Title
DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands
Author
End, C.
Bikker, F.J.
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.
Nieuw Amerongen, A.V.
Rosenstiel, P.
Sina, C.
Franke, A.
Hafner, M.
Kioschis, P.
Schreiber, S.
Poustka, A.
Mollenhauer, J.
Publication year
2009
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-kappaB 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-kappaB activation. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Subject
Health
Inflammatory bowel disease
Innate immunity
Mucosal immunity
Pattern recognition
Scavenger receptor cysteine-rich
Carrageenan
Deleted in malignant brain tumors 1
Dextran sulfate
Glycoprotein
Heparan sulfate
Lipopolysaccharide
Lipoteichoic acid
Unclassified drug
Cell surface receptor
DMBT1 protein, human
Ligand
Phosphate
Animal experiment
Animal model
Antiinflammatory activity
Antimicrobial activity
Binding competition
Cell aggregation
Colitis
Controlled study
Crohn disease
Cytotoxicity
Dose response
Enzyme linked immunosorbent assay
Escherichia coli
Experimental mouse
Host pathogen interaction
Human
Human cell
In vitro study
Innate immunity
Intestine epithelium cell
Mouse
Nonhuman
Protein binding
Protein determination
Protein expression
Protein function
Protein motif
Protein phosphorylation
Salmonella minnesota
Salmonella typhimurium
Streptococcus gordonii
Sulfation
Bacterium
Cell line
Drug antagonism
Epithelium cell
Genetics
Immunology
Intestine
Metabolism
Microbiology
Bacteria
Carrageenan
Cell Line
Dextran Sulfate
Epithelial Cells
Humans
Intestines
Ligands
Phosphates
Receptors, Cell Surface
To reference this document use:
http://resolver.tudelft.nl/uuid:af118702-488a-4c75-b419-08fceb0ab423
DOI
https://doi.org/10.1002/eji.200838689
TNO identifier
27874
Source
European Journal of Immunology, 39 (3), 833-842
Document type
article