DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands

End, C., Bikker, F., Renner, M., Bergmann, G., Lyer, S., Blaich, S., Hudler, M., Helmke, B., Gassler, N., Autschbach, F., Ligtenberg, A. J. M., Benner, A., Holmskov, U., Schirmacher, P., Amerongen, A. V. N., Rosenstiel, Philip, Sina, C., Franke, Andre, Hafner, M., Kioschis, P., Schreiber, Stefan, Poustka, A. and Mollenhauer, J. (2009) DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands European Journal of Immunology, 39 (3). pp. 833-842.

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Abstract

Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappa B activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function in mucosal protection and of its broad pathogen-binding specificity. We report that DMBT1 directly interacts with dextran sulfate sodium (DSS) and carrageenan, a structurally similar sulfated polysaccharide, which is used as a texturizer and thickener in human dietary products. However, binding of DMBT1 does not reduce the cytotoxic effects of these agents to intestinal epithelial cells in vitro. DSS and carrageenan compete for DMBT1-mediated bacterial aggregation via interaction with its bacterial-recognition motif. Competition and ELISA studies identify poly-sulfated and poly-phosphorylated structures as ligands for this recognition motif, such as heparansulfate, LPS, and lipoteichoic acid. Dose-response studies in Dmbt1 (/) and Dmbt1(+/+) mice utilizing the DSS-induced colitis model demonstrate a differential response only to low but not to high DSS doses. We propose that DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-kappa B activation.

Document Type: Article
Keywords: inflammatory bowel diseaseinnate immunity mucosal immunity pattern recognition scavenger receptor cysteine-rich inflammatory-bowel-disease intestinal epithelial-cells malignant brain-tumors crohns-disease salivary agglutinin terminal differentiation streptococcus-mutans bacteria-binding induced colitis nod2
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
ISSN: 0014-2980
Projects: Future Ocean
Date Deposited: 11 Feb 2011 12:14
Last Modified: 19 Apr 2013 12:26
URI: http://eprints.uni-kiel.de/id/eprint/9364

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