Thakran Shalini, Li Hanfen, Lavine Christy L, Miller Mark A, Bina James E, Bina Xiaowen R, Re Fabio
Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Biol Chem. 2008 Feb 15;283(7):3751-60. doi: 10.1074/jbc.M706854200. Epub 2007 Dec 13.
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.
对土拉弗朗西斯菌的天然免疫反应主要由Toll样受体2（TLR2）介导，不过刺激该受体的细菌产物仍不清楚。在此，我们报告鉴定出两种可激活TLR2的土拉弗朗西斯菌脂蛋白，即TUL4和FTT1103。我们证明，TUL4和FTT1103以TLR2依赖的方式刺激人和小鼠细胞产生趋化因子。利用一种依赖嵌合TLR蛋白的检测方法，我们发现TUL4和FTT1103仅刺激TLR2/TLR1异二聚体。我们的结果还表明，尚未鉴定出的土拉弗朗西斯菌蛋白（可能未被脂化）具有刺激TLR2/TLR6异二聚体的能力。通过结构域交换分析，我们确定TLR1胞外部分包含富含亮氨酸重复序列（LRR）9 - 17的延伸区域介导对土拉弗朗西斯菌脂蛋白和三酰化脂肽的反应。用源自TLR1的LRR替换TLR6的相应LRR，可使TLR6识别TUL4、FTT1103和三酰化脂肽。本研究首次鉴定出能够刺激促炎反应的特定土拉弗朗西斯菌产物及其触发的细胞受体。
