title: DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands.
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.
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: End
authors.forename: Floris
authors.initials: F
authors.lastname: Bikker
authors.forename: Marcus
authors.initials: M
authors.lastname: Renner
authors.forename: Gaby
authors.initials: G
authors.lastname: Bergmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Lyer
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blaich
authors.forename: Melanie
authors.initials: M
authors.lastname: Hudler
authors.forename: Burkhard
authors.initials: B
authors.lastname: Helmke
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Frank
authors.initials: F
authors.lastname: Autschbach
authors.forename: Antoon J M
authors.initials: AJ
authors.lastname: Ligtenberg
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Arie V
authors.initials: AV
authors.lastname: Nieuw Amerongen
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.forename: Petra
authors.initials: P
authors.lastname: Kioschis
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Annemarie
authors.initials: A
authors.lastname: Poustka
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
mesh_terms: D001419:Bacteria / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002351:Carrageenan / Q000276:immunology* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate / Q000276:immunology* / Q000494:pharmacology / Q000633:toxicity; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000382:microbiology; D008024:Ligands; D010710:Phosphates / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D002135:Calcium-Binding Proteins; C108174:DMBT1 protein, human; D004268:DNA-Binding Proteins; D008024:Ligands; D010710:Phosphates; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D002351:Carrageenan; D016264:Dextran Sulfate