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Published 15 September 2003. doi:10.1083/jcb.200304093
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© The Rockefeller University Press, 0021-9525/2003/9/1099 $5.00
The Journal of Cell Biology, Volume 162, Number 6, 1099-1110

Article

Importance of extra- and intracellular domains of TLR1 and TLR2 in NF{kappa}B signaling



Frantisek Sandor1, Eicke Latz1, Fabio Re2, Leisa Mandell1, Galina Repik1, Douglas T. Golenbock1, Terje Espevik3, Evelyn A. Kurt-Jones1 and Robert W. Finberg1

1 Department of Medicine, University of Massachusetts Medical Center, Worcester, MA 01605
2 Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115
3 Unit of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway

Address correspondence to Robert W. Finberg, University of Massachusetts Medical Center, Dept. of Medicine, 364 Plantation Street, Worcester, MA 01605-2324. Tel.: (508) 856-2126. Fax: (508) 856-6176. email: Robert.Finberg{at}umassmed.edu

Recognition of ligands by toll-like receptor (TLR) 2 requires interactions with other TLRs. TLRs form a combinatorial repertoire to discriminate between the diverse microbial ligands. Diversity results from extracellular and intracellular interactions of different TLRs. This paper demonstrates that TLR1 and TLR2 are required for ara-lipoarabinomannan– and tripalmitoyl cysteinyl lipopeptide–stimulated cytokine secretion from mononuclear cells. Confocal microscopy revealed that TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. Simultaneous cross-linking of both receptors resulted in ligand-independent signal transduction. Using chimeric TLRs, we found that expression of the extracellular domains along with simultaneous expression of the intracellular domains of both TLRs was necessary to achieve functional signaling. The domains from each receptor did not need to be contained within a single contiguous protein. Chimeric TLR analysis further defined the toll/IL-1R domains as the area of crucial intracellular TLR1–TLR2 interaction.

Key Words: toll-like receptors; innate immunity; mycobacterium tuberculosis; ara-lipoarabinomannan; signal transduction

Abbreviations used in this paper: araLAM, ara-lipoarabinomannan; HEK, human embryonic kidney; LPS, leptospiral lipopolysaccharide; NF{kappa}B, nuclear factor kappa B; Pam3CSK4, tripalmitoyl cysteinyl lipopeptide; PBMC, peripheral blood mononuclear cell; TIR, toll/IL-1R; TLR, toll-like receptor.


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