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J. Biol. Chem., Vol. 283, Issue 48, 33221-33231, November 28, 2008

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Mycobacterium avium Glycopeptidolipids Require Specific Acetylation and Methylation Patterns for Signaling through Toll-like Receptor 2^*

Lindsay Sweet¹, Wenhui Zhang, Heidi Torres-Fewell, Anthony Serianni, William Boggess, and Jeffrey Schorey²

From the Department of Biological Sciences, Eck Center for Global Health and Infectious Disease, and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556

Toll-like receptors (TLRs) recognize pathogen-associated molecules and play a vital role in promoting an immune response against invading microbes. TLR2, one of the key members of the TLR family, recognizes a wide variety of microbial products, including lipoproteins and lipopeptides, from a number of pathogens. Recent studies from our laboratory indicate that glycopeptidolipids (GPLs), a major surface component of Mycobacterium avium and other non-tuberculosis mycobacteria, are ligands for TLR2. However, the molecular requirements necessary for the GPL-TLR2 interaction were not defined in this report. In the present study we isolated different GPL species from M. avium, and using mass spectrometry and NMR analyses, characterized the molecular requirements of the GPL-TLR2 interaction. Interestingly, the extent of the respective acetylation and methylation of the 6-deoxytalose and rhamnose contained within the core GPL structure dictated whether the GPL signaled through TLR2. These experiments illustrate how subtle changes in a complex TLR2 ligand can alter its affinity for this important receptor, and suggest that M. avium could potentially modify its GPL structure to limit its interaction with TLR2.

Received for publication, July 21, 2008 , and in revised form, September 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI056979 and AI052439 from NIAID. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or NIH. 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 Tables S1–S3 and Figs. S1–S5.

¹ Fellow of the Chemistry-Biochemistry-Biology Interface Program at the University of Notre Dame, supported by Training Grant T32GM075762 from NIGMS, NIH.

² To whom correspondence should be addressed: Dept. of Biological Sciences, University of Notre Dame, 130 Galvin Life Science Center, Notre Dame, IN 46556. Tel.: 574-631-3734; Fax: 574-631-7413; E-mail: schorey.1{at}nd.edu.

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