DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands.
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.
End
Caroline
C
Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
Bikker
Floris
F
Renner
Marcus
M
Bergmann
Gaby
G
Lyer
Stefan
S
Blaich
Stephanie
S
Hudler
Melanie
M
Helmke
Burkhard
B
Gassler
Nikolaus
N
Autschbach
Frank
F
Ligtenberg
Antoon J M
AJ
Benner
Axel
A
Holmskov
Uffe
U
Schirmacher
Peter
P
Nieuw Amerongen
Arie V
AV
Rosenstiel
Philip
P
Sina
Christian
C
Franke
Andre
A
Hafner
Mathias
M
Kioschis
Petra
P
Schreiber
Stefan
S
Poustka
Annemarie
A
Mollenhauer
Jan
J
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
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