sciences, University of Tennessee Health Science Center, Memphis, TN 38163

Corresponding Author: fre{at}utmem.edu

The innate immune response to Francisella tularensis is primarily mediated by TLR2, though the bacterial products that stimulates this receptor remain unknown. Here we report the identification of two Francisella lipoproteins, TUL4 and FTT1103, that 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 unlipidated, 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 extracellular 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 Francisella products capable of stimulating a proinflammatory response and the cellular receptors they trigger.

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