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J. Biol. Chem., Vol. 281, Issue 9, 5771-5779, March 3, 2006

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Ligands for the -Glucan Receptor, Dectin-1, Assigned Using "Designer" Microarrays of Oligosaccharide Probes (Neoglycolipids) Generated from Glucan Polysaccharides^*

Angelina S. Palma¹, Ten Feizi², Yibing Zhang, Mark S. Stoll, Alexander M. Lawson, Esther Díaz-Rodríguez, María Asunción Campanero-Rhodes, Júlia Costa, Siamon Gordon^¶, Gordon D. Brown^||3, and Wengang Chai

From the Glycosciences Laboratory, Faculty of Medicine, Imperial College London, Northwick Park and St Mark's Campus, Watford Road, Harrow, Middlesex HA1 3UJ, United Kingdom, Laboratório de Glicobiologia, Instituto de Tecnologia Química e Biológica, Apartado 127, 2781-901 Oeiras, Portugal, ^¶Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom, ^||Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Lower Ground Floor, Wernher and Beit Building South, Groote Schuur Campus Observatory, Cape Town 7925, South Africa

Dectin-1 is a C-type lectin-like receptor on leukocytes that mediates phagocytosis and inflammatory mediator production in innate immunity to fungal pathogens. Dectin-1 lacks residues involved in calcium ligation that mediates carbohydrate-binding by classical C-type lectins; nevertheless, it binds zymosan, a particulate -glucan-rich extract of Saccharomyces cerevisiae, and binding is inhibited by polysaccharides rich in 1,3- or both 1,3- and 1,6-linked glucose. The oligosaccharide ligands on glucans recognized by Dectin-1 have not yet been delineated precisely. It is also not known whether Dectin-1 can interact with other types of carbohydrates. We have investigated this, since Dectin-1 shows glucan-independent binding to a subset of T-lymphocytes and is involved in triggering their proliferation. Here we assign oligosaccharide ligands for Dectin-1 using the neoglycolipid-based oligosaccharide microarray technology, a unique approach for constructing microarrays of lipid-linked oligosaccharide probes from desired sources. We generate "designer" microarrays from three glucan polysaccharides, a neutral soluble glucan isolated from S. cerevisiae and two bacterial glucans, curdlan from Alcaligenes faecalis and pustulan from Umbilicaria papullosa, and use these in conjunction with 187 diverse, sequence-defined, predominantly mammalian-type, oligosaccharide probes. Among these, Dectin-1 binding is detected exclusively to 1,3-linked glucose oligomers, the minimum length required for detectable binding being a 10- or 11-mer. Thus, the ligands assigned so far are exogenous rather than endogenous. We further show that Dectin-1 ligands, 11-13 gluco-oligomers, in clustered form (displayed on liposomes), mimic the macromolecular -glucans and compete with zymosan binding and triggering of tumor necrosis factor- secretion by a Dectin-1-expressing macrophage cell line.

Received for publication, October 21, 2005 , and in revised form, December 1, 2005.

This article is dedicated to the late Gordon Ross, who was a great facilitator of this work.

^* This work was supported by United Kingdom Medical Research Council Program Grant G9601454 (to A. M. L. and T. F.). 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 Table 1.

¹ Supported by a Ph.D. fellowship from Fundação para a Ciência e Tecnologia, Portugal.

³ A Wellcome Senior Fellow in Biomedical Science in South Africa.

² To whom correspondence should be addressed. Tel.: 44-20-8869-3460/3461; Fax: 44-20-8869-3455; E-mail: t.feizi{at}imperial.ac.uk.

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