TY - JOUR
T1 - DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands
AU - End, Caroline
AU - Bikker, Floris
AU - Renner, Marcus
AU - Bergmann, Gaby
AU - Lyer, Stefan
AU - Blaich, Stephanie
AU - Hudler, Melanie
AU - Helmke, Burkhard
AU - Gassler, Nokilaus
AU - Autschbach, Frank
AU - Ligtenberg, Antoon J.M.
AU - Benner, Axel
AU - Holmskov, Uffe
AU - Schirmacher, Peter
AU - Nieuw Amerongen, Arie V.
AU - Rosenstiel, Philip
AU - Sina, Christian
AU - Franke, Andre
AU - Hafner, Mathias
AU - Kioschis, Petra
AU - Schreiber, Stefan
AU - Poustka, Annemarie
AU - Mollenhauer, Jan
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/3
Y1 - 2009/3
N2 - 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-κB 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 polyphosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-κB activation.
AB - 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-κB 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 polyphosphorylated ligands providing a molecular basis for its broad bacterial-binding specificity and its inhibitory effects on LPS-induced TLR4-mediated NF-κB activation.
UR - http://www.scopus.com/inward/record.url?scp=64049093050&partnerID=8YFLogxK
U2 - 10.1002/eji.200838689
DO - 10.1002/eji.200838689
M3 - Journal articles
C2 - 19189310
AN - SCOPUS:64049093050
SN - 0014-2980
VL - 39
SP - 833
EP - 842
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 3
ER -