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J. Biol. Chem., Vol. 281, Issue 41, 31002-31011, October 13, 2006
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Membrane Sorting of Toll-like Receptor (TLR)-2/6 and TLR2/1 Heterodimers at the Cell Surface Determines Heterotypic Associations with CD36 and Intracellular Targeting*
1
From the
Infection and Immunity Group, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom and Department of Biochemical Pharmacology, University of Konstanz, D-78457 Konstanz, Germany
Toll-like receptors (TLRs) are receptors of the innate immune system responsible for recognizing pathogen-associated molecular patterns. TLR2 seems to be the most promiscuous TLR receptor able to recognize the most diverse set of pathogenassociated patterns. Its promiscuity has been attributed to its unique ability to heterodimerize with TLRs 1 and 6 and, most recently, to its association with CD36 in response to diacylated lipoproteins. Thus, it seems that TLR2 forms receptor clusters in response to different microbial ligands. In this study we investigated TLR2 cell surface heterotypic interactions in response to different ligands as well as internalization and intracellular trafficking. Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand. Upon stimulation by the specific ligand, these heterodimers are recruited within lipid rafts. In contrast, heterotypic associations of TLR2/6 with CD36 are not preformed and are ligand-induced. All TLR2 receptor clusters accumulate in lipid rafts and are targeted to the Golgi apparatus. This localization and targeting is ligand-specific. Activation occurs at the cell surface, and the observed trafficking is independent of signaling.
Received for publication, March 24, 2006 , and in revised form, July 25, 2006.
* This work was supported by the Wellcome Trust (to K. T.) and by Heart Research UK (to K. T. and M. T.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.
1 To whom correspondence should be addressed: School of Life Sciences, University of Sussex, JMS Bldg., Falmer, Brighton, BN1 9QG, UK. Tel.: 1273-678362; E-mail: K.Triantafilou{at}sussex.ac.uk.
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