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

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

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)3751-3760
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number7
DOIs
StatePublished - Feb 15 2008

Fingerprint

Francisella
Francisella tularensis
Lipopeptides
Toll-Like Receptor 2
Lipoproteins
Toll-Like Receptors
Chemokines
Assays
Proteins
Substitution reactions
Innate Immunity

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Identification of Francisella tularensis lipoproteins that stimulate the toll-like receptor (TLR) 2/TLR1 heterodimer. / Thakran, Shalini; Li, Hanfen; Lavine, Christy L.; Miller, Mark; Bina, James E.; Bina, Xiaowen R.; Re, Fabio.

In: Journal of Biological Chemistry, Vol. 283, No. 7, 15.02.2008, p. 3751-3760.

Research output: Contribution to journalArticle

Thakran, Shalini ; Li, Hanfen ; Lavine, Christy L. ; Miller, Mark ; Bina, James E. ; Bina, Xiaowen R. ; Re, Fabio. / Identification of Francisella tularensis lipoproteins that stimulate the toll-like receptor (TLR) 2/TLR1 heterodimer. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 7. pp. 3751-3760.
@article{b5b5dbaec3854b00a67b6c3fa23799c0,
title = "Identification of Francisella tularensis lipoproteins that stimulate the toll-like receptor (TLR) 2/TLR1 heterodimer",
abstract = "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 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.",
author = "Shalini Thakran and Hanfen Li and Lavine, {Christy L.} and Mark Miller and Bina, {James E.} and Bina, {Xiaowen R.} and Fabio Re",
year = "2008",
month = "2",
day = "15",
doi = "10.1074/jbc.M706854200",
language = "English (US)",
volume = "283",
pages = "3751--3760",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "7",

}

TY - JOUR

T1 - Identification of Francisella tularensis lipoproteins that stimulate the toll-like receptor (TLR) 2/TLR1 heterodimer

AU - Thakran, Shalini

AU - Li, Hanfen

AU - Lavine, Christy L.

AU - Miller, Mark

AU - Bina, James E.

AU - Bina, Xiaowen R.

AU - Re, Fabio

PY - 2008/2/15

Y1 - 2008/2/15

N2 - 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 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.

AB - 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 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.

UR - http://www.scopus.com/inward/record.url?scp=42949086603&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42949086603&partnerID=8YFLogxK

U2 - 10.1074/jbc.M706854200

DO - 10.1074/jbc.M706854200

M3 - Article

VL - 283

SP - 3751

EP - 3760

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 7

ER -